1434971590Book-web-LR

PROGRAMME AT A GLANCE
51ST INTERNATIONAL CONFERENCE ON MEDICINAL CHEMISTRY
DRUG DISCOVERY AND SELECTION - UNDERSTANDING TARGETS AND MECHANISMS

WEDNESDAY JULY 01, 2015
10:00 Registration
Auditorium AT03
Elsevier Reaxys Workshop : Data-Driven Approaches to Medicinal
11:00
Chemistry : How Large-Scale Normalized Data Empowers Drug Discovery
Auditorium AT02
Opening Ceremony
13:15 Welcome Address
SESSION 1 : Paul Ehrlich Award Lecture - Sponsored by Janssen-Cilag
13:30 L01 - S. Muller
SESSION 2 : Kinases & Oncology - Sponsored by Servier
14:30 L02 - J.D. Charrier
15:15 L03 - T. Barf
16:00 Coffee Break & Exhibition
SESSION 3 : Resistance in Infectious Diseases
16:30 L04 - P. Courvalin
17:15 L05 - J. Bilello
18:00 Welcome Reception
THURSDAY JULY 02, 2015

Auditorium AT02
SESSION 4 : Tools for Cell Therapy
08:30 L06 - M. Uesugi
Auditorium AT02 Auditorium AT03
SESSION 5 : Short Communications - Targeting Apoptosis - Sponsored by SCT SESSION 6 : Short Communications - CNS Diseases - Sponsored by SCT
09:30 SC01 - I. Alves SC03 - C. Rochais
10:00 SC02 - L. Munoz SC04 - F. Bihel
SESSION 7 : Diabetes SESSION 8 : Tools for Target ID
11:15 L07 - R. Deprez-Poulain L09 - Y. Hashimoto
© Chiugoran
12:00 L08 - S. Nomura L10 - P. Brennan
12:45 Lunch & Exhibition
13:30 Poster Session 1 (odd numbers)
13:45 Career Session (Room OE32)
SESSION 9 : Cardiac Diseases SESSION 10 : Structure Based Approaches
Sponsored by 'Fondation de la Maison de la Chimie'
14:45 L11 - A.T. Plowright L13 - T.I. Oprea
JULY 1-3, 2015 | AVIGNON, PROVENCE, FRANCE

15:30 L12 - D. Meibom L14 - P. Bonnet
SESSION 11 : Neglected/Rare Diseases SESSION 12 : GPCRs
16:45 L15 - J. Jiricek L17 - J. Carlsson
17:30 L16 - D.J. Harris L18 - J. Christopher
20:00 Symposium Banquet
FRIDAY JULY 03, 2015

Auditorium AT02
SESSION 13 : Viral Diseases
08:30 L19 - M. Sofia ORGANISED BY
09:15 L20 - J. Wai

10:30 Poster Session 2 (even numbers)
SESSION 14 : Pierre Fabre Award Lecture - Sponsored by Pierre Fabre SOCIÉTÉ DE CHIMIE THÉRAPEUTIQUE (SCT)
11:45 L21 - R. Rodriguez
SESSION 15 : Immuno/Inflammatory Diseases - Sponsored by GSK
13:30 L22 - C. Menet
14:15 L23 - F. Von Nussbaum
SESSION 16 : Poster Prizes and Closing Remarks
15:00 Poster Prizes & Closing Remarks
WITH THE SUPPORT OF
SESSION 17 : Future Events and Closing
15:15 Introduction to RICT 2016
15:30 End of the symposium
SECRETARIAT RICT 2015

LD ORGANISATION | Scientific Conference Producers | Tel: +32 10 45 47 77 | Fax: +32 10 45 97 19 | secretariat@LDOrganisation.com
WWW.SCT-ASSO.FR WWW.RICT2015.ORG
RICT15-CoversBook-HD.indd 1 11/06/15 13:14

THE EXPANDING TOOLBOX OF

MEDICINAL CHEMISTRY
From Chemical Biology to
EXECUTIVE COMMITTEE
Dr C. CONTINO-PEPIN (University of Avignon, France)
Clinical Applications
Prof. P. DALLEMAGNE (University of Caen, France)
Dr G. DURAND (University of Avignon, France) PARC DES EXPOSITIONS ET CONGRES
Prof. H. GALONS (SCT & Paris Descartes University, France) OCTOBER 16, 2015 - DIJON, FRANCE
Dr P. GEORGE (SCT & Independent Scientific Expert & Adviser, France)
Prof. A. POLIDORI (University of Avignon, France)
Prof. J. SAPI (SCT & University of Reims-Champagne-Ardenne, France)
Dr L. VAN HIJFTE (SCT & NovAliX, France) This symposium, jointly organised by the Société de Chimie Thérapeutique (SCT) and the Division of Medicinal
Chemistry & Chemical Biology (DMCCB) of the Swiss Chemical Society, will discuss significant advances that
LOCAL ORGANISING COMMITTEE are part of the expanding scope of Medicinal Chemistry. A panel of experts will highlight these developments in
Mrs A. BARRIERE (Maison de la Recherche, University of Avignon, France)
Dr F. BONNETE (CNRS, Institut des Biomolécules Max Mousseron (IBMM)-University of Avignon, France)
the areas of chemical biology, metabolite pattern optimization, structural biology, analytics and clinical
Dr C. CONTINO-PEPIN (University of Avignon, France) imaging tracers with specific examples.
Dr G. DURAND (University of Avignon, France)
Dr P. GUILLET (University of Avignon, France)
Mr S. RAYNAL (University of Avignon, France) PROGRAMME
Mrs V. VIDAU (University of Avignon, France)
New Therapeutic Modalities to Unleash Pharma Drug Discovery
SCIENTIFIC ADVISORY BOARD
Dr J.-L. BANERES (Institut des Biomolécules Max Mousseron (IBMM), France)
Dr Carlos GARCIA-ECHEVERRIA (SANOFI, Vitry sur Seine, France)
Prof. R. BUREAU (University of Caen, France)
Dr K. BUSH (Indiana University, United States) Learning New Things About Old Drugs: Sulfa Drugs and Tetrahydrobiopterin Biosynthesis
Prof. E. M. CARREIRA (ETH Zürich / SpiroChem, Switzerland) Prof. Kai JOHNSSON (SWISS FEDERAL INSTITUTE OF TECHNOLOGY IN LAUSANNE (EPFL), Lausanne, Switzerland)
Dr P. CHENE (Novartis, Switzerland)
Dr R. COOKE (Heptares, United Kingdom)
Dr C. DOUSSON (Idenix Pharmaceuticals, France) Using Aged Drugs in New Ways, the Concept of Boosting Antibiotics
Prof. P. DUMY (Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), France) Prof. Nicolas WILLAND (UNIVERSITY OF LILLE, Lille, France)
Prof. E. GIRALT (Institute for Research in Biomedicine (IRB), Spain)
Dr J.-C. HARMANGE (Constellation Pharmaceuticals, United States)
Dr J.-M. JIMENEZ (Vertex Pharmaceuticals, United Kingdom) Uncovering and Mitigating Clearance in Early Discovery: New Technologies, New Opportunities, New Mindset
Prof. H. KAGECHIKA (Tokyo Medical and Dental University, Japan) Dr Alfred ZIMMERLIN (NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, Basel, Switzerland)
Prof. D. KIREEV (University of North Carolina, United States)
Dr U. LUCKING (Bayer HealthCare, Germany)
Dr B. MIROUX (University Paris Diderot - Institut de Biologie Physico-Chimique (IBPC), France) Discovery and Development of LC-MS/MS-Based Occupancy Tracers and Positron Emission Tomography
Prof. J. MITTENDORF (Bayer Pharma, Germany) Radioligands
Prof. N. MIYATA (Nagoya City University, Japan) Dr Vanessa Nicole BARTH (ELI LILLY, Indianapolis, United States)
Dr M. MOUREZ (Sanofi-Pasteur, France)
Dr M. NILGES (Pasteur Institute, France)
Dr M. OKANIWA (Takeda Pharmaceutical Company, Japan) Radiotracer Development in the Era of Personalized Medicine: When MedChem Meets Nuclear Medicine
Dr J.-M. PAGES (Aix Marseille University, France) Prof. Roger SCHIBLI (SWISS FEDERAL INSTITUTE OF TECHNOLOGY (ETH), Zürich, Switzerland)
Prof. E. PEBAY-PEYROULA (University Joseph Fourier, France)
Prof. J. ROBINSON (University of Zürich, Switzerland)
Dr H. SHEN (Roche, China)
Dr P. SJÖ (AstraZeneca, Sweden) www.sct-dmccb2015.org
Prof. H. SUGA (University of Tokyo, Japan)
Dr P. P. TAK (EFPIA, United Kingdom)
Dr H. VAN VLIJMEN (Janssen, Belgium) Organising Committee Symposium Secretariat
Dr R. VAZ (Sanofi-Genzyme, United States) Prof. K.-H. ALTMANN (SCS DMCCB & Swiss Federal Institute of Technology, Switzerland) LD Organisation sprl
Prof. S. WANG (University of Michigan, United States) Dr Y. P. AUBERSON (SCS DMCCB & Novartis, Switzerland) Scientific Conference Producers
Dr G. WECKBECKER (Novartis, Switzerland) Dr P. GEORGE (SCT & Independent Scientific Expert & Adviser, France) Rue Michel de Ghelderode 33/2
Dr J. Z. ZHU (UCB, United Kingdom) Prof. J.-L. REYMOND (SCS DMCCB & University of Bern, Switzerland) 1348 Louvain-la-Neuve, Belgium
Prof. J. SAPI (SCT & University of Reims-Champagne-Ardenne, France) Tel: +32 10 45 47 77 - Fax: +32 10 45 97 19
WWW.SCT-ASSO.FR WWW.RICT2015.ORG Prof. A. TARTAR (SCT & University Lille 2, France) secretariat@ldorganisation.com
RICT15-CoversBook-HD.indd 2 Depliant-SCT-DMCCB.indd 1 11/06/15

3/04/2015 13:14
10:28:00
WELCOME
The French Medicinal Chemistry Society (SCT) and the University of Avignon are very pleased to host the
51st International Conference on Medicinal Chemistry (RICT), in Avignon on July 1-3, 2015.
The theme of this year’s meeting is “Drug Discovery and Selection - Understanding Targets and Mechanisms”,
and the Scientific Committee has invited 27 internationally recognised experts in the field, both from industry
and from academia, ensuring the highest quality and diversity of the scientific programme.
The RICT symposium, held every year in another French city, presents an ideal “culture broth” for new ideas,
contacts and collaborations both for confirmed scientists as well as younger scientists and students just starting
out in this exciting and rapidly changing field of drug discovery research and development. For students,
we hope that the low registration fees and inexpensive accommodations have made this high-level meeting
perfectly accessible to them. Needless to say, we all look forward to the poster communications which will be
presented by these young scientists and for which a number of prizes will be awarded. Moreover, a career
session has been included in the programme which should be of benefit to students hoping to find employment
in the medicinal chemistry area.
During the meeting, the SCT will also award the P. Ehrlich Prize to a researcher or research team for his or
her outstanding contributions to medicinal chemistry. Furthermore, the Pierre Fabre Award for Therapeutic
Innovation will be attributed to a researcher having accomplished a decisive action or made a discovery
contributing to a therapeutic innovation.
Apart from the scientific programme we are convinced that participants will also thoroughly enjoy Avignon, a
beautifully preserved medieval town surrounded by the original fortified city walls. The central historical part of
the city, including the Palace of the Popes, the Saint-Benezet bridge, and the fortification walls that surround
the city, is a protected UNESCO heritage site.
It is thus with great pleasure and anticipation that we welcome you in Avignon for what we are sure will be an
extremely rewarding and memorable meeting for everyone!
Dr Christine Contino-Pépin
University of Avignon, Chairwoman of the Local Organising Committee of RICT 2015
Prof. Janos Sapi

President of the French Medicinal Chemistry Society (SCT) and Chairman of the RICT Executive Board
Dr Luc Van Hijfte

Vice-president of the French Medicinal Chemistry Society (SCT)
Organised by:
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EDITORIAL: UNDERSTANDING TARGETS AND MECHANISMS
Drug discovery is evolving rapidly even if the goal remains the same: identify new efficient and safe drugs
to treat patients. And if there is still a lot to do to tackle unmet medical needs, more and more tools are also
available for the researchers to identify the right biological target and the drug that will interact positively with
this target.
Today, the drug discovery activities start from patients with major focus on the human disease tissues and
their differences with the corresponding normal tissue. With the rise of genomic and proteomic tools, more
and more data can be generated from these tissues. Companies and hospitals are creating their own bio-bank
in order to valorise the expertise they develop day after day in treating patients in a specific disease area. A
lot of patient databases are also created and can be queried and analysed to further understand the role of a
target or a specific pathway within a disease. The constantly growing patient data available, combined with the
flow of genomic data and the power of the informatics tools opened new avenues to identify novel targets and
better understand the pathways and the link with the disease. Not surprisingly, big pharma companies recently
signed major partnerships with famous informatics companies (Johnson and Johnson with IBM, Abbvie with
Google) illustrating the attractiveness of combining cloud computing, genomic analysis and drug development.
This patient based approach has also the advantage to give access more rapidly to some potential biomarkers
in the clinical trials and also to lead to a better patient stratification, giving the treatment all the chances to be
evaluated on putative responders and thus reducing the attrition rate.
So understanding the targets and mechanisms is a critical exercise in drug discovery. Part of this work is
related to the identification the natural substrate of a given target (as for example “de-orphanizing” a GPCR),
to the understanding the scope of a biological pathway with identification of the targets involved, and to the
validation of these targets using chemical and biological tools. This target and mechanism knowledge also
helps to further assess target engagement in the in vivo models used in LO phase. In a molecular approach, it
is also important to understand better the conformational impact of a receptor on the signal transduction, and
to lock a receptor in a given conformation thus triggering one or the other signalling pathway and checking
the impact on the disease outcome. Last but not least, understanding the target is useful to select the drug
discovery strategy: orthosteric vs allosteric modulators, small molecules vs antibodies, covalent binding vs
reversible inhibition...
Clearly, there is a lot to understand on the biological targets and mechanisms to better and quicker design
new drugs. All this knowledge on targets can be developed through a tight collaboration between biologists,
bioinformatics, translational sciences, physicians and medicinal chemists. And there are numbers of novel
techniques available through innovation in the academy world or technology driven biotechs. More and
more, big pharma companies develop partnerships and collaborations and some of them are adapting their
internal organisation in order to be more reactive to the outside world and make the best use of these external
innovations a quick and efficient manner in their field of research. Biotechs, academia, hospitals and pharma
companies have common interest to work together and combine their efforts to cover the unmet medical
needs. Around the world, some geographical areas are gathering all these partners close together and thus
are prone to become “clusters of innovation” for the identification of novel targets and new drugs.
As medicinal chemists, we are in the heart of drug discovery, interacting with many different disciplines. Hope
this RICT symposium will favour contacts amongst the medicinal chemists themselves so that we can learn
from each other and thus contribute by our exchanges during conferences, posters or break to future innovation
in drug discovery.
Dr Pierre Deprez
Discovery site head, Paris
Galapagos
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SPONSORED AND SUPPORTED BY
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PREMIUM EXHIBITORS
EXHIBITORS
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MEDIA PARTNERS
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FLOORPLAN
Ground floor
Registration, Plenary room & exhibition
First floor
Parallel Session room, Exhibition & Catering
1: HyphaDiscovery 12: Biotage 23: Chemical Computing Group

2: Mercachem 13: NanoTemper 24: Apollo Scientific
3: 14: Fuji Silysia 25: SpiroChem
4: Co-Add 15: PerkinElmer 26: Fluorochem (Premium Exhibitor)
5: Life Chemicals 16: ChemAxon 27: WuXi AppTec
6: Sigma Aldrich 17: NovAliX 28: Anton Paar
7: Provence Technologies 18: Crelux 29: Activate Scientific
8: AnalytiCon Discovery 19: Optibrium 30: Elsevier (Premium Exhibitor)
9: Galchimia 20: Ambinter 31: CFMOT & Iris Biotech
10: Dotmatics 21: Büchi 32: Neuro-Sys (ground floor)
11: Maybridge 22: Enamine (Premium Exhibitor) 33: Alfa Aesar (ground floor)
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BookRICT.indd 6 15/06/2015 12:02:43

CONTENT
Welcome 1
Editorial 2
Sponsors and Supporters 3
Premium Exhibitors, Exhibitors and Media Partners 4
Exhibition Floorplan 6
Programme 9
Plenary Lectures: Abstracts and Biographies 19
Short Communications: Abstract and Biographies 67
POSTERS: Integrative Approaches 77
POSTERS: Mechanisms of Resistance 87
POSTERS: Revealing Biological Mechanisms 97
POSTERS: Translational Approaches 119
POSTERS: Understanding of the Molecular Space 131
POSTERS: Case Studies 143
POSTERS: Others 155
Exhibitors: Company Descriptions 243
List of Abstracts 253
Index of Authors 263
List of Participants 277
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BookRICT.indd 7 15/06/2015 13:04:15

Annual Meeting
March 13
13-16, 2016
13-16,
in Bonn
Scientific Committee Stefan Laufer
Karl--Heinz
Karl-Heinz
Karl Heinz Baringhaus Vincent Lisowski
Horst Dollinger Christa E. Müller
Pascal George Franz von Nussbaum
Peter Gmeiner Eckhard Ottow
Gilles Guichard Jean-Phillipe Rocher
Jean-Phillipe
Jean
Luc van Hijfte Janos Sapi
Further information will soon be available

available:
www.gdch.de/medchem2016
- 8 Bonn;
photos: Frank Luerweg / Universität - Michael Sondermann / Bundesstadt Bonn
BookRICT.indd 8 15/06/2015 12:02:53

PROGRAMME
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PROGRAMME
Wednesday July 1, 2015
10:00 Registration
Auditorium AT03
11:00 Elsevier Reaxys Workshop: Data-Driven Approaches to Medicinal Chemistry: How

Large-Scale Normalized Data Empowers Drug Discovery (duration: 90-minutes)
12:00 Lunch bag (included in the fee, but subject to prior registration)
Auditorium AT02

Dr Christine CONTINO-PEPIN (UNIVERSITY OF AVIGNON, Avignon, France)
Prof. Philippe OBERT (Vice-Chancellor Research, UNIVERSITY OF AVIGNON, Avignon, France)
Prof. Janos SAPI (SCT & UNIVERSITY OF REIMS-CHAMPAGNE-ARDENNE, Reims , France)
Session 1: Paul Ehrlich Award Lecture

Sponsored by Janssen-Cilag
Session Chair: Prof. Janos SAPI (SCT & UNIVERSITY OF REIMS-CHAMPAGNE-ARDENNE, Reims , France)
Dr Oscar DELGADO (JANSSEN R&D, Toledo, Spain)
13:30 L01 - Paul Ehrlich Awardee - The Synthetic Peptide P140, a Skilled Strategist and
Manipulator of the Immune System
Dr Sylviane MULLER (IBMC-CNRS, Strasbourg, France)
Session 2: Kinases & Oncology

Sponsored by Servier
Session Chair: Dr Olivier MIRGUET (INSTITUT DE RECHERCHES SERVIER, Suresnes, France)
14:30 L02 - Discovery and Characterisation of Potent and Selective Inhibitors of ATR Kinase as
Anti-cancer Agents
Dr Jean-Damien CHARRIER (VERTEX PHARMACEUTICALS, Oxfordshire, United Kingdom)
15:15 L03 - Covalent Kinase Inhibitors: A Practical Guide to Molecular Trapping

Dr Tjeerd BARF (ACERTA PHARMA, Oss, The Netherlands)
Session 3: Resistance in Infectious Diseases

Session Chair Dr Hong SHEN (ROCHE, Shanghai, China)
16:30 L04 - Antibiotic Resistance is an Emerging Disease

Dr Patrice COURVALIN (INSTITUT PASTEUR, Paris, France)
17:15 L05 - Resistance Phenotypes and SAR in HCV Drug Development

Dr John BILELLO (MERCK, Whitehouse Station, United States)
18:00 Welcome Reception (until 19:30)
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PROGRAMME
Thursday July 2, 2015
Auditorium AT02
Session 4: Tools for Cell Therapy

Session Chair: Dr Pascal GEORGE (SCT & INDEPENDENT SCIENTIFIC EXPERT & ADVISER, Longvilliers,
France)
08:30 L06 - Synthetic Molecules for Cell Biology and Cell Therapy
Prof. Motonari UESUGI (KYOTO UNIVERSITY, Kyoto, Japan)
Session 5: Short Communications - Session 6: Short Communications -

Targeting Apoptosis CNS Diseases
Sponsored by SCT Sponsored by SCT
Session Chair: Prof. Muriel AMBLARD Session Chair: Dr Grégory DURAND
(UNIVERSTY OF MONTPELLIER I, Montpellier, (UNIVERSITY OF AVIGNON, Avignon, France)
France)
09:30 SC01 - How do a Proapoptotic and a Cell SC03 - Development of Novel Multi-Target
Penetration Peptide work Together to kill Directed Ligands for Alzheimer’s Disease:
Cancer Cells? Identification of Donecopride
Dr Isabel ALVES (UNIVERSITY OF BORDEAUX, Prof. Christophe ROCHAIS (UNIVERSITY OF
Pessac, France) CAEN, Caen, France)
10:00 SC02 - Allosteric Inhibitors of p38 MAPK- SC04 - Development of Unnatural Basic
MK2 Pathway for Selective Cancer Cell Amino Acids Leading to Orally-Active
Killing NPFF Receptor Antagonists Preventing
Dr Lenka MUNOZ (UNIVERSITY OF SYDNEY, Opioid-Induced Hyperalgesia during the
Sydney, Australia) Treatment of Acute or Chronic Pains
Dr Frédéric BIHEL (CNRS / UNIVERSITY OF
STRASBOURG, Illkirch, France)
10:30 Coffee Break and Exhibition
Session 7: Diabetes Session 8 : Tools for Target ID

Session Chair: Dr Alessandra NURISSO Session Chair: Prof. Sun CHOI
(UNIVERSITY OF GENEVA, Geneva, Switzerland) (EWHA WOMANS UNIVERSITY, Seoul, South-
Korea)
11:15 L07 - From in situ Click to in vivo: Effect of L09 - Retinoids/Steroids as Ligands for
Inhibition of Insulin Degrading Enzyme Pharmacological Chaperon and Protein
Prof. Rebecca DEPREZ-POULAIN Knockdown Approach
(UNIVERSITY OF LILLE, Lille, France) Prof. Yuichi HASHIMOTO (THE UNIVERSITY
OF TOKYO, Tokyo, Japan)
12:00 L08 - Revolutionary Idea Yielded SGLT2 L10 - Chemical Probes for Epigenetic
Inhibitor Canagliflozin for Treatment of Type Proteins
2 Diabetes Prof. Paul BRENNAN (UNIVERSITY OF
Dr Sumihiro NOMURA (MITSUBISHI TANABE OXFORD, Oxford, United Kingdom)
PHARMA CORPORATION, Saitama, Japan)
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PROGRAMME
13:30 Poster Session 1 (Odd numbers)

13:45-14:45 Career session
(Room OE32)
Session 9: Cardiac Diseases Session 10: Structure Based

Approaches
Sponsored by ‘Fondation de la Maison de la
Chimie’
Session Chair: Prof. Joachim MITTENDORF Session Chair: Dr Jean-Paul RENAUD (RIBOSTRUCT,
(BAYER PHARMA, Wuppertal, Germany) Illkirch, France)
14:45 L11 - Phenotypic Screening for the L13 - Drugs, Targets, Diseases and the
Discovery of Novel Molecules for Druggable Proteome
Therapeutic Cardiac Regeneration Prof. Tudor I. OPREA (UNIVERSITY OF NEW
Dr Alleyn T. PLOWRIGHT (ASTRAZENECA, MEXICO, Albuquerque, United States)
Mölndal, Sweden)
15:30 L12 - BAY 1067197 - Discovery of a Partial L14 - Shedding Light on Protein Kinase
Adenosine A1 Agonist for the Treatment of Plasticity
Heart Failure Prof. Pascal BONNET (UNIVERSITY OF
Dr Daniel MEIBOM (BAYER PHARMA, ORLEANS, Orleans, France)
Wuppertal, Germany)
Session 11: Neglected/Rare Session 12: GPCRs

Diseases
Session Chair: Dr Anne VALADE Session Chair: Dr Manuel CASES-THOMAS
(UCB, Braine-l’Alleud, Belgium) (ELI LILLY & COMPANY, Windlesham, United Kingdom)
16:45 L15 - Lessons learned in TB Drug L17 - Two Steps Forward, One Step Back:
Discovery Successes and Failures in Structure-based
Dr Jan JIRICEK (NOVARTIS INSTITUTE Discovery of GPCR Ligands
FOR TROPICAL DISEASES, Singapore, Prof. Jens CARLSSON (STOCKHOLM
Singapore) UNIVERSITY, Stockholm, Sweden)
17:30 L16 - Cerdelga, an Oral Therapy for L18 - Fragment and Structure-Based Drug
Gaucher’s Disease; from Discovery to Discovery for a Family C GPCR: Discovery
Launch of the mGlu5 NAM Pre-clinical Candidate
Dr David J. HARRIS (SANOFI, Waltham, HTL14242
United States) Dr John CHRISTOPHER (HEPTARES,
Hertfordshire, United Kingdom)
- 12 -
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PROGRAMME
Friday July 3, 2015

Auditorium AT02
Session 13: Viral Diseases

Sponsored by IDENIX an MSD Company
Session Chair: Dr Sylvie POCHET (INSTITUT PASTEUR, Paris, France)
08:30 L19 - Sofosbuvir: A Breakthrough Curative Therapy for HCV

Dr Michael SOFIA (TEKMIRA/ONCORE BIOPHARMA, Doylestown, PA, United States)
09:15 L20 - Discovery of HIV Integrase Inhibitors

Dr John WAI (WUXI APPTEC, Shanghai, China)
10:30 Poster Session 2 (Even numbers)
Session 14: Pierre Fabre Award Lecture

Sponsored by Pierre Fabre
Session Chair: Dr Serge GRISONI (CENTRE DE RECHERCHE ET DÉVELOPPEMENT PIERRE FABRE,
Toulouse, France)
11:45 L21 - Pierre Fabre Awardee - Small Molecules, Big Players

Dr Raphaël RODRIGUEZ (INSTITUT CURIE, Paris, France)
Session 15: Immuno/Inflammatory Diseases

Sponsored by GSK
Session Chair: Dr Alexis DENIS (GSK, Courtaboeuf, France)
13:30 L22 - Novel Triazolopyridine Compounds as Selective JAK1 Inhibitors: From Target
Discovery to Filgotinib
Dr Christel MENET (GALAPAGOS, Mechelen, Belgium)
14:15 L23 - Locking the Bioactive Conformation – Discovery of BAY 85-8501, a Potent Inhibitor of
Human Neutrophil Elastase
Dr Franz VON NUSSBAUM (BAYER PHARMA, Berlin, Germany)
Session 16: Poster Prizes and Closing Remarks

Session Chair: Dr Luc VAN HIJFTE (SCT & NOVALIX, Illkirch, France)
Session 17: Future Event and Closing

Session Chair: Prof. Patrick DALLEMAGNE (UNIVERSITY OF CAEN, Caen, France)
- 13 -
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GENERAL INFO
Venue
Université d’Avignon et des Pays de Vaucluse
Campus centre ville – building Sainte Marthe Sud
74, Rue Louis Pasteur
84000 Avignon
France
Registration / Information Desk: Opening hours

The Registration / Information Desk will be open during the following hours:
Wednesday July 1 10:00 – 19:00
Thursday July 2 08:30 – 17:00
Friday July 3 08:30 – 14:00
Poster Sessions
All posters will be displayed during the entire period of the symposium, but should only be attended according
to the following schedule:
• Poster Session 1: posters with odd numbers
Thursday July 2, from 13:30 to 14:45
• Poster Session 2: posters with even numbers
Friday July 3, from 10:30 to 11:45
Posters should be mounted at your arrival on Wednesday July 1 or on Thursday July 2 in the morning. Removing
of the posters should take place on Friday at the end of the poster session. Please note that all posters have
to be removed by the end of the lunch break on Friday.
Therapeutic Innovation: Vocations & Careers

In parallel to the scientific programme on Thursday, July 2 at 13:45, a Careers’ session will be organised
with the intervention of pharma companies and professional associations representatives to illustrate to
young scientists, PhD’s and predoctoral students, the variety of possible jobs and career opportunities in
pharmaceutical R&D.
The career session will take place in room OE31.
Internet Connection
WiFi internet is available for all participants during the symposium.
Banquet
The banquet will take place on Thursday, July 2 at 20:00 at the
Palais des Papes
Place du Palais
84000 Avignon
The Palais des Papes is classified along with the historic centre of Avignon as a UNESCO World Heritage Site
since 1995.
The banquet was subject to registration. If you have booked the banquet, you have received a ticket in your
welcome package.
Emergencies
If during the symposium, you have an urgent question, you can reach us via our cell phone:
+32 495 24 08 64.
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BookRICT.indd 14 15/06/2015 12:04:47

23rd Young Research
Fellow Meeting
February 15-17, 2016
School of Pharmacy, Lille, FRANCE
Plenary Lectures
Rhona COX (AstraZeneca, SE)
Colin FISHWICK (U. Leeds, UK)
Raphaël RODRIGUEZ (Institut Curie, FR)
Laurent SANIERE (Galapagos, FR)
Sandrine VENDEVILLE (J&J, BE)
SCT Prize Lectures
25 Oral Communications*
30 Flash Poster Presentations*
Individual Career Sessions
Poster Sessions
Prestigious Prizes (SCT, ACS, EFMC, RSC, U1177 grants)
for best oral communications, posters & flash posters.
Information, Fees & Accomodation

Web : www.sct‐asso.fr/yrfm_next_meeting.html
Contact : young.medchem@sct‐asso.fr
Registration : 40€
Inserm
U1177 Rooms available from 35€ for 2 nights
www.sct-asso.fr
* Selected from Abstracts
- 15 -
BookRICT.indd 15 15/06/2015 12:02:56

Fluorochem is so much more than just a fluorochemical supplier; we actually stock a
diverse range of products, from fluorinated chemicals and heterocyclics, boronic
acids, sulphur compounds, novel organics, organometallics, silanes, siloxanes and
biochemicals to NMR solvents and tubes, even Silicagel for chromatography and tlc
plates. We have been supplying products for research and development to Pharma-
ceutical companies, Universities, Biotechnology companies and contract research
organisations for nearly 50 years but if, bizarrely, you haven’t heard of us, imagine a
smaller Sigma-Aldrich but with better value products and more exotic exhibition
materials.
It’s difficult to believe these days but the Fluorochem starter pack of NMR consum-
ables, silicagel, TLC plates and Mag Sulphate hasn’t always been around; one can
hardly imagine starting work in a new lab in those darker times… For more details of
these and other special offers visit our web site www.fluorochem.co.uk. Alternatively,
if you need to brighten up your desk or lab with some Fluorochem merchandise or
are interested in grabbing some freebies from bottle openers to posters and stress
hearts then come find our exhibition stand for some goodies and a chat.
- 16 -
ACS-25
BookRICT.indd 16 15/06/2015 12:02:57
Call for Papers:
Epigenetics Special Issues
Submit your primary research articles, letters or reviews
to the participating journals by October 1, 2015
The special issues will publish January 2016

Also, view a collection of previously published articles that showcase
some of the most significant recent research in the epigenetics area.
pubs.acs.org/epigenetics
- 17 - is focusing on Novel Therapeutics Targeting Epigenetics.

Journal of Medicinal Chemistry
ACS-2506 EpigeneticsA4.indd 1 4/22/15 12:01 PM

BookRICT.indd 17 15/06/2015 12:03:01
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- 18 -
BookRICT.indd 18 15/06/2015 12:03:02

PLENARY LECTURES:
Abstracts and
Biographies
- 19 -
BookRICT.indd 19 15/06/2015 12:03:02

Sylviane
©CNRS Photothèque / Cyril FRESILLON
MULLER
IBMC-CNRS, France
S
ylviane Muller is a Distinguished class research
director in the French Centre National de la Recherche
Scientifique (CNRS) and Professor at the Institute of
Advanced Studies of the Strasbourg University, in charge
of the chair Therapeutic immunology. She is deputy director
of the CNRS Molecular and cellular biology Institute (IBMC)
in Strasbourg (France), Chair and Director of the CNRS
Unit entitled Immunopathology and therapeutic chemistry,
and Head and coordinator of the Drug discovery Center for
cancer and inflammation Medalis awarded ‘Laboratory of
Excellence’. She defended a doctoral degree in Molecular
Biology in 1978 and a thesis in Science in 1984 in Strasbourg.
She was a post-doctoral fellow at the Max-Planck Institute for
Immunobiology in Freiburg (Germany). She is the co-author
of 249 publications in peer-reviewed journals and 97 review
articles and chapters. Her scientific activity has led to ~30
patents (most are licenced). She is the co-founder of two
companies, namely Neosystem (1986) and ImmuPharma
(2002). She is a member of the editorial board of several
scientific journals and of international scientific Societies.
She gave numerous lectures in Europe and the US, and
participated to many international meetings as an invited
speaker. She co-organized ten international congresses in
the field of autoimmunity and lupus. She received the CNRS
Silver Medal (2009). She is Chevalier de l’Ordre de la Légion
d’Honneur (2010).
R
esearch field: In 2001, S. Muller started her own
CNRS laboratory at IBMC, where she concentrates
her activity on systemic lupus erythematosus, which
represents a prototype of autoimmune rheumatic disease.
Pr. Muller’s team is interested in understanding the
molecular and cellular pathways involved in autoreactive
lymphocytes activation and the events leading to cell death/
living phenomena (apoptosis, autophagy) that are central
in lupus. Combining fundamental knowledge of lupus with
a long-lasting experience in peptide immunochemistry,
S. Muller and her team were able to develop a very novel
strategy, based on synthetic peptides, designed to modulate
the aberrant immune response and restore immune system
functions in lupus mice and patients. The results of a peptide-
based Phase IIb clinical trial including in ~150 lupus patients
gave extremely promising results and a phase III clinical trial
has started in 2015.
- 20 -
BookRICT.indd 20 3/06/2015 09:45:47

L01
THE SYNTHETIC PEPTIDE P140, A SKILLED STRATEGIST AND

MANIPULATOR OF THE IMMUNE SYSTEM
Sylviane Muller
CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
Nowadays, pharmacologic treatments of inflammatory diseases and autoimmune diseases are largely palliative
rather than curative. Most of them result in non-specific immunosuppression, which can be associated with
disruption of natural and induced immunity with significant, sometimes dramatic, adverse effects. Among the
novel strategies that are under development, tools that target specific molecular pathways and cells, and more
precisely modulate the immune system to restore normal tolerance mechanisms, are central. In these approaches,
peptide therapeutics do constitute a class of agents that display many physicochemical advantages. Within this
class of potent drugs, the phosphopeptide P140 is very promising for treating patients with systemic lupus, and
probably patients with other chronic inflammatory diseases. In a multicenter, randomized, placebo-controlled
phase IIb study for lupus, P140/LupuzorTM was found to be safe and met its primary efficacy end points,
confirming pre-clinical data generated in lupus-prone mice. We recently discovered that P140 targets autophagy,
a finely orchestrated catabolic process, which is decisive in the regulation of inflammation and in the biology of
immune cells. We provided the first evidence showing that P140 acts directly on a particular form of autophagy
called chaperone-mediated autophagy (CMA), which appeared to be hyperactivated in lupus. The “correcting”
effect of P140 peptide on CMA results in a change of MHC-peptide presentation to autoreactive T cells, leading
to a significant improvement of physiopathological status of treated mice. These results shed light on
mechanisms by which P140 could modulate lupus disease in patients. They open very new avenues of
therapeutic intervention in other pathological conditions in which reduction of CMA activity would be desired.
- 21 -
BookRICT.indd 21 3/06/2015 09:45:47

Jean-Damien
CHARRIER
Vertex Pharmaceuticals, United Kingdom
J
ean-Damien Charrier received his PhD degree in
Organic Chemistry in 1996 under the supervision
of Prof. Meslin at the UFR des Sciences et
Techniques in Nantes; he has dedicated this time to
the discovery of hetero Diels-Alder reactions to reach
novel approaches to a range of heterocycles . In 1997,
he joined Professor Young’s group at the University
of Sussex as a post-doctoral Fellow, where in worked
on the synthesis of unnatural aminoacids containing
fluorine and their incorporation into proteins. He joined
Vertex in 1998 where he is currently working.
J
ean-Damien has been involved in a number
of research programmes and has developed
leadership responsabilities for kinase projects,
mostly in the oncology field. In the past few years,
his expertise led him to be appointed as Chemistry
Head for the ATR programme, which resulted into the
discovery of two clinical candidates, one of which, VX-
970, is the topic of today’s presentation.
- 22 -
BookRICT.indd 22 3/06/2015 09:45:47

L02
DISCOVERY AND CHARACTERISATION OF ATR INHIBITORS FOR

THE TREATMENT OF CANCER
Jean-Damien Charrier
Vertex Parmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, OX14 4RW Abingdon, Oxfordshire
DNA damaging agents, such as cisplatin, or ionising radiation (IR), represent the cornerstone for the treatment of
cancer. However, for the majority of patients they provide only modest benefit. One reason for this is the
presence of highly effective cellular processes that detect and repair damaged DNA. ATR kinase is a key
mediator for one such cellular repair process that responds to replication stress, a potentially lethal form of DNA
damage that arises when cells attempt to replicate damaged DNA.
Replication stress can arise from oncogene driven deregulated proliferation or from treatment with DNA
damaging chemotherapy and IR. Accordingly, inhibition of ATR is expected to compromise cancer cell viability
and sensitise cells to DNA damaging agents.
In this talk I will describe the discovery and characterisation of a series of potent and selective ATR inhibitors.
Inhibition of ATR markedly enhances the cytotoxic activity of DNA damaging agents in many cancer, but not
normal, cells. This normal cell tolerance is attributed, in part, to the compensatory activity of overlapping repair
pathways. In contrast, many cancer cells have defects in these overlapping repair pathways e.g. through loss of
function of ATM, or its substrate p53. This drives a reliance on ATR for survival and renders cells highly
sensitive to inhibition of ATR. In multiple mouse xenograft studies inhibition of ATR enhances the efficacy of
DNA damaging drugs and IR at well-tolerated doses. Inhibitors of ATR are currently being assessed in Ph1
clinical studies.
- 23 -
BookRICT.indd 23 3/06/2015 09:45:47

Tjeerd
BARF
Acerta Pharma, The Netherlands
T
jeerd Barf obtained his Ph.D. in Medicinal
Chemistry 1996 from the University of Groningen,
The Netherlands. He subsequently joined
Pharmacia & Upjohn in Uppsala, Sweden, in 1997
and continued his career with the spin-off company
Biovitrum (2000). He has led medicinal chemistry
programs concerning metabolic diseases and
assumed overall program leadership later on. In 2005,
he moved to Organon (Oss, The Netherlands), and
as a Group Leader, his responsibilities encompassed
heading immunology lead finding projects. After the
acquisition by Schering-Plough and the merger with
Merck, he led a global cross-site lead optimization
program in the therapeutic area of autoimmune
diseases. The last decade, he has been intimately
involved in drug discovery programs that utilize the
covalent binding technology, mainly with the focus
on covalent kinase inhibitors in the oncology and
autoimmune disease space. As of 2011, expansion of
these drug discovery activities took place in privately
owned biotech companies. He is one of the founders
of Acerta Pharma and presently holds the position of
EVP of Chemistry.
- 24 -
BookRICT.indd 24 3/06/2015 09:45:47

L03
COVALENT KINASE INHIBITORS: A PRACTICAL GUIDE TO

MOLECULAR TRAPPING
Tjeerd Barf
Acerta Pharma BV
Oss, The Netherlands
Numerous covalent binding drugs have successfully entered the market and benefit patients with a variety of
disorders. The general concept of covalent inhibition can be widely applied to the majority of the protein target
families, and is no longer limited to enzyme families with catalytically active amino acid residues. Selective
targeting of specific non-catalytically active cysteines in the ATP pocket of kinase has resulted in the
identification of potent and selective kinase inhibitors with a beneficial pharmacodynamic profile.
A few years ago, afatinib was approved by the US Food and Drug Administration (FDA) as the first covalent
and irreversible binding kinase inhibitor. Afatinib blocks the epidermal growth factor receptor (EGFR) and
shows efficacy in patients with metastatic lung cancer (NSCLC). Around the same time frame ibrutinib, an
irreversible inhibitor of the kinase Btk, obtained breakthrough registration in different B cell lymphoma
subtypes. Several other irreversible inhibitors are currently undergoing clinical trials.
This class of kinase inhibitors can offer distinct advantages in terms of potency, selectivity and prolonged in vivo
efficacy, since the duration of action becomes a function of target protein turnover, rather than the
pharmacokinetics profile of the inhibitor. Irreversible kinase inhibitors behave in a non-ATP competitive
manner, which is a major upside in our collective efforts to master the human kinome. Typically, high
intracellular ATP levels render conventional reversible kinase inhibitors less efficacious in a cellular context.
This drop in potency is generally not observed when comparing biochemical and cellular assay data obtained
with irreversible kinase inhibitors. Although potential liabilities such as toxic events have to be considered when
embarking on the covalent binding principle, appropriate toolbox assays may help to screen for the most
promising candidates with a good therapeutic window.
- 25 -
BookRICT.indd 25 3/06/2015 09:45:47

Patrice
COURVALIN
Institut Pasteur, France
P
atrice Courvalin, M.D., is Professor de Classe
Exceptionnelle at the Institut Pasteur where
he is the Head of the Antibacterial Agents Unit
since 1983. He and his collaborators are experts in
the genetics and biochemistry of antibiotic resistance.
In particular, he first described and then elucidated
vancomycin resistance in Enterococcus. His research
has led to a revision of the dogma describing natural
dissemination of antibiotic resistance genes. He and
his colleagues demonstrated that a wide variety of
pathogenic bacteria can promiscuously exchange the
genetic material conferring antibiotic resistance, proved
that conjugation could account for dissemination of
resistance determinants between phylogenetically
remote bacterial genera, elucidated the transposition
mechanism of conjugative transposons from Gram-
positive cocci, and more recently, has obtained direct
gene and protein transfer from bacteria to mammalian
cells. His work is reported in more than 290 publications
in international scientific journals.
- 26 -
BookRICT.indd 26 3/06/2015 09:45:48

L04
ANTIBIOTIC RESISTANCE: AN EMERGING DISEASE

Patrice Courvalin
Institut Pasteur, Unité des Agents Antibacteriens, Paris, France
Antibiotics are grouped in classes on the basis of their chemical structure. As a consequence, members of a given
class are closely related molecules, generally share the same target of action, and are, therefore, subject to
cross-resistance. Thus, the reasoning in resistance should be in terms of drug classes rather than in isolated
molecules. Bacteria have developed four major mechanisms of resistance : (i) modification of the target which
leads to decreased affinity of the drug for its target; (ii) production of an enzyme that will detoxify the drug; (iii)
impermeability; and (iv) efflux of antibiotics outside the cells by energy-dependent pumps. The bacterial genome
is composed of the chromosome and of accessory mobile genetic elements. The chromosome contains the
genetic information required for the life cycle of the bacterium whereas, as their name indicates, accessory
genetic elements carry genes that are dispensable although they can provide major advantages for the survival of
the host, such as antibiotic resistance. The chromosome is inherited vertically by the progeny of the cell whereas
genetic elements can also be transmitted to other bacteria. As a result, resistance can be endogenous resulting
from mutations in structural or regulatory chromosomal genes and is generally not infectious from bacteria to
bacteria. In contrast, exogenous resistance is due to horizontal transfer of genetic information amongst bacteria.
There are three levels of (plasmid epidemics) or genes (transposon epidemics). These various levels, which
account for the extraordinary rise in antibiotic resistance, are not only infectious but also exponential as each is
associated with DNA duplication. Acquisition of resistance corresponds to a gain of function and is thus,
generally, associated with a biological cost; resistant derivatives have a lower degree of fitness than the parental
strain. The biological cost determines the stability and potential reversibility of resistance. A compensatory
evolution could occur, thereby reducing the biological cost and leading to stabilization of the resistant bacteria in
a natural population. As dissemination of resistance is closely linked to the magnitude of the selective pressure,
the only hope is to delay this dissemination. This leaves us with a single recommendation: antibiotics should be
used cautiously.
- 27 -
BookRICT.indd 27 3/06/2015 09:45:48

John
BILELLO
ETH Zürich/Spirochem, Switzerland
C
urrent position:
Prin. Scientist, Biology-Discovery, Virology &
Vaccine Late Discovery
R
esearch field:
Infectious disease therapeutics
E
ducation:
- Doctor of Philosophy, Cell & Molecular Biology,
Pennsylvania State University
- Candidate for Masters in Pharmaceutical Chemistry
University of Florida
- Bachelor of Science, Biochemistry; Minor in Biology
University of Delaware
P
rofessional experience:
- 2007-2014: Idenix Pharmaceuticals, Inc.,
Director of Biology, HCV Project Team Leader
Established and utilized models to investigate the
inhibition, resistance and toxicity of small molecules
against hepatitis C, among other side projects and
responsibilities, including a drug discovery project
leader for multiple programs and new target initiatives.
- 2003-2007: Postdoctoral fellow: Microbiology &
Molecular Genetics Harvard Medical School Focused
on a genetic system for generation of a recombinant
gammaherpesvirus for antiviral assays, vaccine vector
candidates for SIV, posttranslational regulation, and
microRNA identification. 2002-2003: Postdoctoral
fellow: Penn State University Generation and
utilization of recombinant insect viruses for gene
transfer of mammalian expression cassettes to primary
hepatocytes.
- 28 -
BookRICT.indd 28 3/06/2015 09:45:48

L05
RESISTANCE PHENOTYPES AND SAR IN HCV DRUG

DEVELOPMENT
John Bilello (1), Bianca Heinrich (2)
1) Merck and Co., West Point, PA

2) Abcam, Inc., Cambridge, MA
Treatment of hepatitis C virus (HCV) infection has rapidly evolved since the initial interferon-alfa (IFN-α)-based
therapy was introduced in the late 1980s. Advanced formulations of IFN-α and coadministration of ribavirin
improved the HCV sustained viral response (SVR) rates to approximately 50%, but were fraught with side
effects. Direct-acting antiviral (DAA) inhibitors of HCV protease were approved in 2010 in combination with
IFN-α and RBV, which further improved SVR rates, but contributed to additional side effects. Potent DAAs
were also developed that target NS5A of the HCV replication complex or the HCV polymerase by
non-nucleoside inhibitors. The protease, non-nucleoside and NS5A replication inhibitors often have
genotype-selective activity and characteristically low barriers to resistance, limiting their utility as
monotherapeutic drugs and allowing for frequent emergence of treatment-associated resistance variants.
Nucleoside inhibitors of the HCV polymerase have relatively high barriers to resistance and are comprised of
modified bases or sugars, with uridine derivatives proving the most successful in the clinic thus far. The design
of nucleoside inhibitors has evolved over years of discovery efforts and is currently focused on nucleoside
prodrugs optimized for therapeutic use. Therapies inclusive of nucleoside prodrugs can achieve SVR rates of up
to 100% and have limited resistance variant signatures. Clinical trials investigating the next generation of HCV
therapies are primarily combination regimens that include a nucleoside prodrug and at least one drug from
another DAA class, with the goals of reducing treatment duration and preventing the emergence of resistance
variants. This presentation will provide a retrospective analysis on the chemical determinants of antiviral
efficacy, genotype selectivity and resistance phenotypes of direct-acting inhibitors of HCV polymerase, protease
and NS5A-mediated replication. The resulting chemical innovation and insight gained through HCV antiviral
drug development will likely serve as a guide for future chemistry efforts combating other viruses and various
non-viral human diseases.
- 29 -
BookRICT.indd 29 3/06/2015 09:45:48

Motonari
UESUGI
Kyoto University, Japan
M
otonari Uesugi is a Professor of The Institute for
Integrated Cell-Material Sciences and Institute
for Chemical Research, Kyoto University. After
completing postdoctoral training in Harvard Chemistry
Department, Dr. Uesugi started his independent career
in Baylor College of Medicine, Houston, where he has
established an interdisciplinary laboratory in the area
of chemical biology. He was tenured in Baylor in 2005,
and moved to Kyoto University as a full professor in
2005.
H
e is a recipient of Tokyo Techno Forum 21 Gold
Medal Award (2006) and German Innovation
Award (2011). Dr. Uesugi and his co-workers
aim to gain a fundamental understanding of biological
events through the study of small molecules.
- 30 -
BookRICT.indd 30 3/06/2015 09:45:48

L06
SYNTHETIC MOLECULES FOR CELL BIOLOGY AND CELL

THERAPY
Motonari Uesugi
Institute for Integrated Cell-Material Sciences (WPI-iCeMS) & Institute for Chemical Research, Kyoto University, Gokasho,
Uji-shi, Kyoto 611-0011, Japan
In human history, bioactive small molecules have had three primary uses: as medicines, agrochemicals, and
biological tools. Among them, we have been focusing on the discovery and use of biological tools. In addition to
tool discovery, our laboratory has recently become interested in exploring another application of small
molecules: small molecules for cell therapy. Although small molecule drugs will continue to be important, cell
therapy will be a powerful approach to curing difficult diseases that small molecule drugs are unable to handle.
However, there are a number of potential problems in bringing cell therapy technologies to the clinic, including
high cost, potential contamination, low stability, and tumorigenesis. Stable, completely defined small molecules,
which are usually amenable to cost-effective mass production, may be able to help the clinical application of cell
therapy.
This presentation provides a quick overview of the recent results we obtained regarding several unique
molecules. These molecules were originally discovered by phenotypic cell-based screenings of our in-house
chemical libraries. Molecular understanding of their mechanisms of actions led to the design of small molecule
tools that can be used both for basic cell biology research and for cell therapy applications.
References
1) Live-cell imaging of endogenous mRNAs with a small molecule. Sato, S., et al. Angew. Chem. Int. Ed. 54, 1855-1858
(2015).
2) Synthetic molecules that protect cells from anoikis and their use in cell transplantation. Frisco-Cabanos, H.L. et al.,
Angew. Chem. Int. Ed., 53 (42), 11208-11213 (2014).
3) Selective elimination of human pluripotent stem cells by a marine natural product derivative. Kuo, T.F., et al., J. Am.
Chem. Soc. 136 (28), 9798-9801 (2014).
4) A chemical probe that labels human pluripotent stem cells. Hirata, N., et al., Cell Reports 6(6), 1165-1174 (2014)
5) VMAT2 identified as a regulator of late-stage beta cell differentiation. Sakano, D. et al., Nat. Chem. Biol. 10, 141-148
(2014).
- 31 -
BookRICT.indd 31 3/06/2015 09:45:48

Rebecca
DEPREZ-POULAIN University of Lille, France
D
r Rebecca Deprez-Poulain is Professor of
Medicinal Chemistry and Industrial Pharmacy
at the School of Pharmacy of Lille, France. Her
research at INSERM U1177 since 2004, focuses on
the inhibition of metalloproteases and on chemical
biology strategies to unravel the role of these targets.
She holds an engineer degree and a PharmD. She
got her PhD under the supervision of Pr Tartar at
CEREP (1999) on combinatorial chemistry and
pharmacological profiling. She did a post-doc on
chemical libraries for the screening on C elegans in
collaboration with DeVGen NV and a second post-
doc at the Institut Pasteur de Lille on the treatment of
malaria.
S
he received the 2009 Servier Prize
“Encouragement à la Recherche” of the
French Medicinal Chemistry Society and was
recently nominated as a junior member of the Institut
Universitaire de France. She’s PI of several national
grants (ANR and FRM) and author of more than 40
articles and reviews.
- 32 -
BookRICT.indd 32 3/06/2015 09:45:49

L07
FROM IN SITU CLICK TO IN VIVO PHARMACOLOGY: EFFECT OF

CATALYTIC SITE INHIBITION OF INSULIN DEGRADING ENZYME
ON GLUCOSE INTOLERANCE.
Rebecca Deprez-Poulain
Drugs and Molecules for Living Systems U1177INSERM/ Institut Pasteur de Lille/Université de Lille, School of Pharmacy 3
rue du Pr Laguesse F-59000 Lille, France.
Insulin degrading enzyme (IDE) is the major enzyme for insulin degradation and thought to be a potential drug
target to treat diabetes.1,2 Studies using knock-out animals, along with genetic studies have linked this enzyme to
this pathology. Few inhibitors are described : dual exosite binders of the enzyme3,4 or non-catalytic site
inhibitors of IDE2. Here, we report the discovery of the first catalytic site inhibitor of IDE for in vivo studies
(BDM44768). Using in situ click chemistry and ESI-TOF MS, we identified potent triazoles inhibitors that were
subsequently optimized to draw the structure-activity properties. The crystallographic and SAXS analyses show
that these inhibitors constrain IDE in a closed conformation. Both X-Ray and ligand-observed 19F-NMR provide
a rational to the differences in activities of 1,4- and 1,5 triazoles isomers. Pharmacokinetic and selectivity
parameters were also measured. Mice acutely treated with the best inhibitor display an increased insulin
signalling and greater glucose intolerance compared to control mice or mice treated with inactive analogue.
Intraperitoneal and oral glucose, insulin and pyruvate tolerance tests (IPGTT, OGTT, ITT and PTT) complete
the vivo profile of these catalytic site inhibitors. Control experiments in IDE-ko littermates demonstrated target
engagement in the effect of inhibitor.
References
1) Shen, Y., et al. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Nature,2006, 443(7113): 870-874
2) Maianti, J. P. et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature
2014, 511, 94-98
3) Charton, J., et al. Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of
insulin-degrading enzyme in amyloid-beta hydrolysis. Eur J Med Chem,2014, 79: 184-193.
4) Charton, J., et al. Structure-activity relationships of Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids,
dual binders of human Insulin-Degrading Enzyme. Eur J Med Chem,2015, 90: 547-567
- 33 -
BookRICT.indd 33 3/06/2015 09:45:49

Sumihiro
NOMURA
Mitsubishi Tanabe Pharma Corporation, Japan
S
umihiro Nomura is a Principal Research
Scientist at the Medicinal Chemistry Research
Laboratories II of Mitsubishi Tanabe Pharma
Corporation, in Saitama, Japan. He is a medicinal
chemist with 32 years of experience, leading
several drug discovery teams for the treatment of
immunological or metabolic disease at Mitsubishi
Tanabe.
H
e received his Ph.D. degree from Hokkaido
University with a thesis regarding the synthesis
of cyclic ether rings found in natural products.
- 34 -
BookRICT.indd 34 3/06/2015 09:45:49

L08
REVOLUTIONARY IDEA YIELDED SGLT2 INHIBITOR

CANAGLIFLOZIN FOR TREATMENT OF TYPE 2 DIABETES
Sumihiro Nomura
Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
According to the glucose toxicity hypothesis, continuous hyperglycemia induces insulin resistance and impaired
insulin secretion in type 2 diabetes.We proposed the concept of a novel antidiabetic agent to eliminate glucose
toxicity independent of insulin action.In the kidney, plasma glucose is filtered through the glomerulus and
reabsorbed in the proximal tubules. Most glucose reabsorption is mediated by sodium glucose co-transporter 2
(SGLT2). Oral administration of the SGLT2 inhibitor we pioneered 1 (T-1095) enhances urinary glucose
excretion and consequently lowers blood glucose levels in diabetic animal models independent of insulin action.
1,2 We explored metabolically more stable C-glucosides 2 with a heteroaromatic ring rather than O-glucosides,
resulting in the discovery of a novel thiophene derivative 3 (canagliflozin, TA-7284/JNJ-28431754).3
Pharmacological profiles and clinical outcomes will be presented. Canagliflozin was approved in USA and the
EU in 2013, and in Japan in 2014.
References
1) Tsujihara, K. et al. J. Med. Chem. 1999, 42, 5311–5324.
2) Oku, A. et al. Diabetes 1999, 48, 1794–1800.
3) Nomura, S. et al. J. Med. Chem. 2010, 53, 6355–6360.
- 35 -
BookRICT.indd 35 3/06/2015 09:45:49

Yuichi
HASHIMOTO
The University of Tokyo, Japan
Y
uichi Hashimoto received his Ph.D. in
pharmaceutical sciences form The University
of Tokyo (UTokyo) in 1982. He became an
assistant professor of the Faculty of Pharmaceutical
Science, UTokyo (1983), then moved to the Institute
of Applied Microbiology, UTokyo as an associate
professor (1989), and finally joined the Institute of
Molecular and Cellular Biosciences, UTokyo as a full
professor (1997 to present).
H
is major research interests span the fields
of basic molecular medicinal chemistry and
bioorganic chemistry, and include studies of the
structural development of bioresponse modifiers and
regulators of protein trafficking/stability.
- 36 -
BookRICT.indd 36 3/06/2015 09:45:50

L09
RETINOIDS/STEROIDS AS LIGANDS FOR PHARMACOLOGICAL

CHAPERONES AND PROTEIN KNOCKDOWN APPROACH
Yuichi Hashimoto
Institute of Molecular & Cellular Biosciences

The University of Tokyo
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Our group has developed various synthetic retinoids (retinobenzoic acids), including tamibarotene (Am80)
which has been launched in Japan (2005) for the treatment of relapsed acute promyelocytic leukemia. Based on
the methodology used in the molecular design of our retinobenzoic acids, we tried to create seed/lead compounds
for the treatment of folding-defective diseases. Two approaches have been undertaken, i.e., (1) development of
pharmacological chaperones which induce normal folding to correct the abnormal trafficking (cellular
localization) of mutated membrane proteins, and (2) development of protein knockdown [selective and n
ongenetic IAP (cellular inhibitor of apopotosis protein)-dependent target protein eraser: SNIPER] method to
induce decomposition of targeted proteins. In this talk, design, synthesis and biological evaluation of (1)
pharmacological chaperones targeting mutated rhodopsin (retinobenzaldehydes aiming the treatment of retinitis
pigmentosa) and mutated NPC1 (oxysterol analogs aiming the treatment of Niemann-Pick type C disease), and
(2) SNIPERs targeting cellular retinoic acid-binding proteins (CRABPs) and some nuclear receptors, including
retinoic acid receptor (RAR) and androgen receptor (AR), will be discussed.
References
1) 1. Karaki F, Ohgane K, Fukuda H, Nakamura M, Dodo K, Hashimoto Y.: Structure-activity relationship study of
non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout.
Bioorg. Med. Chem., 22: 3587-3609 (2014).
2) 2. Ohgane K, Karaki F, Dodo K, Hashimoto Y.: Discovery of oxysterol-derived pharmacological chaperones for NPC1:
implication for the existence of second sterol-binding site. Chemistry & Biology, 20: 391-402 (2013).
3) 3. Misawa T., Hayashi H, Sugiyama Y, Hashimoto Y.: Discovery and structural development of small molecules that
enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2.
Bioorg. Med. Chem., 20: 2940-2949 (2012).
4) 4. Itoh Y, Ishikawa M, Kitaguchi R, Okuhira K, Naito M, Hashimoto Y.: Double protein knockdown of cIAP1 and
CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonists. Bioorg. Med. Chem. Lett., 22: 4453-4457
(2012).
5) 5. Itoh Y, Kitaguchi R, Ishikawa M, Naito M, Hashimoto Y.: Design, synthesis and biological evaluation of nuclear
receptor-degradation inducers. Bioorg. Med. Chem., 19: 6768-6778 (2011).
6) 6. Itoh Y, Ishikawa M, Naito M, Hashimoto Y.: Protein knockdown using methylbestatin-ligand hybrid molecules. J. Am.
Chem. Soc., 132: 5820-5826 (2010).
7) 7. Ohgane K, Dodo K, Hashimoto Y.: Retinobenzaldehydes as proper-trafficking inducers of folding-defective P23H
rhodopsin mutant responsible for retinitis pigmentosa. Bioorg. Med. Chem., 18: 7022-7028 (2010).
- 37 -
BookRICT.indd 37 3/06/2015 09:45:50

Paul
BRENNAN
University of Oxford, United Kingdom
P
aul Brennan received his PhD in organic
chemistry from the University of California,
Berkeley under the mentorship of Paul Bartlett
working on synthetic methodology for combinatorial
chemistry and synthesizing inhibitors for new anti-
bacterial targets. Following three years of post-doctoral
research with Steve Ley in Cambridge University on
the total synthesis of rapamycin, Paul returned to
California to take a position at Amgen. His research
was focussed on designing and synthesizing kinase
inhibitors for oncology. After two years at Amgen, Paul
accepted a position as medicinal chemistry design
lead at the world-renowned Pfizer labs in Sandwich,
UK. Over the next six years Paul designed and
synthesized compounds for most major drug classes:
GPCR’s, CNS-targets, ion-channels and metabolic
enzymes. Following the closure of the Pfizer site
in Sandwich, Paul joined the Structural Genomics
Consortium as the principal investigator for medicinal
chemistry to discover chemical probes for epigenetic
proteins.
- 38 -
BookRICT.indd 38 3/06/2015 09:45:50

L10
CHEMICAL PROBES FOR EPIGENETIC PROTEINS

Paul Brennan
SGC, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford NDMRB, Roosevelt Drive Oxford
OX3 7FZ, UK
Epigenetics is the study of heritable changes in phenotype that are not encoded in an organism’s DNA.
Epigenetic effects due to persistent changes in gene transcription have been linked to chemical modification of
DNA and the proteins that package and regulate DNA in the nucleus, histones. Two of the major
post-translational modifications of histones are acetylation and methylation of lysine residues prevalent in
histone tails. Associated with each mark are reader, writer and erase proteins that regulate and interrogate histone
marks to regulate gene expression. Bromodomains are the major readers of histone acetylation whereas lysine
demethylases (KDMs) are responsible for removing histone methylation marks. The SGC has developed a
number of chemical probes that inhibit bromodomains or KDMs. The use of these epigenetic chemical probes
has been transformative in understanding the function of these epigenetic proteins in cellular models of disease.
- 39 -
BookRICT.indd 39 3/06/2015 09:45:50

Alleyn T.
PLOWRIGHT
AstraZeneca, Sweden
A
lleyn Plowright obtained his PhD in organic
chemistry with Professor Gerald Pattenden
at the University of Nottingham in 1999, and
continued with postdoctoral studies with Professor
Andrew Myers at Harvard University in 2000–2001.
In 2002, he joined AstraZeneca UK as a medicinal
chemist working in the Oncology and then Metabolic
Disease research areas. He moved to AstraZeneca,
Sweden, in 2006 and in 2012 became Senior Principal
Scientist, Medicinal Chemistry in the Cardiovascular
and Metabolic Diseases Innovative Medicines unit.
H
is research interests include drug design,
phenotypic screening and drug discovery for
cardiovascular and metabolic diseases.
- 40 -
BookRICT.indd 40 3/06/2015 09:45:50

L11
PHENOTYPIC SCREENING TO IDENTIFY COMPOUNDS

ENHANCING PROLIFERATION AND DIFFERENTIATION OF
HUMAN CARDIAC PROGENITOR CELLS AND
EPICARDIUM-DERIVED CELLS
Lauren Drowley (1), Anneli Nordqvist (1), Samantha Peel (2), Elizabeth Mouchet (2), Anna Jonebring (3),
Alexander Kvist (3), Mike Firth (2), Marie Jose Goumans (4), Ola Engkvist (3), Gabriella Brolen (3),
Qing-Dong Wang (1), Alleyn Plowright (1)
1) Cardiovascular and Metabolic Diseases Innovative Medicines, AstraZeneca, Mölndal, Sweden

2) Discovery Sciences, AstraZeneca, Alderley Park, UK
3) Discovery Sciences, AstraZeneca, Mölndal, Sweden
4) Leiden University Medical Center, Leiden, The Netherlands
Regeneration of heart tissue after a heart attack has the potential to improve heart function through generation of
new contractile muscle instead of scar tissue. Multipotent progenitor cell populations have been reported to exist
in the heart, some of which can play a role in normal turnover and/or repair after injury. However, these
progenitor cells are quite rare in number and true functional repair after a myocardial infarction does
not spontaneously occur. Identification of compounds and target mechanisms aimed at enhancing repair
through expanding the progenitor cell populations and generating new cardiomyocytes and vasculature is a
promising approach to enable effective regeneration of cardiac tissue.
We have performed phenotypic screens for proliferation of epicardium-derived cells (EPDCs) isolated from
adult human heart and Nkx2.5+ cardiac progenitor cells (CPCs) derived from human iPSCs. The screens were
run as medium throughput assays with the same optimized 8-10K compound set, with hits tested on human
cardiac fibroblasts to remove non-specific cardiac cell proliferative agents. Developing and running these
screens in parallel has allowed us to identify compounds that specifically proliferate CPCs and/or EPDCs
without affecting proliferation of fibroblasts. In addition, a multi-lineage differentiation assay has led to the
discovery of novel compounds and mechanisms, which can induce differentiation of the iPS-derived CPCs
towards the cardiac or endothelial lineages as well as molecules that can induce differentiation of both lineages
simultaneously.
Phenotypic screening is a multi-disciplinary activity and this talk will describe our progress and early findings
using these relevant human cells combined with high content image analysis. The selection and testing of
biologically annotated compound libraries, the use of appropriate computational and bioinformatic tools to help
generate and test early target hypotheses and the subsequent build of chemical clusters and establishing
structure-activity relationships from the hit molecules will be discussed.
The identification of compounds that proliferate CPCs and EPDCs, but not cardiac fibroblasts, has allowed us to
discover novel compounds and targets that have the potential to result in true regeneration of the heart.
- 41 -
BookRICT.indd 41 3/06/2015 09:45:50

Daniel
MEIBOM
Bayer Pharma, Germany
D
aniel Meibom received his PhD degree in
Organic Chemistry under the supervision of
Professor Ekkehard Winterfeldt at the University
of Hannover. In 2001 he joined Bayer working on
combinatorial chemistry, then quickly moved on to
medicinal chemistry projects in therapeutic areas
like CNS and antibacterials. From 2007-2013 he was
responsible for the chemical optimization of several
medicinal chemistry projects in the cardiovascular
field. Since 2014 he is heading a cardiovascular lead
optimization project as a senior scientist. Besides
drug design, his research interests include IT tools for
medicinal chemists.
- 42 -
BookRICT.indd 42 3/06/2015 09:45:51

L12
BAY 1067197 - DISCOVERY AND OPTIMIZATION OF A PARTIAL

ADENOSINE A1 AGONIST FOR THE TREATMENT OF HEART
FAILURE
Daniel Meibom
Bayer Pharma AG, 42096 Wuppertal, Germany
Adenosine, a purine nucleoside, exerts a variety of physiological actions by binding to adenosine cell surface
receptor subtypes (A1, A2a, A2b, and A3) which are widely expressed in the body. In heart the protective effects
of adenosine are primarily mediated by activation of the A1 receptor (A1R) subtype. The broad physiological
effects of A1 receptor activation by full A1 agonists results in desired (e.g. improvement of cardiac energetics,
cardioprotection) and non-desired (e.g. bradycardia, AV block) cardiac and non-cardiac (e.g. kidney, CNS)
effects. Partial A1 receptor agonists can work as agonists with lower efficacy or as weak antagonists depending
on endogenous adenosine levels and receptor reserve leading to an organ-specific beneficial pharmacological
response.
BAY 1067197 is a prodrug of the non-adenosine like compound BAY 84-3174, a potent and selective partial
agonist of the human adenosine A1 receptor. In a canine heart failure model significant improvement of heart
function was observed without any effect on heart rate or blood pressure. Compared to historical experiments
with beta blockers or ACE inhibitors, the effect has a faster onset and is more pronounced. BAY 1067197 might
offer a new principle for the oral treatment of heart failure which is currently evaluated in Phase 2 clinical pilot
trials. The presentation will detail the optimization efforts in this program including PK properties and
cardiovascular effects in vivo.
- 43 -
BookRICT.indd 43 3/06/2015 09:45:51

Tudor I.
OPREA
University of New Mexico, United States
T
udor Oprea completed his medical studies
(MD, PhD) in Timisoara, Romania, followed by
positions at the University of Utrecht, Washington
University School of Medicine and Los Alamos National
Laboratory, as well as AstraZeneca R&D in Sweden
(1996-2002), where he co-developed the “leadlike”
concept and ChemGPS. Since 2002, Oprea joined the
University of New Mexico School of Medicine, where
he has contributed to the identification of selective,
potent compounds for GPER (the G-protein estrogen
receptor), the formyl peptide receptors FPR1 and
FPR2, the small GTP-ases Rac1 and Cdc42, and
the ABCG2 efflux transporter. His work led to clinical
trials for Raltegravir (NCT01275183) and Ketorolac
(NCT01670799).
O
prea co-invented 5 US patents, co-authored
over 140 peer-review publications, and
received the Corwin Hansch Award.
O
prea’s research interests include chemical
space navigation, lead and probe identification,
virtual screening, machine learning,
systems chemical biology, signal transduction and
pharmacokinetics, drug repurposing and clinical
informatics research.
- 44 -
BookRICT.indd 44 3/06/2015 09:45:51

L13
DRUGS, TARGETS, DISEASES AND THE DRUGGABLE PROTEOME

Tudor OPREA
Translational Informatics Division, Department of Internal Medicine, MSC09 5025, University of New Mexico School of
Medicine, Albuquerque NM 87131
The Illuminating the Druggable Genome Knowledge Management Center (IDG KMC) evaluates, organizes and
distils more than 80 protein-centric and 18 gene-centric resources for over 20,000 curated human proteins
(UniProt knowledgebase; http://www.uniprot.org/), with primary focus on 4 protein families: G-protein-coupled
receptors, nuclear receptors, ion channels and kinases.
Data wrangling, coupled with algorithmic processing, text mining of drug labels, patents, medical literature and
clinical records, as well as human curation and drug-target ontology development, yield emergent properties and
knowledge for target-disease associations. Of 20,202 proteins, 36.4% (7,345) are categorized as “Tdark”, i.e.,
lacking “reference into function” data or more than one publication, with an additional 15.1% (3,048 proteins)
lacking relevant disease and functional information. At the opposite end, 3.1% (617 proteins) have a confirmed
mechanism of action ("Tclin+"), with another 1.1% (215) being annotated to interact with drugs ("Tclin") - see
also http://habanero.health.unm.edu/tcrd/.
From genomics to pharmaco- and clinical informatics, this vast array of data and machine learning models are
used to prioritize “Tdark” proteins for further experiment via the IDG Technical Development grants (7 NIH
funded projects - see also http://commonfund.nih.gov/idg/fundedresearch), the International Mouse Phenotype
Consortium (IMPC; http://www.mousephenotype.org/), as well as other collaborations. An interactive
web-based tool that explores the relationship between proteins (focused on the 4 IDG protein families, namely
GPCRs, NRs, kinases and ion channels), developed using text mining, is deployed at NewDrugTargets.org
(http://newdrugtargets.org/). The IDG KMC interface portal (https://pharos.nih.gov/idg/index) supports mining
and interactive browsing of this multi-dimensional data collection, which provides informative summaries for
the broader scientific community.
This data integration effort led to the following observations: i) there appears to be a knowledge deficit, i.e., we
lack understanding of protein function for over 50% of human proteome; ii) less than 5% of the human proteome
is therapeutically addressed by drugs; iii) given current understanding of disease (~8,800 disease concepts,
cf. http://disease-ontology.org/), as well as all diseases addressed by on-label (~2,000) and off-label (~400)
indications, we can now address about a quarter of all diseases using therapeutic agents. To conclude, from
personalized medicine to systems approaches, the field of drug discovery is wide open.
- 45 -
BookRICT.indd 45 3/06/2015 09:45:51

Pascal
BONNET
University of Orléans, France
P
ascal Bonnet is full professor at the Institute
of Organic and Analytical Chemistry (ICOA)
from the University of Orléans, France,
since 2012. He is currently leading the group of
Structural Bioinformatics and Chemoinformatics that
is developing and integrating novel computational
methods in drug discovery. His research interests
focus also on the development of an integrative in
silico platform for kinase research. After completing
his PhD in 2001 at the University of Orléans (France)
and the University of Barcelona (Spain), he moved to a
postdoctoral position at the University of Manchester,
UK. As a scientist, he joined Janssen-Cilag in France
and then Janssen-Pharmaceutica, Belgium, in 2003.
He was involved in several drug discovery projects
mainly in the oncology therapeutic area. Promoted
Principal Scientist in 2010, he was leading the Kinase
Platform at Janssen including biologists, medicinal
and computational chemists.
- 46 -
BookRICT.indd 46 3/06/2015 09:45:51

L14
SHEDDING LIGHT ON PROTEIN KINASE PLASTICITY

Pascal Bonnet
University of Orléans, CNRS, ICOA, UMR 7311, 45067 Orléans, France
With the recent approval of 4 and 3 small-molecule kinase inhibitors in 2013 and 2014 respectively and over 100
NMEs progressing in clinical development, kinase drug discovery is still an active research in academia and
pharmaceutical companies. Protein kinase inhibitors represent one of the most important classes of cancer drugs,
and other inhibitors are currently under investigation for other therapeutic areas such as rheumatoid arthritis and
central nervous system. More than 200 unique protein kinases have been already crystallized, and their
tridimensional representation provides useful information in the rationale design of novel inhibitors. Given this
large number of crystal structures available, analysis at atomic level furnishes important information on the
protein flexibility and functional features relationship. Most of the kinase inhibitors bind into the ATP active site
blocking the catalytic activity of the protein kinases. However, the recent publications of BRAF ATP
competitive inhibitors that paradoxically activate the downstream signaling pathways have highlighted a novel
mechanism by which the protein-inhibitor complex is stabilized in its active conformation. Using strong
expertise from several European research groups, such as molecular biology, medicinal and computational
chemistry and proteomics, we aim to unravel the biomolecular interactions involved in this kinase switch
mechanism. From this work, we have identified conserved energetic patterns and several structural motifs which
seem to be important in protein plasticity. The results will provide useful information for the design of novel and
selective kinase inhibitors.
- 47 -
BookRICT.indd 47 3/06/2015 09:45:51

Jan
JIRICEK
Novartis Institute for Tropical Diseases, Singapore
J
an Jiricek received his Diploma in Chemistry (1999)
at the University of Hannover after completing
an undergraduate research year at Scripps in
the area of bioorganic chemistry. He graduated at
the TU-Berlin in 2003 with summa cum laude in the
field of natural product synthesis. After two years of
postdoctoral studies at GNF in target based medicinal
chemistry, he joined the Novartis Institute for Tropical
Diseases with the main focus on TB drug discovery.
Through 8 years in this field, Jan became an expert
in TB drug discovery where he developed a strong
pipeline of lead series and two preclinical development
candidates. In his current position, appointed team
leader in HAT drug discovery, his responsibility is to
develop a world leading drug discovery portfolio for
HAT and develop novel urgently needed drugs for this
truly neglected disease.
- 48 -
BookRICT.indd 48 3/06/2015 09:45:52

L15
LESSONS LEARNED IN TB DRUG DISCOVERY

Jan Jiricek
Novartis Institute for Tropical Diseases Pte Ltd

10 Biopolis Road, #05-01 Chromos
138670 SINGAPORE
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an airborne infectious disease that infects
almost one-third of the world’s human population. Effective chemotherapy for TB has existed since the 1940s,
however, an important factor contributing to the resurgence of the disease is the emergence of multi-drug
resistant tuberculosis (MDR TB). MDR TB is caused by Mtb that is resistant at least to isoniazid and rifampicin,
the two most potent anti-TB drugs. To identify a new starting points in the development of new TB drugs, the
Novartis internal small molecule chemical library was screened for activity against Mycobacterium bovis BCG
as a surrogate of Mtb by measuring ATP levels using the BacTiter-Glo assay.Subsequent hit confirmation with
Mtb H37Rv led to the identification of a handfull novel chemical entities, which are partially described in this
presentation.
Phenotypic screening requires profound knowledge of the in vivo environment of the bacteria. The media used in
the first HTS biased for hits which were not relevant in vivo and only after optimizing and probing in efficacy
studies, this artefact has been identified and investigated. This lesson led to an improved follow up cascade and
new chemotypes emerged.
The imidazopyridine class, a feasible scaffold for optimization, yielded tool compounds for in vivo testing.
Moderate efficacy was obtained and linked to a bacteriostatic effect of this compound class. The conclusion at
that time was to focus on cidal scaffolds, compounds which kill the bacteria in vitro.
Based on this finding, kill kinetics have been introduced to select cidal scaffolds. Two compound classes have
been identified for lead optimization and both translated to good efficacy in vivo.
The difficulties to translate these chemotypes to development candidates and a link of their properties to their
biological target, will be described.
- 49 -
BookRICT.indd 49 3/06/2015 09:45:52

David J.
HARRIS
Sanofi, United States
H
ead Pre-Development Sciences & Head Waltham
Site, Lead Generation to Candidate Realization
(LGCR), Sanofi. Current responsibilities:
Synthesis development, formulation development, and
analytical research and development for non-biologics
for Sanofi in the US. Prior professional experience:
Genzyme in a number of positions including head of
discovery chemistry, head of process chemistry, and
head of development for non-biologics; Schering-
Plough in process research. Education: Boston
College B.S. in Chemistry, Brandeis University Ph.D. in
Synthetic Organic Chemistry, Massachusetts Institute
of Technology Post-Doctoral Associate.
- 50 -
BookRICT.indd 50 3/06/2015 09:45:52

L16
CERDELGA, AN ORAL THERAPY FOR GAUCHER DISEASE TYPE 1;

FROM DISCOVERY TO LAUNCH
David J. Harris
Sanofi and Genzyme a Sanofi company

153 Second Avenue
Waltham, MA 02451 USA
Gaucher disease, first described by Dr. Philippe Gaucher in 1882, is a recessive autosomal lysosomal storage
disease resulting from the deficient activity of acid b-glucosidase (also known as glucocerebrosidase) resulting in
the accumulation of its substrate glucosylceramide. The glucosylceramide accumulates in the lysosomes of
tissue macrophages, particularly in the spleen, liver, and bone marrow. Manifestations of the disease may
include the enlargement of spleen and liver, anemia, thrombocytopenia, and bone lesions. Gaucher disease type
1 (non-neuropathic) is the most prevalent form in the US, Europe, and Israel, estimated to affect 1 in 40,000 to 1
in 60,000 people, and especially prevalent with those of Ashkenazi Jewish ancestry.
Genzyme’s Ceredase (1991, placental derived) and Cerezyme (1994, recombinant) were the first drugs
approved to treat Gaucher disease. These acid b-glucosidase preparations are infused into patients to replace the
deficient enzyme and provide sufficient catalytic breakdown of glucosylceramide. This type of treatment has
been termed enzyme replacement therapy (ERT). Another approach to the treatment of Gaucher disease is to
partially inhibit the synthesis of glucosylceramide such that the correct balance of acid b-glucosidase activity and
glucosylceramide synthesis are maintained. This approach has been termed substrate reduction therapy (SRT).
As glucosylceramide is the precursor to a diverse family of glycolipids important in human biology it is
important that the above mentioned balance be correctly achieved for an effective therapy. Building on the
concept that was initially developed by Norman Radin, Ph.D. of the University of Michigan and in collaboration
with James A. Shayman, M.D. also of the University of Michigan a research program was pursued to develop a
substrate reduction therapy for Gaucher disease. The successful outcome of this research program was the
development of Cerdelga (eliglustat tartrate) an oral small molecule inhibitor of glucosylceramide synthase that
has been approved and launched for the treatment of Gaucher disease type 1. Aspects of the discovery,
development, and clinical trial results leading to the approval and launch Cerdelga will be presented.
- 51 -
BookRICT.indd 51 3/06/2015 09:45:52

Jens
CARLSSON
Stockholm University, Sweden
T
he goal of his research group is to improve
understanding of receptor-ligand interactions
at the atomic level using computer models.
Using structure-based methods such as molecular
dynamics simulations and molecular docking, they
focus on prediction of how small molecules interact
with G protein-coupled receptors and modulate their
function. Their projects are driven by computational
chemistry and carried out in close collaboration with
experimental groups.
J
ens completed a PhD in computational chemistry
at Uppsala University in 2008 under the
supervision of prof. Johan Åqvist. His postdoctoral
research was carried out in prof. Brian Shoichet’s
group at the University of California in San Francisco
and focused on structure-based ligand discovery. In
2012, he established an independent research group
at Stockholm University, which currently has eight
members. In July 2015, his group will move to the
dept. of Organic Pharmaceutical Chemistry and the
Science for Life Laboratory at Uppsala University.
- 52 -
BookRICT.indd 52 3/06/2015 09:45:52

L17
TWO STEPS FORWARD, ONE STEP BACK: SUCCESSES AND

FAILURES IN STRUCTURE-BASED DISCOVERY OF GPCR LIGANDS
Jens Carlsson
Stockholm University
Science for Life Laboratory
Karolinska Institutet Science Park
Tomtebodavägen 23A
17165 Solna, Sweden
G protein–coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling.
High-resolution crystal structures of GPCRs capturing different receptor conformations are now available, which
have provided insights into the mechanism of activation and ligand selectivity for this important class of drug
targets.
I will first present a series of structure-based screens for novel ligands of the A2A adenosine receptor (A2AAR),
which is a drug target for Parkinson’s disease (antagonists) and ischemia (agonists). As crystal structures for both
inactive- and active-like receptor conformations of the A2AAR have now been determined, molecular docking
screens for novel ligands can be performed. Virtual screens against different conformations of the A2AAR were
carried out to investigate if structure-based methods can be used to identify agonists and antagonists. Our results
shed light on the importance of access to crystal structures and the role of the chemical library in screens for
ligands with specific pharmacological properties.
For most GPCRs, no experimental coordinates are available and structure-based screens are forced to rely on
homology models. However, it is still unclear if models of GPCRs are sufficiently accurate to be used in ligand
discovery. The determination of crystal structures for dopamine and serotonin receptors, and the challenges to
the community to predict these in the GPCR Dock competitions, have enabled us to carry out comparisons of
ligand discovery from models versus crystal structures. Our results from these challenges reveal opportunities
and limitations of the use of homology models in ligand discovery and design of selective lead candidates.
Key publications:
Rodríguez D, Gao ZG, Moss SM, Jacobson KA, and Carlsson J (2015) Molecular docking screening using
agonist-bound GPCR structures: Probing the A2A adenosine receptor. J Chem Inf Model, 54:2004-2021.
Rodríguez D, Ranganathan R, and Carlsson J (2014) Strategies for improved modeling of GPCR-drug
complexes: Blind predictions of serotonin receptors bound to ergotamine. J Chem Inf Model, 54:2004–2021.
Rodríguez D, Brea J, Loza MI, and Carlsson J (2014) Structure-based discovery of selective serotonin 5-HT1B
receptor ligands. Structure, 8: 1140–1151.
Chen D, Ranganathan A, Ijzerman AP, Siegal G, Carlsson J (2013) Complementarity between in silico and
biophysical screening approaches in fragment-based lead discovery against the A2A adenosine receptor. J Chem
Inf Model 53(10):2701-14.
Carlsson J, Coleman RG, SetolaV, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, and Shoichet, BK (2011)
Ligand discovery from a Dopamine D3 receptor homology model and crystal Structure. Nat Chem Biol
7:769-778.
Carlsson J, Yoo L, Gao GZ, Irwin JI, Shoichet BK, and Jacobson KA (2010) Structure-based discovery of A2A
adenosine receptor ligands. J Med Chem 53:3748-3755.
- 53 -
BookRICT.indd 53 3/06/2015 09:45:52

John
CHRISTOPHER
Heptares, United Kingdom
D
r John Christopher is an Associate Director at
Heptares Therapeutics, a clinical-stage biotech
focussed on G protein-coupled receptors. He is
currently leading projects in the hit-to-lead and lead
optimization phases, targeting GPCRs located within
the CNS.
J
ohn has fifteen years experience in the
pharmaceutical and biotech industry, having
started his career at GSK, Stevenage, in 2000. At
GSK he gained valuable experience in the application
of fragment-based and structure-based drug discovery
techniques to multiple target classes and therapeutic
areas, before moving to Heptares in 2010.
J
ohn was awarded his PhD in synthetic chemistry
(supervised by Prof. Philip J. Kocienski FRS)
from The University of Glasgow in 2000.
- 54 -
BookRICT.indd 54 3/06/2015 09:45:53

L18
FRAGMENT AND STRUCTURE-BASED DRUG DISCOVERY FOR A

FAMILY C GPCR: DISCOVERY OF THE mGlu5 NAM PRE-CLINICAL
CANDIDATE HTL14242
John Christopher, Sarah Aves, Kirstie Bennett, Andrew Doré, Jayesh Patel, Benjamin Tehan, Miles
Congreve, Fiona Marshall
Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom
The instability of G protein-coupled receptors (GPCRs) when removed from their membrane environment has
significantly hampered the application of structure-based and fragment-based drug discovery techniques to this
highly important target class. The approach taken at Heptares centres on a unique ability to thermostabilize
GPCRs through mutagenesis, creating stabilised receptors (StaR® proteins). The approach biases the receptors
into biologically-relevant conformations and allows purification of stable, correctly-folded protein, facilitating
techniques that cannot be readily used with wild-type GPCRs, including fragment screening and X-ray
crystallography.
In the first application of our approach to a family C target, an mGlu5 StaR has been created, using a negative
allosteric modulator (NAM) ligand to introduce a conformational bias towards the desired pharmacology for
subsequent drug discovery. Enhanced stability of the mGlu5 StaR, coupled with increased expression and high
DMSO tolerance, allowed us to conduct a robust fragment screen. The screen, in high-concentration radioligand
binding format, yielded high-quality hits from a family C focused set and the general Heptares fragment
collection.
The most favourable hit series was rapidly advanced in a medicinal chemistry campaign using SBDD, to yield
the mGlu5 NAM pre-clinical candidate HTL14242. Aspects of the medicinal chemistry SAR campaign, X-ray
crystallography data of NAMs, including HTL14242, bound to the mGlu5 StaR, and data associated with
HTL14242 will be presented. HTL14242 exhibits high affinity and also potency determined by ex vivo receptor
occupancy, and demonstrates a favourable in vivo PK profile in both rat and dog. Excellent selectivity within the
mGlu receptor sub-family is matched by a clean profile against an extensive panel of targets. Overall the data to
date supports progression of HTL14242 into clinical trials and its potential to treat a range of CNS disorders,
including refractory depression.
- 55 -
BookRICT.indd 55 3/06/2015 09:45:53

Michael
SOFIA
Tekmira/OnCore Biopharma, United States
M
ichael J. Sofia, Ph.D. is currently CSO of
Tekmira/OnCore Inc. a company focused on
the discovery and development of therapies
to treat HBV. Previously he was CSO and Co-founder
of OnCore Biopharma which merged with Tekmira in
March 2015. Prior to co-founding OnCore BioPharma,
Inc., Mike most recently was Senior Vice President of
Chemistry, Princeton Site Head and Senior Advisor at
Gilead Sciences. Previously he was Sr. Vice President
of Chemistry at Pharmasset, Inc. He joined Pharmasset
in 2005 and had responsibility for research strategy,
medicinal chemistry, process research, computational
chemistry and analytical chemistry functions and was
a clinical development project leader. He is an inventor
of Sovaldi (sofosbuvir), a treatment of hepatitis C
infection currently approved and marketed by Gilead
Sciences, Inc. Prior to Pharmasset, he held positions of
Group Director, New Leads Chemistry at Bristol-Myers
Squibb, Vice President of Research at Intercardia
Research Labs (formerly Transcell Technologies) and
was Research Investigator and Project Leader at Lilly
Research Labs, Eli Lilly & Co.
H
e did his postdoctoral training in synthetic
organic chemistry, as an NIH fellow, at Columbia
University and earned his Ph.D. in organic
chemistry from the University of Illinois, Urbana-
Champaign. He received his B.A. degree in chemistry
from Cornell University.
H
e has authored 100 publications, 9 book chapters
and numerous abstracts and is an inventor on
over 30 patents. He also holds a professorship
position at the Baruch S. Blumberg Institute and is on
the editorial board of several scientific journals.
M
ike is the recipient of the PA BIO 2014
Scientific Achievement Award for the discovery
of Sofosbuvir.
- 56 -
BookRICT.indd 56 3/06/2015 09:45:54

L19
SOFOSBUVIR: A CURE FOR HCV

Michael Sofia
Tekmira/OnCore Biopharma, Inc.

3805 Old Easton Rd
Doylestown, PA 18902 USA
Approximately 180 million individuals worldwide are infected with the hepatitis C virus. This virus will
ultimately lead to chronic liver disease, liver cirrhosis and eventually hepatocellular carcinoma. Until recently
treatment of HCV required interferon (IFN)-based regimens that delivered modest cure rates coupled with
significant undesired side effects. The search for IFN-free regimens that are pan-genotypic, that demonstrate
minimal side effects and require shorter duration of therapy led to the discovery of sofosbuvir. Sofosbuvir is a
nucleotide prodrug that targets the HCV RNA dependent RNA polymerase (RdRp), an essential enzyme
necessary for viral replication. Sofosbuvir has become the backbone agent in combination regimens for HCV
curative therapies that have been shown to treat a broad HCV patient population. In a broad patient population,
sofosbuvir based regimens have demonstated cure rates in excess of 95% with no observed resistance and a
stellar safety profile. Sofosbuvir was approved by the US FDA in December 2013 and the EU in January 2014,
and since then its use has contributed to the cure of many patients suffering from HCV. This presentation will
discuss the discovery and development of sofosbuvir as a treatment for HCV.
- 57 -
BookRICT.indd 57 3/06/2015 09:45:54

John
WAI
Wuxi Apptec, China
J
ohn Wai obtained his BSc in chemistry from
the University of Hong Kong and his PhD from
the University of British Columbia, Canada
with late Professor Edward Piers. After finishing
his post-doctoral training with Professor K. Barry
Sharpless, John joined Merck Research Laboratories,
Department of Medicinal Chemistry (West Point, PA)
in 1989. At Merck, he contributed to the discovery
efforts of a number of programs, from target validation
& lead identification to lead optimization & early
development. This includes HIV-1 non-nucleoside
reverse transcriptase inhibitors, ras-farnesyl protein
transferase inhibitors, fibrinogen receptor antagonists,
HIV integrase strand transfer inhibitors, HIV RNase H
inhibitors, gamma secretase inhibitors, etc. Through
the years, John rose through the ranks and was
promoted to be Director of Medicinal Chemistry
in 2005. In 2007, he received the Distinguished
Scientific Award from the inaugural Merck WP Basic
Research Reward and Recognition Forum for his
work on HIV integrase inhibitors. In 2013, John
received the Heroes of Chemistry Award from the
American Chemical Society for his contribution to the
discovery and development of Isentress, the first HIV
integrase inhibitors approved for treatment of AIDS
(2007). In 2014, he joined WuXi AppTec (Shanghai)
as Vice President of Medicinal Chemistry, and has
recently been appointed as Adjunct Professor of
Fudan University, College of Pharmacy, Department
of Medicinal Chemistry.
- 58 -
BookRICT.indd 58 3/06/2015 09:45:54

L20
DISCOVERY OF HIV INTEGRASE INHIBITORS

John Wai
WuXi Apptec (Shanghai) Co., Ltd

288 Fute Zhong Road, Waigaoqiao, Shanghai 200131, China
Human immunodeficiency virus-type 1 (HIV-1) is the etiological agent of acquired immunodeficiency syndrome
(AIDS). The unique nature of the replicative cycle of HIV-1 provides many potential targets for
chemotherapeutic intervention. One of these targets, the viral enzyme integrase, catalyzes the insertion of
proviral DNA into the genome of host cells. Integration is a multistep process which includes three different
biochemical steps: assembly of the proviral DNA on integrase, endonucleolytic processing of the proviral DNA,
and strand transfer of the proviral DNA to host cell DNA. The complexities of the integration process, the
technical challenges of studying the enzyme itself, and the chemical nature of the lead compound presented
many obstacles for early drug discovery efforts. After many years of effort, the viability of integrase strand
transfer inhibitors as a therapeutic target was validated in vitro and the first clinical proof of concept was
achieved in HIV-1 infected patients with L-870810. Further optimization led to the identification of Raltegravir
(Isentress) and its approval for treatment of HIV-1 infection in 2007. This presentation will describe the role of
integrase in HIV-1 infection, the mechanism of action of integrase inhibitors, and key structural features shared
by inhibitors. Discovery efforts in the identification of next generation of strand transfer inhibitors will also be
discussed.
- 59 -
BookRICT.indd 59 3/06/2015 09:45:54

Raphael
RODRIGUEZ
Institut Curie, France
D
r Rodriguez was born October 27, 1978 and
raised in the south of France by his parents
Jean-Paul and Françoise Rodriguez. After
receiving his undergraduate degree at the University
of Avignon in June 2002, he performed graduate
studies at Marseille and Oxford under the supervision
of M. Santelli and Sir J. E. Baldwin. During his Ph.D.
studies, he completed the total synthesis of several
natural products, providing novel chemical ways to
create complex molecular frameworks. Following
completion of his doctoral studies, he joined the
University of Cambridge in November 2005 as a
Cancer Research UK postdoctoral fellow under
the mentorship of S. Balasubramanian and was
promoted to Senior Research Associate in 2009. His
research encompassed the design and synthesis of
small molecules to study the existence and biological
consequence(s) of G-quadruplex nucleic acids in the
human genome. In 2012, Raphaël joined the CNRS
(ICSN, Gif-sur-Yvette, France) as a group leader and
is now based at the Institut Curie Research Centre
(Paris). Current research interests include chromatin
and cancer stem cell biology.
- 60 -
BookRICT.indd 60 3/06/2015 09:45:55

L21
SMALL MOLECULES, BIG PLAYERS

Raphael Rodriguez
Institut Curie, 26 rue d'Ulm, 75005 Paris

France
Natural products and synthetic small molecules are central players in chemical biology studies. Drug substances
can perturb cellular processes underlying diseases, thereby enabling the discovery of biological targets suitable
for therapeutic intervention. Small molecules have been shown to accurately tune protein and nucleic acids
functions in reversible and dose-dependent manners with valuable temporal resolution. Hence, small molecule
approaches are complementary to RNA interference strategies and offer the additional means of identifying
associated chemical hits for drug development. The efficient synthesis of molecular probes remains a worthy
challenge. The impact of synthetic organic chemistry and supramolecular processes on current cell biology and
human medicine will be illustrated.
- 61 -
BookRICT.indd 61 3/06/2015 09:45:55

Christel
MENET
Galapagos, Belgium
C
hristel Menet received an MPhil. in 1999 and
a Ph.D. in 2002 both in organic chemistry at
the Manchester University, in the UK. During
her Ph.D., she was author of 8 publications. Christel
then started her industrial carrier at EvotecOAI, where
she developed her expertise in parallel synthesis.
Quickly, she joined Faust pharmaceuticals for a
new position in 2004, where she did her initiation to
medicinal chemistry and neurodegerative diseases,
looking for active drugs for mGluRs. Christel Menet
then moved to new challenges at Galapagos. Her
carrier at Galapagos was paved with successes
including the discovery of 7 active small molecules,
which moved to preclinical studies. 3 compounds
were tested in phase I clinical trial with a positive
proof of mechanism in auto-immune diseases. From
these 3, 2 are currently in phase II, GLPG0778 and
GLPG0634. The two compounds already showed
promising results, Psoriasis for GLPG0778 and RA for
GLPG0634. GLPG0634 was the first selective JAK1
inhibitor known in clinical trials in inflammatory and
auto-immune conditions.
C
hristel is today leading a group of 25 researchers
and she is inventor of more than 16 patents.
- 62 -
BookRICT.indd 62 3/06/2015 09:45:55

L22
NOVEL TRIAZOLOPYRIDINE COMPOUNDS AS SELECTIVE JAK1

INHIBITORS: FROM TARGET DISCOVERY TO FILGOTINIB
(GLPG0634)
Christel Menet
Galapagos NV, Generaal de Wittelaan L11 A3, Mechelen 2800, Belgium
Background: Janus kinases (JAKs), a family of kinases with four members (JAK1, JAK2, JAK3 and TYK2)
involved in signal transduction of cytokines, are implicated in the pathogenesis of rheumatoid arthritis (RA).
Small molecule JAK1/2, JAK1/3 and JAK3 inhibitors have demonstrated an improvement of RA symptoms in
several clinical trials and show promise as future oral RA therapy. A selective JAK1 inhibitor may show
advantages over earlier compounds by preserving the anti-inflammatory activity in the absence of e.g. typical
JAK2 side effects such as anemia. Objective: Synthesis and characterization of selective JAK1 inhibitors with
anti-inflammatory activity Initial screening of the BioFocus SoftFocus® kinase library compounds against JAK1
led to identification of one main chemical series showing promising activity and selectivity in a JAK
biochemical assay. This series forms a structurally distinct class of potent orally active JAK inhibitors, based on
the triazolopyridine scaffold. Further development of the compounds by optimization of ADME and
pharmacokinetic properties led to the identification of compounds with excellent in vivo activity in rodent
collagen-induced arthritis models (CIA), comparable to the activity shown by TNFα blocker etanercept
(Enbrel®). In these in vivo studies, a significant reduction in inflammation was observed, as well as bone
protection at low dose. The structure-activity relationship was expanded to identify a lead compound in the
series, GLPG0634. While in biochemical assays GLPG0634 inhibited JAK1 and JAK2 specifically over JAK3
and TYK2, in human whole blood assays GLPG0634 inhibited JAK1 30-fold over JAK2. These data indicate
that GLPG0634 selectively inhibits JAK1- over JAK2-dependent signaling in a cellular environment. This
compound showed good safety with no severe adverse events reported at therapeutically relevant exposures in
Phase I studies, and subsequently entered a Phase II Proof-of-Concept clinical trial in rheumatoid arthritis
patients in July 2011. -Statistically significant improvement already seen in four weeks: 83% of patients showed
improvement in ACR20 score -Unique and clean safety profile: neither anemia nor increase in LDL/cholesterol
observed -First JAK1 selective compound to demonstrate clinical efficacy The results were confirmed by a
4-week multicenter trial, in which Filgotinib was administered in five study arms at a wide range of once-daily
dosages of placebo, 30, 75, 150 or 300 mg. In summary, we identified a series of compounds that showed good
activity in biochemical and cellular assays against the novel drug target JAK1. This series demonstrated
promising ADME/PK properties and several compounds showed activity in in vivo models of RA. The lead
compound, filgotinib (GLPG0634), was positive in a Phase 2 Proof-of-Concept and Phase 2b clinical evaluation
for treatment of rheumatoid arthritis. Discovery and SAR of the series will be presented.
- 63 -
BookRICT.indd 63 3/06/2015 09:45:55

Franz
VON NUSSBAUM Bayer Pharma, Germany
F
ranz von Nussbaum studied Chemistry at
the University of Munich (LMU). He got his
‘Diplomarbeit’ & PhD with Prof. Dr. Wolfgang
Steglich: “Biosynthesis, Synthesis & Structure
Elucidation of Secondary Metabolites from Fungi”
in 1998 and was Postdoc with Prof. Dr. Samuel
Danishefsky at Columbia University, New York (1999–
2000, “Total Synthesis of Spirotryrostatin B”) with a
Feodor-Lynen Fellowship (Alexander-von-Humboldt
Stipend).
H
e worked in Medicinal Chemistry at Bayer, from
2000 until 2009:
• Central Research, Leverkusen, Natural Product

Chemistry, Lead Generation, Pharma & Crop
Protection
• Pharma Business Unit, Wuppertal, from 2002 on
• Chemistry coordinator in antibacterial research
• Project leader in cardiovascular research
• “Innovation Price for Medicinal Chemistry/
Pharmaceutical Chemistry” of the German
Chemical Society / German Pharmaceutical
Society GdCh / DPhG, 2008
F
ranz worked as Executive Board Support at
Bayer-Schering Pharma, Berlin, 2009-2010.
F
ranz von Nussbaum is currently Director in
Medicinal Chemistry at Bayer HealthCare, Berlin
since 2011. (Exploratory Research in Oncology)
- 64 -
BookRICT.indd 64 5/06/2015 08:55:55

L23
FREEZE THE BIOACTIVE CONFORMATION! DISCOVERY OF THE

HIGHLY POTENT AND SELECTIVE ELASTASE INHIBITOR BAY
85-8501 FOR THE TREATMENT OF PULMONARY DISEASES
Franz von Nussbaum (1), Volkhart M.-J. Li (2), Swen Allerheiligen (3), Sonja Anlauf (3), Lars Bärfacker
(3), Martin Bechem (4), Martina Delbeck (4), Mary F. Fitzgerald (5), Michael Gerisch (6), Heike
Gielen-Haertwig (3), Helmut Haning (3), Axel Harrenga (3), Dagmar Karthaus, Dieter Lang (1), Klemens
Lustig (1), Daniel Meibom (3), Joachim Mittendorf (3), Ulrich Rosentreter (3), Martina Schäfer (7), Stefan
Schäfer (4), Jens Schamberger (3), Leila A. Telan (3), Adrian Tersteegen (2)
1) Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353 Berlin (Germany)

franz.nussbaum@bayer.com
2) Lead Discovery Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany)
volkhart.li@bayer.com
3) Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany)
(Ulrich Rosentreter is retired)
4) Department of Cardiology Research Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany)
5) COPD Research, Bayer Healthcare AG, Slough SL2 4LY, Berkshire (United Kingdom)
6) DMPK Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany)
7) Lead Discovery, Structural Biology Berlin, Bayer HealthCare AG, 13353 Berlin (Germany)
Human neutrophil elastase (HNE) is a key protease for matrix degradation. In inflammatory diseases, high HNE
activity is observed. HNE has been discussed as a target in various pulmonary diseases (COPD, PH, ALI,
ARDS). Accordingly, HNE inhibitors have been proposed as an option to re-establish the protease–antiprotease
balance in these diseases. However, despite various efforts in academia and in industry, so far only very few
SMOL HNEi (small-molecule elastase inhibitors) have reached clinical testing. Overall, the clinical outcome has
been very sparse with only sivelestat reaching the market for the treatment of ALI/ARDS in Japan and South
Korea. Hence, there is still a high medical interest in selective and tolerable elastase inhibitors that are suitable
for clinical testing.
In this situation we have embarked on a program heading for efficient and selective elastase inhibitors. Starting
from a submicromolar inhibitor identified in a high-throughput screen, various chemical core modifications have
led us to dihydropyrimidinones as a novel, lead structure class featuring an induced-fit binding mode. Further
optimization yielded orally active compounds with favorable pharmacokinetics in rodents. While maintaining
exquisite target selectivity, high picomolar potency was achieved. These compounds showed efficacy in vivo in
rodents. Currently, BAY 85‑8501 is being tested in clinical studies for the treatment of pulmonary diseases.
- 65 -
BookRICT.indd 65 3/06/2015 09:45:56

NOTES
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- 66 -
BookRICT.indd 66 15/06/2015 12:06:06

SHORT COMMUNICATIONS:
Abstracts and
Biographies
- 67 -
BookRICT.indd 67 15/06/2015 12:06:06

Isabel
ALVES
University of Bordeaux, France
I
sabel Alves did her undergraduate studies in
Portugal and obtained her PhD in Biochemistry
from the University of Arizona (Tucson, USA) with
Prof. Gordon Tollin and Victor Hruby in 2004. Then
she joined the University Pierre et Marie Curie for
a post-doctoral fellowship with Dr. Sandrine Sagan
where she continued to work with G-protein coupled
receptors (GPCRs). In 2006 she obtained a CNRS
research position (CR1) to work in the mechanisms
of action of membrane active peptides. In 2010 she
moved to the CBMN in Bordeaux. She has since then
developed a plasmon waveguide resonance (PWR)
technique to follow molecular interactions taking
place at lipid membranes. More specifically she has
been investigating, using PWR and other biophysical
approaches, the mechanisms of interaction of
membrane active peptides (cell penetrating, viral,
antimicrobial, amyloides) and the activation and
signaling of GPCRs and role of lipids in these
processes.
- 68 -
BookRICT.indd 68 3/06/2015 09:45:56

SC01
HOW DO A PROAPOPTOTIC AND A CELL PENETRATING PEPTIDE

WORK TOGETHER TO KILL A CANCER CELL?
Isabel Alves (1), Manon Carré (2), Marie-Pierre Montero (2), Diane Braguer (2), Solange Lavielle (3)
1) CBMN UMR 5248 CNRS, U. Bordeaux

2) Inserm CR02 UMR S 911, U. Marseille
3) LBM UMR 7203 CNRS, UPMC
The peptide KLA (acetyl-(KLAKLAK)2-NH2), which is rather non toxic for eukaryotic cell lines, becomes
active when coupled to the cell penetrating peptide, penetratin (Pen), by a disulfide bridge. Remarkably, the
conjugate KLA-Pen is cytotoxic, at low micromolar concentrations, against a panel of seven human tumor cell
lines of various tissue origins, including cells resistant to conventional chemotherapy agents but not to normal
human cell lines. Live microscopy on cells possessing fluorescent labeled mitochondria shows that in tumor
cells, KLA-Pen had a strong impact on mitochondria tubular organization instantly resulting in their aggregation,
while the unconjugated KLA and pen peptides had no effect.
But, mitochondria in various normal cells were not affected by KLA-Pen. The interaction with membrane
models of KLA-Pen, KLA and penetratin were studied using dynamic light scattering, calorimetry, plasmon
resonance, circular dichroism and ATR-FTIR to unveil the mode of action of the conjugate. To understand the
selectivity of the conjugate towards tumor cell lines and its action on mitochondria, lipid model systems
composed of zwitterionic lipids were used as mimics of normal cell membranes and anionic lipids as mimics of
tumor cell and mitochondria membrane. A very distinct mode of interaction with the two model systems was
observed. KLA-Pen may exert its deleterious and selective action on cancer cells by the formation of pores with
an oblique membrane orientation and establishment of important hydrophobic interactions. These results suggest
that KLA-Pen could be a lead compound for the design of cancer therapeutics.
References
1) Alves ID, Carré M, Montero M-P, Castano S, Lecomte S, Marquant R, Lecorché P, Burlina F, Schatz C, Sagan S,
Chassaing G, Braguer D, Lavielle S. (2014) A proapoptotic peptide conjugated to penetratin selectively inhibits tumor cell.
Biochim. Biophys. Acta 1838, 2087-98.
- 69 -
BookRICT.indd 69 3/06/2015 09:45:57

Lenka
MUNOZ
University of Sydney, Australia
L
enka Munoz received PharmD (Doctor of
Pharmacy) in 2001 from the Comenius University,
Slovakia and PhD in Medicinal Chemistry in 2005
from the University of Bonn, Germany. Her post-
doctoral fellowship at the Northwestern University,
USA (2006-2007) was in molecular pharmacology
and preclinical drug development. Currently, Lenka
is a Senior Lecturer in Pharmacology and Head of
the Molecular Innovations in Kinase Therapeutics
laboratory at The University of Sydney, Australia.
She has built her program of research around the
key themes of medicinal chemistry with a focus on
understanding the molecular mechanism of action
of kinase inhibitors. In particular, her laboratory has
developed novel inhibitors and published on research
that focuses on p38 MAPK-MK2, LRRK2 and DYRK1A
signalling in neurodegeneration and neuro-oncology.
- 70 -
BookRICT.indd 70 3/06/2015 09:45:57

SC02
ALLOSTERIC INHIBITORS OF p38 MAPK-MK2 PATHWAY FOR

SELECTIVE CANCER CELL KILLING
Lenka Munoz
Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2006, Australia
Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) is a checkpoint kinase regulating
DNA damage response (DDR), a mechanism that is crucial for survival of cancer cells. Defects in the DDR can
be exploited therapeutically in the treatment of cancer, and kinases of the DDR machinery, including MK2, have
been identified as promising avenues for targeted cancer therapeutics. Majority of reported MK2 inhibitors bind
into the ATP pocket of the targeted kinase. Because MK2 has high affinity for ATP, the efficacy of
ATP-competitive MK2 inhibitors is compromised by intracellular ATP concentration. This results in low
biochemical efficiency index and compounds that do not possess drug-like properties.
We have addressed this issue by developing a library of non-ATP competitive MK2 inhibitors. Our compounds
inhibit the phosphorylation of MK2 by binding to the allosteric pocket of p38 MAPK, an upstream
MK2-activating kinase. This mechanism, known as prevention of activation, has the advantage of low
competition with ATP and better biochemical efficiency index. In cell-based assays, we aimed to determine the
effect of MK2 inhibition on checkpoint signalling and survival of glioblastoma cells. Our novel MK2 inhibitors
exhibited potent anti-proliferative efficacy in glioblastoma cell lines and primary gliomaspheres, without
affecting the viability of non-malignant healthy cells. Intriguingly, we discovered an unexpected non-kinase
target for this class of compounds that is underlying their anti-proliferative activity. I will present data revealing
the chemistry development and biological mechanism of action of these new tumour-selective compounds. I will
also discuss how in-depth biological understanding of a molecular target is necessary in the early stages of the
drug discovery and how mechanism of action can determine later success or failure of the emerging drug
candidates.
- 71 -
BookRICT.indd 71 3/06/2015 09:45:57

Christophe
ROCHAIS
CERMN University of Caen, France
C
hristophe Rochais received his PhD with the
group of Professor S. Rault from the University
of Caen Basse-Normandie (2005). After
completing a postdoctoral fellowship at the Centre for
Biomolecular Sciences of the University of Nottingham
(2007), under the supervision of Professor Peter
M. Fischer, he was appointed lecturer in Organic
Chemistry in the School of Pharmacy at the University
of Caen in 2007. Since January 2014, he has assumed
the position of professor in Organic Chemistry.
H
is research interests include medicinal
chemistry in the field of enzymatic inhibition, as
well as receptor modulation, in order to develop
pharmacological tools and bioactive compounds.
Since 2012 he has been leading a research program
dedicated to the development of pleiotropic agents
of interest in the treatment of Alzheimer’s disease
(PLEIAD).
- 72 -
BookRICT.indd 72 3/06/2015 09:45:57

SC03
DEVELOPMENT OF NOVEL MULTI-TARGET DIRECTED LIGANDS

FOR ALZHEIMER'S DISEASE: IDENTIFICATION OF
DONECOPRIDE
Christophe Rochais
Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN) - UPRES EA 4258 - FR CNRS INC3M -
SFICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques - Bd Becquerel
F-14032 Caen, France
Targeting more than one molecular cause implied in the pathogenesis of Alzheimer’s disease (AD) with a sole
drug is considered a promising challenge, because it may address the numerous failures that recently occurred
during clinical trials that were conducted in this area. A new strategy is now emerging on the basis of the
assumption that a single compound may be able to hit multiple targets, more particularly for the treatment of
diseases like neurodegenerative syndromes, which involve multiple pathogenic factors. This concept known as
“Multi-Target-Directed Ligands” (MTDLs) can be used with a great potential benefit towards multiple targets
implicated in the complex AD.1
We will present in this communication some of these recent examples and our own contribution to this field.
Among the different candidate that we have identified we will more particularly discuss the case of Donecopride.
2 This original compound associates acetylcholinesterase inhibition and 5-HT4R activation.
Starting from an in silico high throughput screening and a rational drug design strategy we have identified that
RS67,333, a reference 5-HT4R partial agonist, possesses moderate AChE inhibition properties.
Pharmacomodulation of this hit and rapid evaluation of in vitro biological activities against both targets as well
as drugability led to the identification of a novel family of pleiotropic ligands. These efforts allowed us to select
donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM)/(h)AChEI (IC50 = 16 nM) that further
promotes sAPPα release (EC50 = 11.3nM). Donecopride could improve memory performances at 0.3 and 1
mg/kg on the object recognition test.3 In vivo results obtained in the 5XFAD mouse model of AD will be
presented.
This presentation will also focus on other examples of MTDL recently identified according to this strategy.
References
1) Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J. Med. Chem.; 2008,
51 (3), 347–372.
2) Lecoutey, C.; Hedou, D.; Freret, T.; Giannoni, P.; Gaven, F.; Since, M.; Bouet, V.; Ballandonne, C.; Corvaisier, S.;
Malzert-Fréon, A.. Mignani, S.; Cresteil, T.; Boulouard, M.; Claeysen, S.; Rochais, C.; Dallemagne, P. Proc. Natl.Acad. Sci.
USA, 2014, 111(36), E3825–E3830.
3) Rochais, C.; Lecoutey, C.; Gaven, F.; Giannoni, P.; Hamidouche, K.; Hedou, D.; Dubost, E.; Genest, G.; Yahiaoui, S.;
Freret, T.; Bouet, V.; Dauphin, F.; Sopkova de Oliveira Santos, J.; Ballandonne, C.; Corvaisier, S.; Malzert-Fréon, A.; Legay,
R.; Boulouard, M.; Claeysen, S.; Dallemagne, P. J. Med. Chem., 2015, 58 (7), 3172–3187.
- 73 -
BookRICT.indd 73 3/06/2015 09:45:57

Frederic
BIHEL
CNRS University of Strasbourg, France
F
rédéric Bihel is currently senior researcher at the
French National Center for Scientific Research
(CNRS), within the Laboratoire d’Innovation
Thérapeutique (UMR7200) at the University of
Strasbourg. His research interests are mainly focused
on developing chemical tools targeting GPCRs.
Prior to join the CNRS in 2005, he got a Ph.D. in
organic chemistry (2002) from the University of the
Mediterranean (J-L Kraus’ lab, Marseille, France) for
his works on the development of isocoumarines as
gamma-secretase inhibitors in the Alzheimer’s disease
field. In 2003, he moved to the Harvard Medical School
and BWH (Boston, MA, USA) in Michael Wolfe’s
lab where he designed helical peptides allowing the
identification of an initial substrate-binding site of the
gamma-secretase, distinct of the active site. Since
2007, a part of his research program is devoted to
the development of heterocyclic or peptidic ligands
of a GPCR subfamily called the RF-amide receptors
(NPFF1 & 2, GPR10, GPR54 and GPR103), and their
potential use in pain modulation.
- 74 -
BookRICT.indd 74 3/06/2015 09:45:58

SC04
NOVEL ORALLY-ACTIVE NPFF RECEPTOR ANTAGONISTS

PREVENTING OPIOID-INDUCED HYPERALGESIA
Frédéric Bihel
Laboratoire d’Innovation Thérapeutique, UMR7200, CNRS, University of Strasbourg

Faculty of pharmacy, 74, route du Rhin, 67401 Illkirch (France)
http://www.medchem.unistra.fr
The development of drugs that can more effectively and safely treat both acute and chronic pain (resulting from
post-operative surgery, cancer, neuropathies, etc) remains a major unmet challenge in pharmaceutical industry.
Opiate analgesics, such as morphine or fentanyl, continue to be the cornerstone medication for treating moderate
to severe pain, but their use upon chronic administration suffers from important side-effects such as
opioid-induced tolerance, addiction and hyperalgesia. Several anti-opioid systems have been reported as valuable
targets for blocking opioid-induced hyperalgesia (OIH). Among them, the NPFF-receptors belonging to the
GPCR family were recently identified as one of the keystone of the opioid-induced hyperalgesia. In a first
approach, we developed the first NPFF-receptor antagonist (RF9), and its co-administration with opioid
analgesics (fentanyl) led to block the delayed and long lasting paradoxical opioid induced-hyperalgesia and
prevent the development of associated tolerance.1,2 However the dipeptide nature of RF9 limited its application
to subcutaneous or intravenous administration.Based on an extensive SAR study, we were able to develop a
peptidomimetic of RF9 containing only one unnatural amino-acid.3,4 The development of this novel basic amino
acid was obtained by using a specific metal-catalyzed reaction applied for the first time to amino acids. Using
mild conditions, a selective ruthenium-catalyzed reduction of tertiary amides was optimized to afford in very
high yields novel families of chiral α, β or γ amino acids exhibiting a large diversity of basic side chains.
Obtained at a gram-scale with a Fmoc protection at the N-terminus, these unnatural amino acids are directly
suitable for peptide synthesis in liquid or solid phase in order to develop new unnatural peptides.5,6 When
applied to the development of new ligands of NPFF receptors, we were able to design and synthesize RF313 as
the first orally-active NPFF receptor antagonist able to reverse opioid-induced hyperalgesia in several pain
models (post-operative pain, neuropathic pain, inflammatory pain). Active at low dose (1 mg/kg p.o. in rat),
RF313 is also able to extend the duration of the analgesic effect induced by the opiates.7
References
1) Simonin F. et al. RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance
associated with hyperalgesia. P Natl Acad Sci USA 2006, 103, 466-471
2) Elhabazi K. et al. Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate
treatments. Brit J Pharmacol 2012, 165, 424-435.
3) Gealageas R. et al., Development of sub-nanomolar dipeptidic ligands of neuropeptide FF receptors. Bioorg Med Chem
Lett 2012, 22, 7471-7474
4) Bihel F et al, Development of a Peptidomimetic Antagonist of Neuropeptide FF Receptors for the Prevention of
Opioid-Induced Hyperalgesia. Acs Chem Neurosci 2015, 6 (3), 438-45.
5) Bihel F. et al. Novel non-natural amino acids, their process of preparation and uses thereof (2014) EP14306411
6) Schneider S. et al. submitted manuscript (2015)
7) Elhabazi K. et al. submitted manuscript (2015)
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- 76 -
BookRICT.indd 76 15/06/2015 12:07:10

POSTERS:
Integrative Approaches
- 77 -
BookRICT.indd 77 15/06/2015 12:07:10

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BookRICT.indd 78 3/06/2015 09:45:58

IA001
NEW POLYAMINOQUINOLINE IRON CHELATOR FOR

ANTINEOPLASIC AGENT VECTORIZATION
David deniaud (1), Vincent Corcé (2), Sébastien Gouin (1), Renaud Stéphanie (3), Cannie Isabelle (3),
François Gaboriau (3)
1) LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des
Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France
2) Université Pierre et Marie Curie - Institut Parisien de Chimie Moléculaire (UMR 8232) - 4, place Jussieu, 75252 Paris
cedex 05
3) INSERM, UMR991, CHRU Pontchaillou, 35033 Rennes, France; Université de Rennes1, 35043 Rennes, France
Objective: Quilamines are hybrid molecules associating one hydroxyquinoline iron chelators moiety with a
polyamine backbone. These Quilamines were designed to target (polyamine) and inhibit (chelator) the tumor
cells growth in which the polyamine transport system (PTS) is overactivated. We previously demonstrated in
vitro, that the Quilamine HQ1-44 showed the highest selectivity for the PTS and consequently the highest
antiproliferative efficiency, especially in the human colon adenocarcinoma cell line (HCT116).1-3 The objective
of this study is to demonstrate the involvement of the PTS in the HQ1-44 activity, both in vitro and in vivo.
Methods: The antiproliferative efficiency of HQ1-44, including its effect on DNA synthesis and cell cycle,
cytotoxicity and ability to modulate both iron and polyamine metabolisms, were analyzed in vitro in HCT116
cells.
HCT116 cells, were sub-cutaneously xenografted in Swiss nude mice which were treated with 40 mg.kg-1
HQ1-44 by daily intraperitoneal injection for two weeks. Systemic polyamine depletion (which is known to
activate the PTS) was induced by a polyamine deficient chow and/or treatment by the polyamine biosynthesis
inhibitor, a–difluoromethylornithine (3% in drinking water).
Results: In vitro, the antiproliferative efficiency of HQ1-44 in HCT116 is modulated by the PTS efficiency and
associated to inhibiting effects on DNA synthesis and cell cycle arrest. The cytostatic effect of HQ1-44 results
from its dual inhibiting action on both iron and polyamine metabolisms, involved in tumor proliferation. In vivo,
the antitumor activity of HQ1-44, which is not associated to side effects, is also modulated by the PTS
efficiency.
Conclusion: The antitumor activity of the polyaminoquinoline HQ1-44, associated with its antiproliferative
effect and its absence of toxicity is tightly connected to the PTS efficiency in tumors. Co-treatment with HQ1-44
and polyamine deprivation therapy (pharmacological and nutritional) could be promising as adjuvant treatment
in cancer therapies due to the PTS selectivity of Quilamine HQ1-44 in tumor cells.
References
1) ) Corcé V.; Morin E.; Guihéneuf S.; Renault E.; Renaud S.; Cannie I.; Tripier R.; Lima L.; Julienne K.; Gouin G.; Loréal
O.; Deniaud, D.; Gaboriau F. Bioconjugate. Chem., 2012, 1952-1968 "Polyaminoquinoline Iron Chelators for Vectorization
of Antiproliferative Agents: Design, Synthesis and Validation"
2) Gaboriau F., Deniaud D.; Corce V.; Julienne Aphecetche K.; Renault E. Brevet PCT Int. Appl. 2013, WO 2013092556 A1
20130627 “Preparation of polyaminoquinoline metal chelators for vectorization of antiproliferative agents“
3) Corcé V.; Renaud S.; Cannie I.; Julienne K.; Gouin G.; Loréal O.; Gaboriau F.; Deniaud, D. Bioconjugate. Chem., 2014,
320-334 “Synthesis and Biological Properties of Quilamines II, New Iron Chelators with Antiproliferative Activities
- 79 -
IA002
NEW APPROACH TO THE DISCOVERY OF NOVEL

ANTIMICROBIALS
Johannes Zuegg, Mark A. Blaskovich, Alysha G. Elliott, Matthew A Cooper
Community for Open Antimicrobial Drug Discovery, Division of Chemistry and Structural Biology, Institute for Molecular
Bioscience, University of Queensland, St Lucia, QLD 4072, Australia, j.zuegg@uq.edu.au
The antibiotic pipeline is broken, with a dearth of new antibiotics, a collapse in pharmaceutical company
research1, and the exhaustion of chemical diversity contained in pharma libraries. “The low hanging fruit from
the antibiotic tree has probably already been picked and new sources of compounds are needed.”2 We believe
that there is an untapped resource contained in the laboratories of synthetic organic chemists; synthetic
compounds prepared for other projects that have never been tested for their antimicrobial potential. These
compounds, which are sitting at the back of benches and freezers, may have been synthesised to validate new
synthetic routes, develop new methodologies, or create unusual structures. A global screening initiative will
uncover this significant and rich chemical diversity held outside of corporate screening collections by providing
a low-barrier access to testing.
Antibacterial drugs occupy a unique property space that is different to drugs developed for other therapeutic
areas, suggesting that libraries from commercially sources3 lack the physicochemical properties ideal for activity
against bacteria. A comprehensive study on the antimicrobial space illustrates the current status of our
knowledge and the short-comings of the data. There is a requirement to extend the source of chemical diversity
in the investigatation of antimicrobial activity.
We have created a Wellcome Trust-supported not-for-profit Open-Access pipeline, the Community for Open
Antimicrobial Drug Discovery (CO-ADD; co-add.org), to provide free antimicrobial screening for any
interested researcher. CO-ADD builds upon a suite of established in vitro and in vivo assays, medicinal
chemistry and core researcher expertise, aiming to unearth new chemical diversity for the treatment of bacterial
infection.
In this presentation we will discuss the properties of antimicrobial-like compounds by using chemoinformatic
analysis of the current data. We will also present how the organic/medicinal chemistry community can contribute
in solving an imminent threat to public health, and add chemical diversity to the pool of potential antimicrobials.
References
1) Cooper M.A. and Shlaes D.A.Fix the antibiotics pipeline. Nature, 2011, 472, 32.
2) Payne, D.J, Dwynn, M.N, Holmes, D.J and Pompliano, D.L. Drugs for bad bugs: confronting the challenges of
antimicrobial discovery. Nat Rev Drug Discov. 2007, 6, 29-40.
3) Zuegg, J.; Cooper, M. A. Drug-likeness and increased hydrophobicity of commercially available compound libraries for
drug screening. Curr. Top. Med. Chem. 2012, 12, 1500-13.
4) O'Shea, R.; Moser, H. E. Physicochemical properties of antibacterial compounds. J. Med. Chem. 2008, 51, 2871-8.
- 80 -
IA003
COLON CANCER CHEMOTHERAPY: DESIGN AND MULTI-STEP

SYNTHESIS OF VECTORIZED CHALCONES BY POLYAMINE TAILS
Benjamin Rioux (1), Christelle Pouget, Josiane Semaan, Aurélie Gamond, Aurélie Laurent, Aline Pinon,
Alain Simon, Bertrand Liagre, Jean-Luc Duroux, Catherine Fagnère, Vincent Sol
1) EA 1069 Laboratoire de Chimie des Substances Naturelles, University of Limoges, Faculty of Pharmacy, 2 rue du Dr
Marcland 87025 Limoges cedex, France
2) E-mail: benjamin.rioux@etu.unilim.fr
Many natural compounds are found to possess anticancer properties but are dropped due to their lack of
selectivity against cancer cells or their low bioavailability. So, a great interest is currently focused to the
development of drugs specifically vectorized to cancer cells. A hopeful compound is arguably the
spermine-podophyllotoxin conjugate F14512, which has provided a major antitumor activity.1 Natural
polyamines, such as spermine or spermidine, are key regulators of cell growth and differentiation. Besides,
tumor tissues have been found to up-regulate polyamine transport system (PTS) for the uptake of exogenous
polyamines. Therefore, the targeting of tumor cells with polyamine-containing drugs has been considered as a
valuable approach. The polyamine tail contributes to target the PTS in cancer cells, enhance the water solubility
of the drugs and in some cases, make these molecules DNA-interacting agents.2, 3
Besides, flavonoids, which constitute a wide family of natural phenolic compounds, are known for their many
biological effects like antioxidant, anti-inflammatory and anti-proliferative activities.4, 5 Our own interest in both
flavonoids, especially chalcones, and anticancer agents led us to design new potent antiproliferative compounds
by combining a spermine or a spermidine moiety with various chalcone cores. These are selected for their
activity against the proliferation of colon cancer cell lines through a structure-activity relationship study that we
performed.
The synthesis and biological evaluation of the different chalcones and of their polyamine counterparts will be
reported.
Figure 1. general synthetic scheme of chalcone polyamine compounds
References
1) J.M. Barret, A. Kruczynski, S. Vispé, J.P. Annereau, V. Brel, Y. Guminski, J.G. Delcros, A. Lansiaux, N. Guilbaud, T.
Imbert, and C. Bailly, Cancer Research, 2008, 68 (23), 9845
2) Y. Wang, X. Zhang, J. Zhao, S. Xie, and C. Wang, Journal of Medicinal Chemistry, 2012, 55, 3502
3) V.Corcé, E. Morin, S. Guihéneuf, E. Renault, S. Renaud, I. Cannie, R. Tripier, L.M.P. Lima, K. Julienne, S.G. Gouin, O.
Loréal, D. Deniaud, and F. Gaboriau, Bioconjugate Chemistry, 2012, 23, 1952
4) L. Le Marchand, Biomedicine Pharmacotherapy, 2002, 56, 296
5) S. Ducki, D. Rennison, M. Woo, A. Kendall, J. Fournier Dit Chabert, A.T. McGown, and N.J. Lawrence, Bioorganic
Medicinal Chemistry, 2009, 17, 7698
- 81 -
IA004
IMIDAZOPYRIDINE-FUSED [1,3]-DIAZEPINONES : SYNTHESIS AND

ANTIPROLIFERATIVE ACTIVITY
Audrey GALLUD, Ophélie VAILLAND, Dominique ARAMA, Ludovic MAILLARD, Vincent
LISOWSKI, Jean MARTINEZ, Marcel GARCIA, Nicolas MASURIER
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Institut des Biomolécules Max Mousseron (IBMM UMR 5247
CNRS), Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093
Montpellier Cedex 5, France
Azepine core is considered as a privileged structure to access active compounds displaying a wide range of
pharmacological activities. In particular, polyfused azepine derivatives, like pyrrolobenzodiazepines,
indolobenzazepinones, Hymenialdisine or Paullone derivatives showed promising antiproliferative activity,
associated with various mechanisms of action[1] (Figure 1).
Recently, we reported an efficient approach to access polyfused diazepinone derivatives, based on the
imidazo[1,2-a]pyridine (IP) nucleus, an aza analog of indole [2-3]. In continuation to this study and since some
polyfused IP derivatives have been described to possess antitumor activities [4], we decided to evaluate the
antiproliferative potency of IP-fused diazepinones. The synthesis of pyrido-imidazo[1,3]diazepinones derivatives
and preliminary biological results will be presented in this communication
References
1) Gallud, A.; Vailland, O.; Maillard, L.T.; Arama P. D.; Dubois, J.; Maynadier, M.; Lisowski, V.; Garcia, M.; Martinez, J.;
Masurier, N. Eur. J. Med. Chem., 2014, 75, 382-390
2) Masurier, N.; Aruta, R.; Gaumet, V.; Denoyelle, S.; Moreau, E.; Lisowski, V.; Martinez, J.; Maillard, L.T. J. Org. Chem.,
2012, 77, 3679-3685
3) Arama, D. P.; Lisowski, V.; Scarlata, E.; Fulcrand, P.; Maillard, L.T.; Martinez, J.; Masurier N. Tetrahedron Lett.., 2013,
54, 1364-1367
4) Andaloussi, M.; Moreau, E.; Masurier, N.; Lacroix, J.; Gaudreault, R.C.; Chezal, J.M.; El Laghdach, A.; Canitrot, D.;
Debiton, E.; Teulade, J.C.; Chavignon O. Eur. J. Med. Chem., 2008, 43, 2505-2517
- 82 -
IA005
SYNTHESIS AND COMPLEXATION OF BIS-PHOSPHONIC ACID

DOTA LIKE CHELATOR AND ITS NMR RELAXATION PROPERTIES
Satya Chilla (1), Jan Kotek (3), Ondrej Zemek (3), Ivan Lukes (3), Luce Vander Elst (1), Robert N. Muller
(2), Sophie Laurent (1,2)
1) Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of
Mons, Mendeleev Building, 19 Avenue Maistriau, B-7000 Mons, Belgium
2) Centre for Microscopy and Molecular Imaging (CMMI), AcadémieWallonie - Bruxelles, Charleroi-Gosselies, Belgium.
3) Department of Inorganic Chemistry, Charles University, Prague-2, Czech republic
Magnetic resonance imaging (MRI) has emerged into an effective tool in biomedical researches for
understanding biological processes in living organisms. MRI has great consideration in clinical diagnosis since it
has an excellent spatial resolution, non-invasiveness and has limitless tissue penetration. The resolution and
tissue specificity can be further enhanced by lanthanide complexes due to their exceptional magnetic and optical
properties.1The technological advances in MRI demands in parallel to increased the demand for contrast agents
(CA) that play role effectively at various field strengths and comprises optical properties from selected probes
can be used to provide detailed information at sub-cellular levels. The advantage of multimodality combination
is that a single multimodal probe could be sufficient to address similar pharmacokinetics and co-localization of
signal in each modality, which allows to avoid injecting multiple doses of agents. It is a very difficult task to
address all functionalities on a single molecule since the sensitivity of the each modality is different by several
orders of magnitude.
Figure: Schematic diagram of Gd-DOAGA2P-Methyl quinoline

In this communication we report the synthesis of bis-phosphoric acid derivative of macrocycle DOTA and its
complexation. The goal was to enhance the overall exchange rate of the bound water molecules. In addition to
that, a molecular antenna to serve as a light-harvesting moiety was introduced on cyclen nitrogen. We envisage
that through the antenna, intramolecular energy transfer can be conveyed. The gadolinium complex of
DOAGA2P-methyl quinoline was found to be only partially water-soluble and therefore unsuitable for in vivo
applications. Thus, the second ligand DOA2P-methyl quinoline and DOAGA2P ligandswere synthesized to
overcome the solubility issues of DOAGA2P-methyl quinoline in water.2 The synthesis of DOAGA2P was
similar to that of DOAGA2P-methyl quinoline. The Gd-complex of DOAGA2P was also found to be partially
water-soluble. Consequently the fused aromatic ring is the probable responsible for the insolubility of complex
in aqueous media. Different type of antenna analogues are under consideration to investigate for better solubility
of the dual model contrast agent.
References
1) a) S. Laurent, L. Vander Elst, R.N. Muller, Contrast Agents for MRI: Recent Advances, in “Encyclopaedia of Magnetic
Resonance”, eds R. K. Harris and R. Wasylishen, John Wiley: Chichester. DOI: 10.1002/9780470034590.emrstm1049.
Published 15th Mars 2009. b) P. Herman, J. Kotek, V. Kubicek, Ivan Lukes, Gadolinium(III) complexes as MRI contrast
agent: ligand design and properties of the complexes, Dalton. Trans. 3027 – 3047 (2008). c)C.F.G.C. Geraldes, S. Laurent,
Classification and basic properties of contrast agents for magnetic resonance Imaging, Contrast Media & Molecular Imaging,
4(1), 1-23 (2009)
2) a)J.M. M. Griffin, A. M. Skwierawska, J. N. Marx, H. C. Mannig, D. J. Bornhop Tetrahedron let., 2001, 42, 3823-3825. b)
P. Lebduskova, P. Hermann, L. Helm, E. Toth, J. Kotek, K. Binnemans, J. Rudovsky, I. Lukes, A. E. Merbach Dalton Trans.,
2007, 493-501
- 83 -
IA006
ASSESSMENT OF BIOACTIVE COMPONENTS FROM CAESALPINIA

PARAGUARIENSIS AS ROS SCAVENGERS AND COLLAGENASE
INHIBITORS IN HUMAN SKIN FIBROBLASTS
Melina Araceli Sgariglia, José Rodolfo Soberón, Diego Alejandro Sampietro, Marta Amelia Vattuone
National Scientific and Technical Research Council - Argentina

National University of Tucumán - Argentina
Address: Monteagudo street, Nº 220, 1st floor (4000) San Miguel de Tucumán, Tucumán-Argentina
E-mail. melinasgariglia@gmail.com; Tel: +54 381 156453387
Our research group works on bio-guided isolation of molecules from plant sources. On the one hand, the
detection and identification of bioactive compounds allows us to validate native plant species used traditionally
as medicine, while that a collection of bioactive molecules and chemically different may be obtained. Usually, to
select bioactive compounds were used enzyme activity assays, as the MMPs. These enzymes, which are very
important in the degradation and remodeling process of tissues, were synthesized and secreted by a variety of
cell types, and actually it is now known that tissues affected by various diseases, including cancer, overexpress
different enzymatic isotypes, so they are interesting targets. But, the problem encountered with this approach
was that some compounds which were bioactives under in vitro conditions, showed no such activity in cell
culture tests. This could be due to the different capacities to cross biological membranes, therefore, and we
needed a parameter which allows us to select compounds that may be able to exert effects on biological systems.
For this, we selected ellagic derivatives (EAD; analog compounds), isolated from Caesalpinia paraguariensis
bark1, and previously identified as antioxidant compounds, to be assayed on cell culture and to determine their
intracellular ROS scavenging activity assisted for fluorescent probe. Their inhibitory activity on collagenase was
assayed in the same cell model, and the correlation between both activities was analyzed.
The assays were performed on fibroblast cultures (HS68 cell) under high production of ROS (low pH value2)
and UVB-induced collagenase (MMP-1)3. Briefly, the cells (1.5 × 104cells/well) were exposed to different
compounds (EAD: A. ellagic acid; B. 3-O-methyl ellagic; C. 3,3’di-O-methylellagic; D. 3,3’di-O-methyl
ellagic-4-O-β xylopyranoside, 10 uM) and positive control (Apigenin) for 3 h, then were treated with H2DCFDA
(10 uM in PBS, 1 h at 37 °C), then the ROS production was induced at pH 5 for 6 h (37 °C). ROS/RNS
production was measured by fluorometry (λex = 488 nm, λem = 520 nm). In order to determine the MMP-1
inhibition level on fibroblasts (1.5 × 105cells/well), these were treated with test compounds (10 uM) for 3 h, and
then were exposed to a 100 mJ/cm2 dose of UVB light. After 6 h on culture conditions, supernatants were
separated and processed4, and the collagenase activity was determined using Pz peptide (Fluka)5,6. All proper
controls and repetitions were made for each assay (ρ ≤0,05).
The results showed that the methylated compounds (B and C) were more effective on the intracellular ROS/RNS
scavenging (>70 %, P < 0.05), and the values obtained were similar to those for apigenin; this measurement also
reflects the capacity of each compounds to cross the membrane and exert its scavenging effect, where the
presence of oxidizing species was detected by fluorescence-H2DCF probe. For collagenase activity the same
trend was observed, and inhibition order according to IC50, show that A < D < C < Apigenin < B. The analysis
shows a positive correlation (r = 0.8) between the capacity of each compounds to cross cell membrane and its
corresponding inhibition on MMP-1.
References
1) Journal of Ethnopharmacology 2013, 147 (1): 63-73.
2) Investigative Ophthalmology & Visual Science 2006, 47 (5): 1902-1910.
3) Biological and Pharmaceutical Bulletin 2008, 31(2): 284-289.
4) European Journal of Dermatology 2009; 19 (2): 129-134.
5) Archives of ophthalmology 2001;119 (1) :71-80.
6) BMC Complementary and Alternative Medicine 2012, 12:106.
- 84 -
IA007
"DRY" CO-CRYSTALLIZATION AND IN SITU DIFFRACTION FOR

AUTOMATIC LIGAND SCREENING BY X-RAY
CRYSTALLOGRAPHY
Muriel Gelin (1), Vanessa Delfosse (1), Frederic Allemand (1), Francois Hoh (1), Yohann Damaz (2),
Michel Pirocchi (2), Jean-luc Ferrer (2), William Bourguet (1), Gilles Labesse (1), Jean-francois Guichou
(1)
1) CNRS, UMR5048 – Université de Montpellier, Centre de Biochimie Structurale, F-34090 Montpellier, France.
2) Université Grenoble Alpes, IBS, F-38044 Grenoble, France
X-ray crystallography is now the best method to access structural information for biological macromolecules at
high resolution. By mid-2014, 89,988 crystal structures have been deposited in the Protein Data Bank (PDB;
www.rcsb.org/pdb). X-ray crystallography in the field of rational drug design is of utmost importance for
determining the mode of binding of known or potential binders, including weak binders, in order to guide lead
optimization[i].
Herein, we applied a more convenient delivery of ligands prior to the crystallization step. It is based on coating
the crystallization wells with the desired small molecules and allowed the solvent to evaporate prior to setting up
protein crystallization in a classical way. A seminal example used methanol as a quickly evaporating solvent but
this makes pipetting and storage of chemical compounds more complex. Furthermore, it still required manual
crystal handling for both soaking and freezing[ii]. Here, instead, we developed “dry” co-crystallization and
combined it with in situ[iii] diffraction.
In this study, we have developed further the technique of pre-coating of crystallization plates with small
molecules in order to accelerate ligand screening using X-ray crystallography[iv]. Indeed, its combination with
in situ diffraction alleviates the requirement for crystal manipulation and freezing. In this case, direct X-ray data
collection can be performed in ~ 2 hours on a laboratory anode or in ~ 10 minutes on a bending magnet
(BM30A, ESRF) and one crystal is usually sufficient (but for triclinic and monoclinic space groups which
represent ~30% of observed lattices in protein crystals). This new methodology can be rapidly disseminated as it
relies solely on the use of liquid dispensers widely distributed. Thus, the proposed method of in situ “dry”
co-crystallization provides an ideal way for accelerating and automatizing ligand screening by X-ray
crystallography.
References
i) Murray, C.W. & Blundell, T.L. Curr. Opin. Struct. Biol. 20, 497-507 (2010).
ii) Davies, D.R. et al. J. Med. Chem. 52, 4694-4715 (2009).
iii) le Maire, A., et al. Acta Crystallogr. D Biol Crystallogr. 67, 747-755 (2011).
iv) Gelin, M. et al. Acta Crystallogr. D Biol Crystallogr. under revision (2015).
- 85 -
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BookRICT.indd 76 3/06/2015 11:06:25

POSTERS:
Integrative Approaches
- 87 -
BookRICT.indd 77 4/06/2015 15:06:00

- 88 -
BookRICT.indd 80 3/06/2015 09:45:58

MR001
NOVEL PYRROLO[1,2-a]QUINOXALINES AS ANTIPARASITIC

AGENTS : DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION
Jean Guillon (1), Luisa Ronga (1), Anita Cohen (2), Patrice Le Pape (3), Solène Savrimoutou (1), Noël
Pinaud (4), Catherine Mullié (5), Philippe Vincendeau (6), Elisabeth Mouray (7), Fabrice Pagniez (3),
Sébastien Hutter (2), Nadine Azas (2), Stéphane Moreau (1), Philippe Grellier (7), Pascal Sonnet (5)
1) Univ. Bordeaux, UFR des Sciences Pharmaceutiques, INSERM U869, ARNA Laboratory, Bordeaux, France
2) Aix-Marseille Univ., Laboratory of Parasitology, UMR-MD3, Faculty of Pharmacy, Marseille, France
3) Université de Nantes, Département de Parasitologie et Mycologie Médicale, IICiMed, EA1155, UFR des Sciences
Pharmaceutiques, Nantes, France
4) Univ. Bordeaux, ISM – CNRS UMR 5255, 351 cours de la Libération, Talence, France
5) Université de Picardie Jules Verne, CNRS FRE 3517, UFR de Pharmacie, Amiens, France
6) UMR 177 IRD CIRAD, Université de Bordeaux, Laboratoire de Parasitologie, Bordeaux, France
7) UMR 7245 CNRS / Muséum National d'Histoire Naturelle, 75005 Paris, France
The molecules derived from the chemistry of the pyrrolo[1,2-a]quinoxaline heterocycle could be considered as
interesting pharmacophores able to provide active compounds in various fields of pharmacology. These
pyrrolo[1,2-a]quinoxaline building blocks could be considered as bioisosteres compared to biologically active
synthetic or natural molecules, allowing to integrate them into the design and synthesis of new systems with
potential biological activities. We have conducted new pharmacomodulations around this platform with new
molecular functionalization for obtaining biologically active derivatives in the field of parasitology. Thus, we
have performed the design, the synthesis and the biological evaluation of the in vitro antiparasitic activities of
new pyrrolo[1,2-a]quinoxalines. In that way, the activities toward Plasmodium falciparum strains were
investigated for two series (A and B) [1,2]; moreover three other series (C, D and E) were tested for in vitro
antiparasitic activity upon Leishmania spp.Strains [3-7].
References
1) Bioorg. Med. Chem. 2008, 16, 9133-9144.
2) Eur. J. Med. Chem. 2011, 46, 2310-2326.
3) Bioorg. Med. Chem. 2007, 15, 194-210.
4) J. Enzyme Inhib. Med. Chem. 2007, 22, 541-549.
5) Anal. Sci. 2008, 24, x35-x36.
6) X-ray Struct. Anal. Online 2009, 25, 109-110.
7) Eur. J. Med. Chem. 2014, 81, 378-393.
- 89 -
MR002
EFFLUX PUMP BLOCKERS IN GRAM-NEGATIVE BACTERIA: NEW

HYDANTOIN BASED MODULATORS TO IMPROVE ANTIBIOTIC
ACTIVITY
Ewa Otrebska-Machaj (1,2), Jacqueline Chevalier (2), Jadwiga Handzlik (1), Ewa Szymańska (1), Jakub
Schabikowski (1), Gérard Boyer (2), Jean -Michel Bolla (2), Katarzyna Kiec-Kononowicz (1), Jean -Marie
Pagès (2), Sandrine Alibert (2)
1) Department of Technology and Biotechnology of Drugs, Jagiellonian University-Medical College, Medyczna 9, 30-688
Krakow, Poland
2) UMR-MD1, Aix Marseille Université / IRBA, Facultés de Médecine et de Pharmacie, 27 boulevard Jean Moulin, 13385
Marseille cedex 05, France.
Multidrug resistant (MDR) bacteria are an increasing health problem associated with the lack of new active
antibiotic agents for treating infectious diseases. One of the most effective resistance mechanism that contributes
to the spreading of MDR Gram-negative bacteria is the active drug efflux pumps that expel all usual antibiotic
classes out of the cell. Drug pumps are attractive target in order to restore the susceptibility towards the expelled
antibiotics by blocking their efflux activity in bacterial cells. A series of diphenylhydantoin derivatives were
investigated for their blocking properties at the AcrAB-TolC efflux system in Gram-negative Enterobacter
aerogenes. Compounds showing chemosensitizing effect on nalidixic acid, chloramphenicol and sparfloxacin
activity were the starting point for new pharmacomodulations to obtain a new generation of compounds with an
improved activity against the bacterial efflux mechanism in resistant isolates.
References
1) Bolla J-M, Alibert-Franco S, Handzlik J, Chevalier J, Mahamoud A, Boyer G et al. Strategies for bypassing the membrane
barrier in multidrug resistant Gram-negative bacteria. FEBS lett 2011; 585: 1682-90.
2) Handzlik J, Szymańska E, Chevalier J, Otrebska E, Kiec-Kononowicz K, Pagès J-M et al. Amine-alkyl derivatives of
hydantoin: new tool to combat resistant bacteria. Eur J Med Chem 2011; 46: 5807-16.
3) Handzlik J, Szymanska E, Alibert S, Chevalier J, Otrebska E, Pekala E et al. Search for new tools to combat
Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin. Bioorg Med Chem 2013; 21: 135-45
- 90 -
MR003
EFFLUX PUMP: AN ATTRACTIVE TARGET TO TACKLE

BACTERIAL RESISTANCE
Jessica Hernandez, Joannah N'Gompaza Diarra, Estelle Dumont, Gérard Boyer, Jean-Michel Bolla,
Jean-Marie Pagès, Sandrine Alibert
Aix-Marseille University / IRBA, UMR-MD1, Membrane Transporters-Chemoresistance-Drug Design, Faculties of Medicine

and Pharmacy, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France. http://pharmacie.univ-amu.fr/umr-md1
jessica.hernandez.1@etu.univ-amu.fr
The emergence of multidrug-resistant (MDR) pathogens is a worldwide health problem. In Gram-negative

bacteria, transporters belonging to the resistance-nodulation-cell division (RND) superfamily play an essential
role in MDR phenotype. Indeed, efflux pumps (EP) extrude out of the bacterial cell a wide range of substrates,
especially different families of antibiotics that contribute more and more to the treatment failure of infectious
diseases.
In this context, a new strategy to overcome antimicrobial resistance is to find the way to block the active drug
efflux using “escort molecules” of usual antibiotics, to improve and restore their efficacy.[1]
The screening of various chemical libraries on Enterobacteriaceae allowed selecting BG1190 as hit compound to
design and synthesize quinolone antibiotic chemosensitizers based on the quinazolinone scaffold capable to
target AcrAB-TolC EP (see figures). The challenge is to identify pharmacophores that bind AcrB moiety of this
transporter and to determine their role in the pump activity. Molecular modeling and QSAR studies guide the
pharmacomodulations and the rational synthesis of new blockers of antibiotic efflux. This study would allow a
better detection and a better understanding of antibiotic resistance and propose alternative methods to prevent
and to treat bacterial infectious diseases.
Project funding was supported by grant ANR-11-BS07-019-01 “IBEF” from Agence Nationale de la Recherche
(ANR, France)
References
1) J. -M. Bolla, S. Alibert-Franco, J. Handzlik, J. Chevalier, A. Mahamoud, G. Boyer, K. Kiec- Kononowicz, J. - M. Pagès,
FEBS letters 2011, 585, 1682
- 91 -
MR004
PROPERTIES OF PHENOTHIAZINE DERIVATIVES ON THE

BACTERIAL EFFLUX PUMP SYSTEM
Aurélien STUTZMANN (1), Arnaud CACLARD (1,2), Fabrice BIOT (1,2), Eric VALADE (1,2), Sandrine
ALIBERT (1), Gérard BOYER (1), Jean-Michel BOLLA (1), Jean-Marie PAGES (1)
1) UMR-MD1, Aix-Marseille Université, IRBA, Facultés de Médecine et de Pharmacie, Marseille, France.

2) Unité de Bactériologie/UMR-MD1, Institut de Recherche Biomédicale des Armées (IRBA), Brétigny-sur-Orge, France.
Antimicrobial drugs have been crucial tools of health for decades due to their effectiveness in control of bacterial
infections. However, some pathogens rapidly developed Multi-Drug Resistance (MDR) to antibiotics.1 Gram
negative bacteria belong to these drug resistant pathogens and the overexpression of efflux mechanisms
contributes widely to the MDR phenotype (Fig. 1). During the recent years, investigation of inhibition of MDR
attracted world-wide.2 Among effective compounds that proved to inhibit resistance, some phenothiazine
derivatives were found.3
By a medicinal chemistry approach, phenothiazine derivatives were synthesized in order to be tested as

adjuvants of usual antibiotics on Burkholderia thailandensis, a Gram-negative bacteria specie.4 The activity of
phenothiazines N-substituted with various functional groups was determined using Epsilometer test method and
two opposite effects were observed according to the substituent nature (Fig. 2). Indeed, phenothiazine derivatives
have no direct activity on bacteria but potentiate the activity of diverse classes of antibiotics or could have an
effect on efflux pump expression.
This subject also open new perspectives to the Public and Army Healthcare in the field of the natural or
provoked biological risk.
References
1) Wong K., Ma J., Rothnie A, Biggin P.C., Kerr I.D. Trends Biochem. Sci. 2014, 39(1), 8-16.
2) Bolla J.M., Alibert-Franco S., Handzlik J., Chevalier J., Mahamoud A., Boyer G., Kieć-Kononowicz K., Pagès J.M. FEBS
Lett. 2011, 585(11), 1682-1690.
3) Martins M., Dastidar S.G., Fanning S., Kristiansen J.E., Molnar J., Pagès J.M., Schelz Z., Spengler G., Viveiros M.,
Amaral L. Int. J. Antimicrob. Agents, 2008, 31, 198-208.
4) Biot F., Lopez M., Poyot T., Neulat-Ripoll F., Lignon S., Caclard A., Thibault F., Peinnequin A., Pagès J. -M., Valade E.
PLoS One 2013, 8(12):e84068. - 92 -
MR005
IN SILICO SCREENING AND ANTIBACTERIAL EVALUATION OF

AMINOGLYCOSIDE PHOSPHOTRANSFERASE INHIBITORS
Elise Kaplan (1), Nadia Leban (1), Emma Graille (1), Jean-François Guichou (2), Laurent Chaloin (1),
Corinne Lionne (1)
1) Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé (CPBS), Montpellier, France.
2) Centre de Biochimie Structurale (CBS), Montpellier, France
Emergence of multi-drug resistant bacteria leads to increasing fatal issues especially in hospitals. Resistance to
aminoglycoside antibiotics is mainly due to the expression of modifying enzymes, such as aminoglycoside
phosphotransferases (APH).
The aim of this study is to find APH allosteric inhibitors that will bind to small cavities of the enzyme, thereby
blocking its activity by perturbing its dynamics.
Target cavities, identified by molecular dynamic simulations, were used to virtually screen 12’000 compounds of
the Zinc database. The 14 high-ranked compounds were tested in vitro to evaluate their efficiency to inhibit APH
activity. One compound was identified as a potent non-competitive inhibitor of APH(2”)-IVa and was restoring
gentamicin susceptibility of a clinical strain expressing this enzyme. Evaluation of the efficiency of 21
structurally-related analogs permits to highlight the most favorable substituents for APH inhibition. The most
active compounds are currently tested on different resistant bacteria isolates to determine if they are able to
restore the susceptibility to aminoglycosides.
This study provides the basis for the development of combined chemotherapies (antibiotic with enzyme
inhibitor) which may overcome antibiotic resistance in a clinical context.
- 93 -
MR006
POOR CELL DETOXIFICATION ENABLES LIPOPHILIC PT(IV)

PRODRUGS TO BYPASS CISPLATIN RESISTANCE
Ilaria Zanellato, Ilaria Bonarrigo, Elisabetta Gabano, Mauro Ravera, Domenico Osella
Università del Piemonte Orientale, Dipartimento di Scienze ed Innovazione Tecnologica (DiSIT), viale T. Michel 11,
Alessandria, Italy
The biological properties of a series of cisplatin-based Pt(IV) prodrug candidates, namely trans,cis,cis-
[Pt(carboxylato)2Cl2(NH3)2], where carboxylato = CH3(CH2)nCOO− [(1), n = 0, (2), n = 2; (3), n = 4; (4), n = 6]
having a large interval of lipophilicity are discussed.
Their antiproliferative activity has been evaluated in vitro on a large panel of human cancer cell lines. As
expected, the potency increases with the chain length: 3 and 4 resulted by far more active than cisplatin on all
cell lines of about one or two orders of magnitude, respectively. Both complexes retained their activity also on
cisplatin-resistant cell line, and exhibited a progressive increase of the selectivity compared with non-tumor
cells. These results were confirmed with more prolonged treatment (up to 14 days) studied on multicellular
tumor spheroids (MCTSs). In this case the Pt(IV) complexes exert a protracted antiproliferative action, even if
the drug is removed from the culture medium.1
To unravel the relationship between lipophilicity, cell accumulation, DNA platination and antiproliferative
activity, the A2780 ovarian cancer cell line was chosen. The most lipophilic complexes of the series enter the
cells by enhanced passive diffusion making very high the corresponding accumulation, DNA platination and cell
growth inhibition. In these cases, even if the Pt(IV) complex is removed from the culture medium, its
accumulation was unchanged and its DNA platination was very high and prolonged during the time, indicating
poor detoxification efficiency. While cisplatin is a substrate for the copper transporter systems Ctr1 and
ATP7A/B, the opposite was shown for the Pt(IV) complexes under investigation. For Pt(IV) complexes having
lipophilicity similar to cisplatin, the lack of protein-mediated transport is not fully compensated by the increase
in passive diffusion, resulting in cellular accumulation and biological activity similar to that of cisplatin. On the
contrary, the high and prolonged platination activity of the most lipophilic complexes of the series could be
ascribed to the huge cellular accumulation of the Pt(IV) prodrug, that is gradually reduced to cisplatin and, in
this form, binds DNA. This mechanism could explain the ability of 3 and 4 to bypass cisplatin resistance, when
associated to reduced influx or increased efflux, and their prolonged antiproliferative activity.2
References
1) Ilaria Zanellato, Ilaria Bonarrigo, Donato Colangelo, Elisabetta Gabano, Mauro Ravera, Manuela Alessio, Domenico
Osella. Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: How long the organic
chain should be? Journal of Inorganic Biochemistry (2014) 140: 219–27.
2) Mauro Ravera, Elisabetta Gabano, Ilaria Zanellato, Ilaria Bonarrigo, Manuela Alessio, Fabio Arnesano, Angela Galliani,
Giovanni Natile, Domenico Osella. Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based
dicarboxylato Pt(IV) prodrugs, Journal of Inorganic Biochemistry, (2015) paper under review, MS n. JIB-15-0115R1
- 94 -
MR007
MURINE HEPATOMA MH22A CELLS RESISTANT TO

AZIRIDINYL-BENZOQUINONE RH1: ENZYME ACTIVITIES AND
PROTEOMIC ANALYSIS
Aušra Nemeikaitė-Čėnienė (1), Marija Ger (2), Henrikas Nivinskas (2), Mindaugas Valius (2), Narimantas
Čėnas (2)
1) State Research Institute Center of Innovative Medicine, Molėtų Pl. 29. Vilnius, Lithuania
2) Institute of Biochemistry of Vilnius University, Mokslininkų 12, Vilnius, Lithuania
A novel anticancer agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is activated by

NAD(P)H:quinone oxidoreductase (NQO1) which is overexpressed in many tumors. Here we present the
properties of two RH1-resistant murine hepatoma MH22a cell sublines, which were not cross-resistant to
duroquinone, daunorubicin, and quercetin. Their above 10-fold resistance to RH1 was accompanied by a
significant decrease in the activity of NQO1 and glutathione-S-transferase, and the insignificant changes in the
activity of prooxidant enzymes NAD(P)H oxidases and cytochrome c reductases, as well as of the antioxidant
ones, glutathione reductase, catalase, and superoxide didmutase. According to the data of proteomic analysis, the
expresion of over 400 proteins was altered in RH1-resistant cells, including the reduced expression of xenobiotic
metabolism enzymes (n=17), the decrease of cell cycle positive regulators (n=15), and the increase in the level of
DNA repair proteins (n=5), and the annexin family members (n=5). RH1-resistant cells also possessed the
altered levels of proteins involved in energy production and metabolism (n=46). Our data provide the general
insight onto the mechanisms of tumor cell resistance to RH1, and, presumably, towards other
aziridinyl-substituted quinones.
This research was funded by the European Social Fund under Global Grant Measure No.
VP1-3.1-ŠMM-07-K01-103 (Scientific Council of Lithuania).
- 95 -
MR008
FRAGMENT-BASED DRUG DESIGN OF ECTO-5’NUCLEOTIDASE

INHIBITORS: APPLICATION TO CANCER TREATMENT
RESISTANCE
Rahila Rahimova (1), Suzanne Peyrottes (2), Corinne Lionne (1), Laurent Chaloin (1)
1) Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS - Université de
Montpellier, 1919 route de Mende, 34293 Montpellier cedex 5, France.
2) Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS – Université de Montpellier, Campus Triolet,
cc1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
An increasing number of research articles has demonstrated that escaping immune response facilitates the
development and progression of many human cancers. In light of this consideration membrane anchored
ecto-5'-nucleotidase (CD73) has emerged as a new appealing target for cancer treatment resistance. It is
considered as a potent immune suppressor by adenosine produced from tumoral cells. In human being, CD73 is
the primarily responsible enzyme for adenosine generation by catalyzing the hydrolysis of extracellular
adenosine monophosphate (AMP) to adenosine. Thus, it constitutes the major control for regulating the
extracellular pool of adenosine. Furthermore, numerous studies showed that increased enzymatic activity induces
solid tumor progression and metastasis. Decreasing its activity by genetic knock-down or by using monoclonal
antibodies has been shown to significantly reduce tumor growth and metastasis. These results suggest that
developing new inhibitors of human CD73 may represent an effective therapy, alone or in combination with
other anticancerous drugs, to struggle cancer treatment resistance.
Herein, we applied the fragment-based drug design (FBDD) approach on the recently solved crystal structure.
We first initiated in silico search of chemically and enzymatically stable substrate analogs by targeting the AMP
binding site (Gold program). In parallel, virtual screening of fragment libraries has been carried out by targeting
a newly identified allosteric binding site. The most interesting fragments will be used as starting structures for
the development of more complex compounds. To evaluate the inhibitory potential of selected compounds, the
development of an in vitro assay with the purified recombinant enzyme was required. Optimization of the
expression and the purification of fully active protein either from inclusion bodies of E. coli or from eukaryotic
cells are currently in progress. The highest ranked fragments issued from virtual screening will be presented as
well as further strategies to optimize these hits. Finally, the discovery of new potent and selective CD73
inhibitors will offer new therapeutic strategies against cancer resistance.
- 96 -
POSTERS:
Revealing Biological
Mechanisms
- 97 -
BookRICT.indd 81 15/06/2015 12:09:14

- 98 -
BookRICT.indd 82 3/06/2015 09:45:58

RB001
EXPLORING THE MOLECULAR MECHANISM OF DNA

METHYLATION INHIBITION BY ZEBULARINE USING
COMPUTATIONAL TOOLS
Fedaa Attana, Juan Aranda, Iñaki Tuñón
Department of Physical Chemistry, University of Valencia, Spain
Zebularine is a cytidine analogue (see figure) described as a potent inhibitor of DNA methyltransferases
(DNMTs) and used for cancer therapy [1]. After reduced, deoxyzebularine is incorporated into DNA and then the
fraudulent base can form covalent bonds with the DNMT, resulting in the depletion of active enzymes and the
demethylation of DNA [2]. It was observed that there is an increase in the binding of DNA to DNMTs when
zebularine is incorporated into the DNA, compared to deoxycytidine, together with a strong decrease in the
dissociation rate [1]. Our motivation is to study the Enzyme DNA interaction when deoxycytidine is substituted
by zebularine and compare with previous results of natural DNA/Enzyme simulation to rationalize these findings
at the molecular level.
We chose the M.HhaI enzyme to model the reaction .The starting point to simulate the system is a x-ray 3D
structure [2] of the DNA-enzyme complex with the target nucleic base flipped out and ready to undergo the
methylation reaction in presence of SAM (the cofactor)[3]. The first challenge was to develop forcefield
parameters (AMBER in our case) for deoxy-zebularine as non-standard residues presented in the system. The
AMBER parameters for deoxy-zebularine were the same as those of deoxycytidine, with adjustment of charges
and atom types around position 4 of the pyrimidine ring. Charges were derived using RESP methodology to keep
consistent with original nucleic acid AMBER charges. We performed Molecular Dynamics simulations
considering the enzyme plus DNA in an orthorhombic box of water molecules, including sodium counterions to
neutralize the charge of the system. Once the system was equilibrated we analysed the most important
interactions formed between the enzyme and DNA, the interactions within the active site, how the unpaired base
is stabilized and how the DNA helix accommodates the great perturbation provoked by a flipped out base. The
results are compared with those obtained when DNA contains the natural base instead of deoxy- zebularine.
References
1) C. Champion, D. Guianvarc'h, C. Sénamaud-Beaufort . PLoS ONE, 5, (2010), e12388.
2) G. Egger, G. Liang, A. Aparicio , P. A. Jones. Nature, 429, (2004), 457-463.
3) F. K. Shieh, B. Youngblood, N. O. Reich, J. Mol. Biol., 362, (2006), 516-527.
- 99 -
RB002
INTERROGATING THE BROMODOMAIN FAMILY THROUGH

CHEMICAL BIOLOGY
Steven Bellon (1), Andrea Cochran (2)
1) Constellation Pharmaceuticals
215 First Street, Suite 200
Cambridge, MA 02142
2) Genentech
Department of Early Discovery Biochemistry
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080
The bromodomain family of acetyl-lysine binding proteins are extremely well suited to a chemical biology
approach. While the bromodomain-ligand interactions are formally protein-protein interactions, the binding
sites are in many cases quite druggable. In addition, sequence analysis across the family of binding sites reveals
a perfect blend of sequence similarity to enable target hopping as well as sequence differences that allow the
development of highly selective probe molecules. Our strategy is to make potent, selective, and cell active
probes against the entire bromodomain family, and then to use these probes to broadly interrogate biology in
different contexts. We will discuss the status of our platform activities, as well as give specific examples of our
chemical probe work with the bromodomains PCAF and CBP.
- 100 -
RB003
FLUORESCENT LIGANDS TO TRACK GPCRs

Elsa Pflimlin (1), Iullia Karpenko (1), Candide Hounsou (2), Andrey Klymchenko (3), Elodie Dupuis (4),
Eric Trinquet (4), Jean-Philippe Pin (2), Marcel Hibert (1), Thierry Durroux (2), Dominique Bonnet (1)
1) Laboratoire d’Innovation Thérapeutique, UMR7200 CNRS/Université de Strasbourg, Labex MEDALIS, Faculté de

Pharmacie, 74 route du Rhin, 67401 Illkirch.
2) Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I et II, 141 rue de la
Cardonille, 34094 Montpellier.
3) Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74
route du Rhin, 67401 Illkirch
4) Cisbio Bioassays, 30200 Codolet
G-protein-coupled receptors (GPCRs) represent the largest family of cell surface membrane proteins encoded by
the human genome and more than 30% of all marketed therapeutics act on them. In the last decade, homo- and
hetero-oligomerization of GPCRs have been described as a new way to modulate receptor pharmacology and
functional activity.1 Thus, heteromer-targetted drug discovery opens new perspectives both in Academic pursuits
and for the Pharmaceutical industry.
In this context, we have set up innovative fluorescent-based assays in order to gain a better understanding of
GPCR functional architecture but also to set up new receptor-selective high-throughput screening (HTS) assays
for heterodimeric GPCRs. Owing to their high sensitivity and to their reduced environmental safety risk,
fluorescent technologies represent a powerful molecular tool to study ligand-GPCR interactions. However, the
prerequisite to develop such methods is to design and to synthesize high affinity and selective fluorescent
probes.
As we will illustrate, synthetic methods have been set up to facilitate the access to original fluorescent GPCR
probes. Thus, we have designed and synthesized selective non peptide fluorescent ligands to detect vasopressine
and dopamine heterodimers at the cell surface and to set up a novel TR-FRET assay to screen for heterodimers.2
The first environment sensitive (“Turn-on”) probes to detect and to monitor oxytocin GPCR at the surface of
living cells will be also presented.3
References
1) Ferre, S.; Casado, V.; Devi, L. A.; Filizola, M.; Jockers, R.; Lohse, M. J.; Milligan, G.; Pin, J. P. and Guitart, X.
Pharmacol. Rev., 2014, 66, 413−434.
2) (a) Loison, S.; Cottet, M.; Orcel, H.; Adihou, H.; Rahmeh, R.; Lamarque, L.; Trinquet, E.; Kellenberger, E.; Hibert, M.;
Durroux, T.; Mouillac, B.; Bonnet, D. J. Med. Chem., 2012, 55, 8588-8602; (b) Hounsou, C.; Margathe, J.F., Oueslati, N.;
Belhocine, A.; Dupuis, E.; Thomas, C.; Mann, A.; Ilien, B.; Rognan, D.; Trinquet, E.; Hibert, M.; Pin, J.P.; Bonnet, D. and
Durroux, T. ACS ChemBiol., 2015, 10, 466–474.
3) (a) Karpenko, I.A.; Klymchenko A. S.; Gioria, S.; Kreder, R.; Shulov, I.; Villa, P.; Mély, Y.; Hibert, M.; Bonnet, D.
Chem. Commun., 2015, 51, 2960-2963. (b) Karpenko, I.A.; Collot, M.; Richert, L.; Valencia, C.; Villa, P.; Mély, Y.; Hibert,
M.; Bonnet, D. and Klymchenko, A. S. J. Am. Chem. Soc., 2015, 137, 405-412.
- 101 -
RB004
PREDICTING REGIOSELECTIVITY AND LABILITY OF

CYTOCHROME P450 METABOLISM USING QUANTUM
MECHANICAL SIMULATIONS
Jonathan Tyzack, Nicholas Foster, Peter Hunt, Matthew Segall
Optibrium Ltd, 7221 Cambridge Research Park, Cambridge CB25 9TL, UK
In this poster we will describe recent developments to a method for predicting Cytochrome P450 metabolism
that combines quantum mechanical (QM) simulations to estimate the reactivity of potential sites of metabolism
on a compound with a ligand-based approach to account for the effects of orientation and steric constraints due
to the binding pockets of different P450 isoforms. The resulting models achieve accuracies of 85-90% on
independent test sets across multiple P450 isoforms. While valuable, predicting the relative proportion of
metabolite formation at different sites on a compound is only a partial solution to designing more stable
compounds. The advantage of a QM approach is that it provides a quantitative estimate of the reactivity of each
site, from which additional information can be derived regarding the vulnerability of each site to metabolism in
absolute terms. One such measurement is the site lability, which is a measure of the efficiency of the product
formation step and an important factor influencing the rate of metabolism. We will illustrate how this provides
valuable guidance to redesign compounds and overcome issues due to rapid P450 metabolism.
The research leading to these results has received funding from the European Union Seventh Framework
Programme (FP7/2007-2013) under the grant agreement no 602156
References
1) StarDrop, Optibrium Ltd, Cambridge, UK
2) J.P. Jones et al. (2002) Drug Metab. Dispos. 30(1): 7-12
3) G. Cruciani et al. (2005) J. Med. Chem. 48(22): 6970-6979
4) M. Hennemann et al. (2009) ChemMedChem 4(4): 657-669
5) P. Rydberg et al. (2010) ACS Med. Chem. Lett. 1(3): 96-100
6) J. Zaretzki et al. (2011) J. Chem. Inf. Model. 51(7): 1667-1689
- 102 -
RB005
PISTON-DRIVEN ACTIVATION MECHANISM OF VKORC1, THE

HUMAN VITAMIN K EPOXIDE REDUCTASE
Nolan Chatron (1), Florent Langenfeld (1), Etienne Benoit (2), Virginie Lattard (2), Luba Tchertanov (1)
1) Centre de Mathematiques et de Leurs Applications (CMLA-UMR 8536 CNRS), Ecole Normale Superieure de Cachan, 61
avenue du President Wilson, 94235 Cachan, France
2) INRA-VetAgro Sup, USC 1233, Ecole Nationale Vétérinaire de Lyon, 69280 Marcy l’Etoile, France
Blood coagulation is a crucial physiological process, vital for many living organisms. Vitamin K epoxide
reductase complex subunit 1 (VKORC1) plays a key role in this process, through the catalysis of vitamin K
recycling - from its inactive epoxide form to the biologically active hydroquinone form[1]. VKORC1, an
endoplasmic reticulum membrane protein, is the primary target for vitamin K antagonists (VKAs)[2].
Appearance of VKORC1 mutations promotes patient’s resistance to VKA drugs and/or alteration of VKORC1
activity. Our aim is to clarify the VKORC1 catalytic mechanisms and the resistance mechanisms to VKAs on the
atomic scale. To the best of our knowledge, no structural data is available for the human VKORC1 (h-VKORC1
WT), therefore in our study we used in silico modeling combined with molecular dynamics (MD) simulations.
The first step consists to build a structural model of VKORC1 using the recent X-ray data for its bacterial
homolog[3]. The generated model denotes a four-helix structure of VKORC1 (Fig. 1 A-B) that is consistent with
the experimentally determined enzymatic mechanism regulating the electron transfer from cysteine residues
43-51 (in blue) to cysteine residues 132-135 (in green). Each pair of transmembrane helices (TM) is linked by
either short loops (TM3-TM4 and TM2-TM3) or a long and highly flexible luminal loop (Loop 1/2, linking
TM1-TM2) with a small horizontal helix (HH) in the middle, overhanging the membrane surface.
Figure 1. Structural modeling and dynamics simulations of h-VKORC1 WT. Schematic (A) and all atom (B) representations of the generated model;
cysteine residues 43-51 and 132-135, involved in the catalytic mechanism of VKORC1, are shown in blue and green colors, respectively. VKORC1 is
shown as cartoon (in orange) with catalytic cysteine residues denoted as spheres with sulfide atoms colored in gold. Membrane is depicted as grey
and red spheres. Two conformations (C and D) depicts the two different states of h-VKORC1WT .
Molecular Dynamics (MD) simulations (2 x 100 ns) revealed significant conformational changes, evidenced as a
two-state transition of the h-VKORC1WT. The MD simulations data were explored by principal components
analysis and cross-correlation analysis, which evidenced highly concerted motions of protein residues from Loop
1/2, HH and the four TMs. We observed that the two coiled sub-fragments of Loop 1/2, separated by HH, show
anti-correlated movement, which highly correlates with the HH displacement. The longer the distance between
the two coiled sub-fragments, the larger the extent between HH and TMs (Fig. 1 C-D). When the two coiled
sub-fragments of Loop 1/2 adjoin, the HH moves towards the catalytic site, perturbing its topology by altering
the inter-helices space. We denominate these highly concerted movements which involve nearly all structural
subunits of h-VKORC1WT and its all catalytic residues – C43 (LL), C51 (HH), C132 and C135 (TM4) – the
‘piston- driven mechanism’. This purely mechanistic description depicts plausibly a first step of the h-VKORC1
WT activation which precede the enzymatic reaction(s). Validation of the proposed model and its mechanisms
will be performed through the study of the VKORC1 mutants, resistant to VKAs, combining in silico, in vitro
and in vivo approaches.
References
1) Rishavy et al., Novel insight into the mechanism of the vitamin K oxidoreductas. J Biol Chem (2011)
2) Watzka et al., Thirteen novel VKORC1 mutations associated with oral anticoagulant resistance: insights into improved
patient diagnosis and treatement, J Thrombosis &Haemostasis (2010)
3) Liu et al., Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron
transfer. Nature (2014)
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RB006
MOLECULAR MECHANISM OF SALINOMYCIN-INDUCED CANCER

STEM CELL DEATH
Antje Hienzsch (1), Trang Thi Mai (1), Ahmed Hamaï (2), Maryam Mehrpour (2), Raphaël Rodriguez
(1,3)
1) Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, 91198 Gif
sur-Yvette, France.
2) Institut Necker Enfants-Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris
Cité, 14 rue Maria Helena Vieira Da Silva, 75993 Paris Cedex 14, France.
3) Institut Curie Research Center, CNRS UMR 3666, Organic Synthesis and Cell Biology Group, 26 rue d’Ulm, 75248 Paris
Cedex 05, France.
Multidrug resistance and tumor relapse are the major challenges in today’s cancer therapy. Mounting evidence is
showing that a small subpopulation of cancer cells, the so-called Cancer Stem Cells (CSC), may play an
important role in these events. These cells gained properties like tumor initiation and the possibility to invade
into tissues and initiate metastasis. In 2009, the natural product Salinomycin (SAL), widely used as an
anticoccidial drug in poultry farming, was found to selectively affect CSCs from breast cancer cell lines more
effectively than commonly used chemotherapeutic agents, including Paclitaxel. More recently, additional
phenotypes reliant on Salinomycin treatment in various cancer cell lines have been reported, including the
increase of oxidative stress by reactive oxygen species, the inhibition of the p-glycoprotein, Wnt-pathway and
autophagic flux, as well as the induction of apoptosis.
However, the explicit mechanism by which SAL primarily operates is still unknown. In order to address this
point, we prepared several SAL-analogues. These analogues performed in similar action with SAL on CSC
population, but much more selective and at considerably lower concentration. We observe antiproliferative
activity in non-adherent conditions (e.g. mammosphere assays) at 30 nM concentration. In-depth cellular assays
revealed the primary cellular localization of Salinomycin at a molecular level. Further biochemical investigations
provide more insights into the mechanism how SAL actually eradicates cancer stem cells and links several
observations of previous studies suggesting sharpened strategies for treating resistant cancers.
- 104 -
RB007
A SPECTROSCOPY-BASED NEW PARADIGM TO EXPLAIN AND

OVERCOME RESISTANCE OF MYCOBACTERIUM TUBERCULOSIS
TO THE PRO-DRUGS ISONIAZID AND ETHIONAMIDE
Peter C. LOEWEN (2), Vania BERNARDES-GENISSON (3), Wladimir SOUGAKOFF (4), Anabella
IVANCICH (1)
1) Laboratoire de Bioénergétique et Ingénierie des Protéines, UMR 7281 CNRS et Aix-Marseille Université. Marseille,
France.
2) Department of Microbiology. University of Manitoba. Winnipeg, Canada.
3) Laboratoire de Chimie de Coordination. UPR 8241. CNRS et Université Paul Sabatier
4) UMRS CR7 et U1135. CIMI-Paris. Université Pierre et Marie Curie et INSERM. Faculté de Médecine Pitié-Salpêtrière.
Mycobacterium tuberculosis (TB) re-emerges as a major Public Health risk due to appearance of
multidrug-resistant strains. The first-line antituberculosis treatment is based on isoniazid (INH), rifampicin,
pyrazinamide and ethambutol. The macroscopic understanding of the activation mechanism of isoniazid (INH)
that involves a radical reaction resulting in the formation of the INH-NADH adduct and the evidence for the
crucial role of the TB heme enzyme KatG, a bifunctional catalase-peroxidase, in such activation are reasonably
established. However, the description of the molecular mechanism for the enzyme-catalyzed activation of INH
by TB KatG is yet under debate (recently reviewed in (1)) and prevents to rationalize the molecular basis of the
complex resistance strategy developed by the TB bacterium to the treatment with INH, which is mostly linked to
the occurrence of mutations in KatG. New physicochemical-based approaches to understand molecular aspects
of the KatG enzyme-mediated activation mechanisms of the pro-drugs isoniazide are crucial in assisting the
rational design of efficient anti-TB drugs circumventing current TB resistance pathways. We propose a
spectroscopy-based new paradigm to rationalize TB resistance to INH, that is based on our findings on KatG
catalytic intermediates (2) and the INH binding site which is far from the heme active site of KatG (3), with INH
oxidation occurring via a Trp radical and involving catalytically-relevant long-range electron transfers (2, 4).
Accordingly, these crucial long-range electron-transfer mechanisms related to the catalytic reaction may better
rationalize other frequently found mutations in KatG isolated from INH resistant patients, called missense-type,
and which are far from the heme site. A very recent and preliminary EPR characterization of such resistant-KatG
variants containing mutations other than S315T shows very encouraging results, since it is demonstrated that the
differences on the EPR spectrum of such mutants well-agree with perturbations (allosteric effects) on the
extended H-bonding network, that we have previously shown to be crucial for the catalase-like reactivity of
KatG as well as for the formation of alternative Trp-based radical intermediates of the peroxidase-like
cycle. Novel INH and ETH analogs targeted to be oxidized by the Trp radical intermediates of mutant KatGs of
resistant TB strains will be discussed.
References
1) O. J. Njuma, E. N. Ndontsa, D.C. Goodwin (2014) Arch. Biochem. Biophys. 544, 27-39.
2) R. Singh, J. Switala, P.C. Loewen, A. Ivancich (2007) J. Am. Chem. Soc. 129, 15954–15963
3) B. Wiseman, X. Carpena, M. Feliz, L.J. Donald, M. Pons, I. Fita, P.C. Loewen. (2010) J. Biol. Chem. 285, 26662-26673.
4) J. Colin, B. Wiseman, J. Switala, P.C. Loewen, A. Ivancich (2009) J. Am. Chem. Soc., 131, 8557–8563
- 105 -
RB008
THE PRESTWICK CHEMICAL LIBRARY, A VALUABLE TOOL FOR

SCREENING
Jean-Marie Contreras (1), Christophe Morice (1), Jean-Marc Simon (1), Bruno Didier (2), Marie-Louise
Jung (1), Thierry Langer (3)
1) Prestwick Chemical, 220 Blvd Gonthier d'Andernach, 67400 Strasbourg-Illkirch, FRANCE

2) University of Strasbourg, Therapeutic Innovation Laboratory, UMR7200 CNRS, Faculty of Pharmacy, 74 route du Rhin,
67400 Illkirch, FRANCE
3) University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, AUSTRIA
The discovery of novel drug molecules is a long, risky, and costly process and constant efforts are undertaken in
order to optimize this task. The use of smart and focused chemical libraries has proven its efficiency for hit
identification during early drug discovery. The Prestwick Chemical Library ® (PCL) is a product arising from
medicinal chemistry expertise comprising currently 1280 off-patent drugs, thus presenting a large degree of
chemical and pharmacological diversity within a relatively small number of compounds. The PCL was designed
to reduce the risk of "low quality" hits and the cost of the initial screening and may be used for a) assay
validation; b) finding hits for a new optimization program; c) repurposing/repositioning; d) finding modulators
of stem cell differentiation. Diversity in terms of chemical structure and biological activity will be illustrated and
discussed in the poster. Drug repurposing examples and successful screening results will be also reported. The
PCL comes in different formats with a fully-annotated database which was recently updated. Numerous
publications refer to the PCL for 10+ years.
- 106 -
RB009
REVERSIBLE AND COVALENT DNA BINDING OF AN

ANTHRACYCLINE DERIVATIVE: JEM-150
Shyam K Konda (1), Suzanne M Cutts (2), Don R Phillips (2), J Grant Collins (1)
1) School of Physical Environmental and Mathematical Sciences,

University of New South Wales, Australian Defence Force Academy, Northcott Drive,
Campbell, ACT 2600, Australia.
E-mail: shyam.konda@student.adfa.edu.au
2) Biochemistry Department
La Trobe University
Bundoora, VIC, 3083
Australia
Anthracyclines are a class of drugs that are widely used in cancer treatment. However, their usage is limited by
their cardiotoxicity. This toxicity promoted a search for new anti-cancer agents with no compromise in
therapeutic activity, but with reduced toxicity. JEM-150
(1,4-bis((2-((2-aminoethyl)amino)ethyl)amino)-5,8-dihydroxyanthracene-9,10 dione) is a second generation
derivative of mitoxantrone that displays low toxicity and pre-clinical studies are under progress. JEM-150 binds
DNA by intercalation like its parent drug. However, covalent binding is also observed between anthracyclines
and DNA in the presence of formaldehyde, which can be found at elevated level in some types of cancer cells.1
JEM-150 forms covalent adducts with DNA at guanosine residues. Further, studies have shown that if the
cytosine at the binding site is methylated at the 5-position, ten-times more covalent adducts are formed. We have
studied the reversible binding of the JEM-150 with oligonucleotides that contain methylated and non-methylated
cytosines by NMR and molecular modelling. Through the observation of intermolecular NOEs, it was
established that JEM-150 intercalates from the major groove at a non-methylated CpG site and via the minor
groove at a 5MeCpG site. This study revealed that the covalent adducts formation is governed by the mode of
pre-association of the JEM-150 with DNA.
References
1) S. Kato, P.J. Burke, D.J. Fenick, D.J. Taatjes, V.M. Bierbaum,T.H. Koch, Chem. Res. Toxicol. 13 (2000) 509–516.
- 107 -
RB010
SELECTIVE TARGETING LYSOSOME WITH SMALL MOLECULES

Trang Mai, Antje Hienzsch, Tatiana Caneque, Raphaël Rodriguez
1 Avenue de la Terrasse, 91190 Gif-sur-Yvette
Natural products and synthetic small molecules are central players in chemical biology studies. Lysosomes, the
intracellular compartments are filled with numerous hydrolases, act as the cellular recycling machinery to
degrade most of the cellular components. Small molecules such as Marmycin A and Salilomycin accumulate into
lysosomes, cause lysosomal membrane permeabilization and the consequent leakage of the cathepsin enzymes
from the lysosomal lumen to cytosol leads to "lysosomal cell death". Drug substances can perturb cellular
processes underlying diseases, thereby enabling the discovery of biological targets suitable for therapeutic
intervention. Small molecules have been shown to accurately tune protein and nucleic acids functions in
reversible and dose-dependent manners with valuable temporal resolution. Hence, small molecule approaches
are complementary to RNA interference strategies and offer the additional means of identifying associated
chemical hits for drug development. The efficient synthesis of molecular probes remains a worthy challenge. The
impact of synthetic organic chemistry and supramolecular processes on current cell biology and human medicine
will be illustrated.
- 108 -
RB011
DEVELOPMENT OF HIGHLY POTENT AND SELECTIVE

PREVENTION OF ACTIVATION (POA) MK2 INHIBITORS
Mickael Mogemark, Emma Evertsson, Magnus Munck af Rosenschold, Monica Norberg, Sarah Lever,
Hans Lonn, Frank Narjes, Peter Bold, Katerina Pardali, Ulf Hedstrom, Andy Davis
AstraZeneca R&D, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, 431 83 Molndal, Sweden
Mitogen activated protein kinases such as p38 MAPK (p38) and MAPK-activated kinase-2 (MK2) are attractive
targets for inflammatory diseases such as rheumatoid arthritis (RA), Crohn´s disease, inflammatory bowel
syndrome (IBS) and chronic obstructive pulmonary disease (COPD).1 Since p38α plays a dual role in the
inflammation cascade, due to activation of MK2 and MSK1, inhibition of p38α should not only decrease the
pro-inflammatory mediator TNFa which signals through MK2, but also the anti-inflammatory mediator IL-10,
through inhibition of the MSK1 pathway. Inhibition of MK2 on the other hand, should block only the production
of TNFa, whilst sparing the anti-inflammatory mediator IL-10.2 In our MK2 programme we conducted a high
throughput screening to identitfy two series of compounds, which inhibited the phosphorylation of non-activated
MK2 by p38α via a prevention of activation (PoA) mechanism.3,4 It was evident from X-ray structures, that the
compounds bound to the ATP pocket of p38α, but they had a higher affinity to the heterodimeric complex of
p38a-MK2 compared to p38α alone.3 The development of two novel lead series having excellent potency, good
physicochemical properties and kinase selectivity profile will be described. Furthermore, human cell results
leading to the invalidation of the hypothesis of sparing IL-10 will be presented.
References
1) Senthil Duraisamy, Malini Bajpai, Usha Bughani, Sunanda G Dastidar, Abhijit Ray & Puneet Chopra; Expert Opinionon
Therapeutic Targets (2008), 12, 921-936
2) Matthias Gaestel, Alexey Kotlyarov and Michael Kracht; Nature Rev. Drug Discovery (2009), 8, 480–49
3) John G. Cumming, Judit É. Debreczeni, Fredrik Edfeldt, Emma Evertsson, Martin Harrison, Geoffrey A. Holdgate,
Michael J. James, Scott G. Lamont, Keith Oldham, Jane E. Sullivan, and Stuart L. Wells, J. Med. Chem., 2015, 58, 278−293
4) Walter Davidson, Lee Frego, Gregory W. Peet, Rachel R. Kroe, Mark E. Labadia, Susan M. Lukas,
- 109 -
RB012
A NEW CONCEPT OF DUAL TARGETING DRUGS: DTP 348 A

CARBONIC ANHYDRASE IX INHIBITOR SPECIFIC FOR HYPOXIC
TUMORS
Nanda Kumar PARVATHANENI (1,2), Ludwig DUBOIS (2), Sarah G.J.A.PEETERS (2), Simon J.A
VAN KUIJK (2), Ala YAROMINA (2), Giuseppina DE SIMONE (3), Claudiu T. SUPURAN (4), Philippe
LAMBIN (2), Jean-Yves WINUM (1)
1) Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-ENSCM Université de Montpellier, ENSCM 8 rue de
l’EcoleNormale, 34296 Montpellier Cedex, France
2) Department of Radiation Oncology (MAASTRO Lab), GROW—School for Oncology and Developmental Biology,
Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD, Maastricht, The Netherlands
3) Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy.
4) Università degli Studi di Firenze, Neurofarba dept., Via U Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy
Hypoxia is one of the most devastating phenomenon while treating remote and solid tumors by
radio/chemotherapies. pH regulating transmembrane carbonic anhydrase IX is associated with poor prognosis
and therapy resistance. This made carbonic anhydrase IX as potential anticancer therapeutic target.
We developed series of nitroimidazoles incorporating sulfamide/sulfonamide/sulfamate moieties were having
radio/chemo sensitization property to target tumor-associated carbonic anhydrase isoforms IX and XII. Most of
the new compounds were nanomolar inhibitors of these isoforms. Inhibition efficacy of these molecules strongly
suggested by crystallographic studies on adduct of DTP-348 with hCAII. By reducing hypoxia-induced extra
cellular acidosis in HT-29 and HeLa cell lines these molecules showed significant activity of CAIX inhibition,
this was shown by crystal structure. (in vitro)
Lead molecule in sulfamide series (DTP-348) showed chemosensitization co-treated with Doxorubicin and
radiosensitization (in vivo) of carbonic anhydrase IX containing hypoxic tumors.
We were motivated to proceed with pre-clinical trials on DTP-348 with encouraging ADME (in vitro) screening
results, pharmacokinetic and cytotoxicity data.
References
01) McDonald PC, Winum JY, Supuran CT, Dedhar S. Oncotarget 2012, 3, 84-97
02) Dubois L, et al. Radiother. Oncol.2013, 108, 523-528.
03) Rami M, et al. J. Med. Chem.2013, 56, 8512−8520.
04) Dubois L, Lambin P, Supuran C.T, Winum J-Y Patent. June 2012: WO 2012/087115.Under license DualTPharma.
- 110 -
RB013
A DELICATE BALANCE - TARGETING PI3K AND/OR

MICROTUBULE DE-POLYMERIZATION
D. Rageot (1), T. Bohnacker (1), F. Beaufils (1), A. E. Prota (2), J. E. Burke (3), A. Melone (1), A. Inglis
(3), L. Fusco (1), V. Cmiljanovic (1,6), N. Cmiljanovic (1,6), K. Bargesten (2), G. Sáez-Calvo (4), O. Pertz
(1), A. B. Aher (5), A. Akhmanova (5), J. F. Díaz (4), D. Fabbro (6), M. Zvelebil (7), R. L. Williams (3), M.
O. Steinmetz (2), M. P. Wymann (1)
1) Dept. Biomedicine, University of Basel, Switzerland

2) Dept. Biology & Chemistry, Paul Scherrer Institut, Villigen, Switzerland
3) MRC Lab. Mol. Biol., Cambridge, UK
4) CIB Centro de Invest. Biológicas, Madrid, Spain
5) Dept. Biology, Utrecht University, The Netherlands
6) PIQUR Therapeutics AG, Basel, Switzerland
7) The Institute of Cancer Research, London, UK
Phosphoinositide 3-kinases (PI3K) have a central role in growth, proliferation, survival and migration, thus
being considered as drug target in oncology.[1] BKM120 is one of the clinically most advanced PI3K inhibitors
(PI3Ki) listed in more than 80 clinical studies. However, BKM120 was reported to disrupt microtubules (MT)
off-target.[2]
We defined structural factors of PI3K- and tubulin-binding of BKM120. A pure PI3K inhibitor (PQR309) and a
potent MT-disruptor (MTD147), differing from BKM120 by only one atom, allowed profiling of BKM120’s
PI3Ki and MT-disrupting activity: cell growth profiles of PQR309 clustered with other PI3Ki. BKM120
matched MTD147, yielding a G2/M cell cycle arrest at concentrations of 50% growth inhibition. Interestingly,
these BKM120 concentrations are within its reported AUC0-24 levels at day 8 in patient plasma.[3, 4] Therefore
the two activities of BKM120 cannot be separated at relevant doses, complicating the understanding of drug
action and impacting on the rational of combination therapies.
Using X-ray crystallography we found that BKM120 binds to the colchicine pocket on β-tubulin. We further
highlight the importance of the pyrimidine core orientation for tight tubulin binding. Interestingly, activities of
regioisomers of the pyrimidine core are inversed for PI3Ki and tubulin association, and modulate binding by a
factor of >30x. Finally, a combination of biochemical, cellular and structural data suggests an inverted
orientation of BKM120 in the catalytic cleft of PI3K as previously proposed.[5] Dissecting BKM120 functions
allowed reassessment of its dominant activity, allowing to increase drug safety, and to flexibly control PI3K
and/or MT targeting in combination therapy.
References
1) M. P. Wymann, R. Schneiter, Nat Rev Mol Cell Biol 9, 162 (2008)
2) S. M. Brachmann et al., Mol Cancer Ther 11, 1747 (2012)
3) J. C. Bendell et al., J Clin Oncol 30, 282 (2012)
4) C. Saura et al., Clin Cancer Res 20, 1935 (2014)
5) S. M. Maira et al., Mol Cancer Ther 11, 317 (2012)
- 111 -
RB014
INSIGHTS INTO THE MECHANISM OF ACTION OF BACTERICIDAL

LIPOPHOSPHONOXINS
Natalia Panova (1), Eva Zborníková (1), Ondřej Šimák (1), Radek Pohl (1), Milan Kolář (2,3), Kateřina
Bogdanová (3), Renata Večeřová (3), Tomáš Látal (2), Gabriela Seydlová (4), Radovan Fišer (4), Romana
Hadravová (1), Hana Šanderová (5), Michaela Šiková (5), Petra Lovecká (6), Ivan Barvík (7), Libor
Krásný (5), Dominik Rejman (1)
1) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2,
166 10 Prague 6, Czech Republic.
2) TRIOS, Ltd., Zakouřilova 142, Prague 4, 149 00, Prague, Czech Republic.
3) Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15
Olomouc, Czech Republic.
4) Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 43 Prague 2,
Czech Republic.
5) Institute of Microbiology, Academy of Sciences of the Czech Republic v.v.i., Vídeňská 1083, 142 20 Prague 4, Czech
Republic.
6) University of Chemistry and Technology, Technická 5, 166 28 Prague, Czech Republic.
7) Division of Biomolecular Physics, Institute of Physics, Faculty of Mathematics and Physics, Charles University in Prague,
Ke Karlovu 5, 121 16 Prague 2, Czech Republic.
The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to
the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial
compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit
selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains.1 Here, we
systematically searched for the mechanism of action of LPPOs. It was experimentally determined that LPPO do
not inhibit biosynthesis of neither DNA, RNA, proteins, lipids nor peptidoglycan. Furthermore we show that at
their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In
an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of
their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell
disintegration revealed by TEM. Further, we show that LPPOs are not genotoxic as determined by the Ames test
and are well tolerated by living mice when administered orally or peritoneally. Finally, using one of the most
potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to
readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class
of compounds with a potential as antibacterial agents.
Acknowledgement: The work was supported by grant no. TA02010035 (Technological Agency of the Czech
Republic)
References
1) Rejman D, Rabatinova A, Pombinho AR, Kovackova S, Pohl R, Zbornikova E, et al. Lipophosphonoxins: new modular
molecular structures with significant antibacterial properties. J. Med. Chem. 2011;54(22):7884-98. doi: 10.1021/jm2009343.
PubMed PMID: 22007704.
- 112 -
RB015
A SYSTEMATIC REVIEW OF THE UTERINE RELAXANT EFFECT

OF HERBAL SOURCES
Golnaz Rezaeizadeh (,1), Sedigheh Hantoushzadeh (2), Sima Ghiasi (3), Shekoufeh Nikfar (4), Mohammad
Abdollahi (3)
1) Family health institute, Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences (TUMS),
Tehran, Iran
2) Family health institute, Breast feeding Research Center, Tehran University of Medical Sciences, Tehran, Iran
3) Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
4) Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of
Medical Sciences, Tehran, Iran
Preterm birth is a worldwide tragedy with a high incidence. Several medications, are used to inhibit acute
preterm labor; but tocolysis by these drugs do not extend pregnancy beyond 1-2 days. So new medications
should be discovered for the treatment of preterm labor. For this purpose we reviewed all studies in which plant
extracts or their effective materials inhibit the uterine contractions. All electronic databases were searched up to
1st February 2012 with the most relevant keywords. Studies related to the relaxant effect of plant extracts or their
effective materials on the human or animal myometrium both in vivo and in vitro were included. Of initial
search, 259 records were reviewed and finally, 72 were included.
About the mechanism of these plant extracts or their effective materials we found that the nitric oxide pathway,
unlike human myometrium, dose not play an important role in relaxation of pregnant and non-pregnant rat
myometrium, but it probably acts on laboring rat myometrium. Another issue is about the store operated calcium
entry (SOCE), a voltage independent calcium entry pathway, which is upregulated in late pregnant and active
laboring rat myometrium and causes an increase in basal tone in these tissues, which is nifedipine resistant. In
this review, agents which blocked agonist-induced myometrium contractions in a calcium free solution, probably
acted via blocking the SOCE. SOCE can block by cyclic nucleotides. β-agonists and phosphodiesterase(PDE)
inhibitors can increase the cyclic nucleotides, but unlike β-agonists which are desensitizing at the end of the
pregnancy, PDE inhibitors can completely relax the pregnant myometrium. Studies have shown that some of the
effective materials that were reviwed in this study(osthole, Naringenin, Kaempferol and quercetin) are PDE
inhibitors.
Conclusion:It seems that laboring uterus responsiveness to different tocolytics vary from non-laboring uterus, so
further studies should work on the pharmacology of the laboring uterus and evaluated the effect of these PDE
inhibitor materials on blocking the SOCE, in human laboring myometrial cells and also determine the structure
activity relationship of these tocolytic compounds.
- 113 -
RB016
IDENTIFICATION OF NOVEL DRUG-LIKE SIRT INHIBITORS WITH

ANTI-ANGIOGENIC ACTIVITY
Lucie Ryckewaert (1), Sarah Berndt (1), Gilles Carpentier (2), Lionel Sacconnay (1), Ali Kannuna (1),
Pierre-Alain Carrupt (1), Muriel Cuendet (1), Alessandra Nurisso (1), Claudia Simoes-Pires (1)
1) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, Geneva,
Switzerland
2) CRRET Laboratory, University of Paris Est Creteil Val de Marne, Avenue du Général de Gaulle 61, 94010 Créteil Cedex,
France
Among the eighteen human histone deacetylases isoforms (HDACs), class III HDACs, also known as sirtuins
(SIRTs), are promising targets against some types of cancer such as prostate carcinomas and chronic
myelogenous leukemia [1-5]. In the present work we aimed at identifying novel SIRT catalytic inhibitors,
starting from a highly diverse library of drug like compounds generated in silico [6]. From the screening in vitro
of more than 600 compounds, two of them exhibited potent SIRT1 inhibitory activities (IC50< 20µM). Their
kinetic profiles were determined, revealing uncompetitive mechanisms of inhibition. Moreover, these
compounds displayed a non selective inhibitory behavior toward SIRT2. Computational structural studies
supported these experimental evidences. Fibrin bead assays were carried out to analyse the inhibitory effect of
both compounds against the three-dimensional sprouting of HUVECs, together with MTT cell growth assay.
Finally, different cellular mechanisms were explored [7, 8], highlighting a strong sirtuin-dependent
anti-angiogenic activity.
References
1) Bolden, J.E., M.J. Peart, and R.W. Johnstone, Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug
Discov, 2006. 5(9): p. 769-784.
2) Olmos, Y., J.J. Brosens, and E.W.F. Lam, Interplay between SIRT proteins and tumour suppressor transcription factors in
chemotherapeutic resistance of cancer. Drug Resistance Updates, 2011. 14(1): p. 35-44.
3) Roth, M. and W.Y. Chen, Sorting out functions of sirtuins in cancer. Oncogene, 2014. 33(13): p. 1609-1620.
4) Herranz, D., et al., SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene, 2013. 32(34): p.
4052-4056.
5) Yuan, H., et al., Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Vol. 119. 2012.
1904-1914.
6) Martel, S., et al., Large, chemically diverse dataset of logP measurements for benchmarking studies. Eur J Pharm Sci,
2013. 48(1-2): p. 21-9.
7) Oellerich, M.F. and M. Potente, FOXOs and sirtuins in vascular growth, maintenance, and aging. Circulation research,
2012. 110(9): p. 1238-1251.
8) Peck, B., et al., SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol
Cancer Ther, 2010. 9(4): p. 844-55.
- 114 -
RB017
RUTHENIUM(II) BASED COMPOUNDS AS DUAL TOPOISOMERASE

I AND II INHIBITORS
Mariana S. Camargo (1,), Monize M. Silva (1), Sara D. Vieira (2), Silvia Castelli (2), Alessandro Desideri
(2), Alzir A. Batista (1)
1) Universidade Federal de São Carlos - São Paulo, Brazil
2) Università Degli Studi di Roma Tor Vergata-Italy
Cancer continues to cause high mortality rates and develop resistance to chemotherapeutic drugs. Several
ruthenium-based compounds present lower systemic toxicity than the major metallo-drugs used for cancer
treatment1. Recently, different classes of ruthenium complexes have received considerable attention as
topoisomerase inhibitors2. DNA topoisomerases are essential enzymes that regulate the topological state of DNA
during cellular processes such as replication, transcription, recombination, and chromatin remodeling3. Although
the biological functions of topoisomerases are important for ensuing genomic integrity, topoisomerase I and II
proved to be excellent targets of clinically significant classes of anticancer drugs4. Our preliminary studies
showed that the ruthenium compounds: [Ru(pySH)(bipy)(dppb)]PF6 (1), Ru(HSpym)(bipy)(dppb)]PF6 (2) and
[Ru(SpymMe2)(bipy)(dppb)]PF6 (3), [dppb = 1,4-bis (diphenylphosphino)butane; bipy = 2,2’-bipyridine; HSpy
= 2-mercaptopyridine; HSpym = 2-mercaptopyrimidine; HSpymMe2 = 4,6-dimethyl-2-mercaptopyrimidine]
have higher cytotoxicity than doxorubicin and cisplatin against HepG2 cells and mutagenicity absence when
assessed by Ames test and micronucleus assay. These compounds also interact with DNA by electrostatic
interaction and with albumin by hydrophobic interaction. Thus, aiming to elucidate the cytotoxic mechanisms of
these compounds, the purpose of this study was to evaluate their capacity on inhibiting topoisomerase IB (Topo
I) and IIα (Topo II) by supercoiled DNA relaxation assay, catalytic cycle studies and molecular docking. The
results showed that compounds 2 and 3 fully inhibited Topo I activity in 50 and 25µM, respectively. Compound
3, the most active, inhibited cleavage reaction impeding the binding of the Top I to DNA and slow down the
religation reaction. Molecular docking showed that this compound preferentially binds close to the residues of
the active site when Topo I is free and lays on the DNA groove downstream of the cleavage site in Topo I - DNA
cleavage complex. Topo II relaxation assay showed that compounds 2 and 3 also fully inhibit this enzyme in
concentration of 125 µM being both compounds dual Top I and II inhibitors, while compound 1 showed to be
weak inhibitor of both evaluated enzymes. Since drugs able to act simultaneously against both types I and II
topoisomerases have been shown to be valuable and some of these drugs have been advanced to clinical trials4;
compound 3 can be considered in further studies for a possible use as anticancer agent.
References
1) Menezes, C. S.; de Paula Costa, L. C.; de Melo Rodrigues Avila, V.; Ferreira, M. J.; Vieira, C. U.; Pavanin, L. A.;
Homsi-Brandeburgo, M. I.; Hamaguchi, A.; de Paula Silveira-Lacerda, E., Analysis in vivo of antitumor activity, cytotoxicity
and Interaction between plasmid DNA and the cis-dichloro-tetra-amine-ruthenium(III) chloride. Chem Biol Interact 2007,
167 (2), 116-24.
2) Du, K.-J.; Wang, J.-Q.; Kou, J.-F.; Li, G.-Y.; Wang, L.-L.; Chao, H.; Ji, L.-N., Synthesis, DNA-binding and topoisomerase
inhibitory activity of ruthenium (II) polypyridyl complexes. European journal of medicinal chemistry 2011, 46 (4),
1056-1065.
3) Moukharskaya, J.; Verschraegen, C., Topoisomerase 1 inhibitors and cancer therapy. Hematology/oncology clinics of
North America 2012, 26 (3), 507-525.
4) Salerno, S.; Da Settimo, F.; Taliani, S., Simorini, F.; La Motta, C.; Fornaciari, G. M.; Marini, A. Recent advances in the
development of dual topoisomerase I and II inhibitors as anticancer drugs. Current Med Chem 2010 17(35), 4270-4290.
- 115 -
RB018
3-HYDROXY-3',4,4',5'-TETRA-METHOXY-CHALCONE INDUCES
G2/M ARREST AND TRIGGERS APOPTOSIS IN HUMAN HT-29 AND
HCT-116 COLORECTAL CANCER CELLS
Josiane Semaan (1), Aline Pinon (1), Benjamin Rioux (1), Lama Hassan (1), Christelle Pouget (1),
Catherine Fagnère (1), Vincent Sol (2), Mona Diab Assaf (3), Bertrand Liagre (1), Alain Simon (1)
1) Laboratoire de Chimie des Substances Naturelles - EA1069

Faculté de Pharmacie - 2 rue du Dr Marcland, 87025 Limoges Cedex
2) Laboratoire de Chimie des Substances Naturelles - EA1069
Faculté des Sciences et Techniques - 123 avenue Albert Thomas, 87060 Limoges Cedex
3) Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon
Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its
prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and
antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative
3-hydroxy-3',4,4',5'-tetra-methoxy-chalcone (HTMC) on proliferation, cell cycle distribution, apoptosis and its
mechanism of action in human colorectal HT-29 and HCT-116 cancer cells. HTMC decreased cell viability in a
dose-dependent manner with IC50 values about 35 µM and 0.5 µM for HT-29 and HCT-116 cells respectively.
Flow cytometric analysis revealed G2/M cell cycle accumulation in HT-29 cells and significant G2/M arrest in
HCT-116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. Western blot assay showed
that HTMC enhanced expression of p-p53, p21 and cyclin B1 proteins while the protein expression of Cdc2, an
essential kinase for the G2 to M transition, was downregulated thereby contributing to cell cycle arrest.
HTMC-treatment induced overexpression of pro-apoptotic death receptor 5 (DR5), caspase-8 and caspase-3
activation, poly-(ADP-ribose)-polymerase (PARP) cleavage and DNA fragmentation. Taken together, our results
indicated that HTMC induced cell cycle arrest in G2/M phase by modulating the p53/p21/Cdc2/cyclin B1
pathway before triggering programmed cell death that mainly occurred through activation of the extrinsic
apoptotic pathway. In addition, HTMC upregulated the phosphorylation of prosurvival Akt and extracellular
signal-regulated kinases (ERK)1/2 proteins at earlier time for HT-29 cells compared to HCT-116 cells, which are
deficient in cyclooxygenase-2 (COX-2). COX-2 is well known to play a critical role during colorectal
tumorigenesis and in chemoresistance, and is frequently overexpressed in colorectal cancer, as shown in HT-29
cells. Thus, colorectal tumor cells that highly express COX-2, should be less sensitive to anticancer drugs, which
act by inducing apoptosis, such as HTMC. Despite the activation of survival pathways, our results suggest that
HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention.
- 116 -
RB019
TRANSCRIPTOMIC ANALYSES: NEW INSIGHTS ON EAPB0503

ANTICANCER AGENT
Zahraa Zghaib (1,3), Kamel Hadj-Kaddour (1), Laure-Anais Vincent (1), Michel Bellis (2), Pierre-Antoine
Bonnet (1), Georges Moarbess (3), Issam Kassab (3), Mona Diab-Assaf (3), Pierre Cuq (1), Carine
Masquéfa (1)
1) Oncopharmacochimie et Pharmacotoxicologie cutanée, IBMM CNRS UMR 5247, Faculté de Pharmacie, Université de
Montpellier
2) Stress oxydant et neuroprotection IBMM CNRS UMR 5247, Université de Montpellier
3) Tumorigenèse et Pharmacologie Antitumorale, EDST-HADATH Liban
Imidazoquinoxalines (called Imiqualines) are a new series of anticancer heterocyclic compounds synthesized by
coupling imidazole ring to quinoxaline. Two identified leader molecules, EAPB0203 and EAPB0503, have
shown their efficiency in particularly against melanoma (A375) and T-cell lymphomas (Hut 102). EAPB0203
and EAPB0503 block A375 melanoma cells in the M phase of the cycle and inhibit purified tubulin
polymerization, leading to tubulin network disruption in both A375 and MCF7 cell lines1,2,3,4. Further studies
showed that Imiqualines bind to tubulin on the colchicine binding site (data under writing).
In order to refine another mechanism of action different of the mechanism cited above, a transcriptomic analysis
(using Affymetrix Human Genome-U133 plus.2 microarrays) was performed on A375 treated either by EAPB or
by 13 other anticancer drugs with known mechanism of action; all of them were used at 10 µM for 6 hours.
Microarray data analysis revealed several differentially expressed genes that we classified by a process involving
successively three methods - RMA (Robust Multi-array Average), RDAM (Rank Difference Analysis of
Microarrays) and MGSA (model-based gene set analysis). The lists of differentially expressed genes are used by
different comparisons of EAPB with the reference anticancer agents. Then, MGSA analyzes are performed ten
times for each list and we kept as significant the GO terms for which the average of the ten scores is greater than
or equal to 0.5. This method enables to analyze long lists of Gene Ontology terms and summarize them. Beside
that we submitted the GO terms selected in a web server REVIGO (Reduce+Visualize Gene Ontology) to
visualize the remaining terms in semantic similarity-based scatterplots, interactive graphs, or tag clouds.
References
1) Moarbess G. et al. Blood, 111: 3770-7. 2008.
2) Moarbess G. et al. Bioorg. Med. Chem. 16: 6601-10. 2008.
3) Deleuze-Masquefa C. et al. Eur. J. Med. Chem. 44:3406-11, 2009.
4) Khier S. et al. Drug Metab Dispos. 38:1836-47. 2010.
- 117 -
NOTES
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- 118 -
BookRICT.indd 82 15/06/2015 12:10:57

POSTERS:
Translational Approaches
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BookRICT.indd 83 15/06/2015 12:10:57

- 120 -
BookRICT.indd 84 3/06/2015 09:45:58

TA001
DESIGN AND BIOLOGICAL EVALUATION OF CENTRAL

SELECTIVE ACETYLCHOLINESTERASE INHIBITORS BY MEANS
OF A “BIO-OXIDIZABLE PRODRUG” STRATEGY
Anaïs Barré (1,2), Vincent Gembus (2), Cyril Papamicaël (1), Pierre Bohn (2), Francis Marsais (2),
Vincent Levacher (1,2)
1) Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, 76821 Mont
Saint Aignan Cedex, France.
2) VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
The efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer’s
disease is plagued by adverse effects arising from peripheral cholinergic activation. To improve their efficiency
we designed new central AChE inhibitors based on an original “bio-oxidizable” prodrug strategy.
Our lipophilic prodrugs are able to cross the Blood Brain Barrier (BBB) in order to enter the Central Nervous
System (CNS). Then the key activation step of these prodrugs involve the oxidation of a dihydroquinoline or
dihydropyridine I to the corresponding quinolinium or pyridinium salt II unmasking the positive charge required
for binding to the catalytic anionic site of the AChE enzyme.
The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of
rivastigmine,(1) while the pyridine series are based on analogues of donepezil.(2)
The biological evaluation of a lead compound via peripheral injection in mice, as well as its radiosynthesis for ex
vivo studies was realized and afforded very promising results.(3)
References
1) a) P. Bohn, F. Marsais, V. Levacher, et al., Organic & Biomolecular Chemistry 2009, 7, 2612; b) F. Marsais, P. Bohn, V.
Levacher, New heterocyclique coumpounds, their préparation and their use as medicaments in particular as anti-Alzheimer
agents, WO 2006103120.
2) F. Marsais, V. Levacher et al., Preparation of oxidizable pyridine derivatives as prodrugs for acetylcholinesterase
inhibitors and potent anti-Alzheimer agents, WO 2014114742.
3) P. Bohn, V. Levacher, et al., ACS Chem. Neurosci. 2015, accepted.
- 121 -
TA002
IMPROVED ANALGESIC: BU08028 A NOVEL, BIFUNCTIONAL

NOP/MOP LIGAND
Gerta Cami-Kobeci (1), Stephen M. Husbands (2), Mei-Chuan Ko (3), Lawrence Toll (4)
1) Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.
2) Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK
3) Wake Forest University, Winston-Salem, North Carolina, USA
4) Torrey Pines Institute for Molecular Studies, Port St. Lucie, Fl, USA
Although mu opioid (MOP) analgesics, such as morphine, are the preferred analgesics, they possess well
characterised, unwanted effects such as respiratory depression and abuse potential.
When a NOP (nociceptin receptor) agonist is co-administered with a MOP agonist, the combination produces a
synergistic effect, resulting in enhanced analgesia.[1] This suggests the possibility of obtaining strong analgesia
with only low efficacy partial agonism at both MOP and NOP receptors. Buprenorphine possesses partial MOP
agonist activity and, importantly, low efficacy, modest potency NOP partial agonism. However, one study has
detected no NOP receptor involvement in buprenorphine-induced physiological responses in primates[2] and so
an improved analgesic might have a buprenorphine-like profile but with enhanced NOP activity. To this end we
have synthesized novel buprenorphine-like analogs with increased NOP affinity and efficacy.
Fig 1. Structures of Buprenorphine and BU08028

Structure-activity relationship studies suggested that the region of space occupied by the tert-butyl group in
buprenorphine was key to good NOP receptor activity.[3] We have discovered BU08028, and other compounds,
having binding affinity at MOP receptors similar to that of buprenorphine and, as desired, higher affinity and
considerably higher efficacy than buprenorphine at NOP receptors. BU08028 has been evaluated in vivo for
attenuation of acute pain, using the tail flick assay and these results will be presented.
In measures of hyperalgesia, both in rodents (rats) and non-human primates (rhesus monkey) BU08028 was a
potent, long-acting anti-hyperalgesic with both MOP and NOP components to its activity. When administered
alone in doses up to 0.01 mg/kg, BU08028 did not induce itch scratching, a standard side-effect of opioids such
as buprenorphine.
More importantly, BU08028 at antinociceptive doses, did not compromise physiological functions including
respiration and cardiovascular activities measured using radio-telemetric probes.
Compared to MOP agonists, buprenorphine and remifentanil, BU08028 did not produce reinforcing effects in
monkeys under the progressive-ratio schedule of drug self-administration.
BU08028 therefore represents a potential analgesic agent, with low side effect profile.
This work was supported by NIDA grants DA020469 (SMH), DOD/Army W81XWH-13-2-0045 (M-ChKo) and
DA023281 (LToll).
References
1) Ko, M. Ch, Husbands, S. M.; ACS Symposium Series 1131, 2013.
2) Cremeans, C. M; Gruley, E; Kyle, D; Ko, M. Ch; J. Pharmacol. Exp. Ther., 2012, 343, 72-81.
3) a) Cami-Kobeci, G.; Polgar, W. E.; Khroyan, T. V.; Toll, L.; Husbands, S. M.; J. Med. Chem., 2011, 54, 6531-6537. b)
Khroyan, T. V.; Polgar, W. E.; Cami-Kobeci, G.; Husbands, S. M.; Zaveri, N. T.; Toll, L.; J. Pharmacol. Exp. Ther., 2011,
336, 952-961. c) Cami-Kobeci, G.; Polgar, W. E.; Khroyan, T. V.; Toll, L.; Husbands, S. M.; Pharmacological Reports, 2011,
63 (1), 210.
- 122 -
TA003
PHOTOTHERMIC ACTIVATED PHASE-SHIFTED

PERFLUOROCARBON DROPLETS FOR THERANOSTIC
APPLICATIONS IN CANCER
Marine Soulié (1), Florian Corréard (2), Ahmed Al-Kattan (3), Stéphane Desgranges (1), Guillaume
Baffou (4), Lucie Somaglino (6), Marie-Anne Esteve (2), Diane Braguer (2), Andrei Kabashin (3), Khaled
Metwally (1,5), Serge Mensah (5), Nicolas Taulier (6), Christine Contino-Pépin (1)
1) Avignon Université/ CNRS/ Montpellier 1/ Montpellier 2, IBMM UMR5247, Equipe Chimie BioOrganique et Systèmes
Amphiphiles, F-84000, Avignon, France.
2) Aix Marseille Université, INSERM, CRO2 UMR S 911, 13385 Marseille, France.
3) Aix Marseille Université, CNRS, LP3 UMR 7341, Campus de Luminy, 13288, Marseille Cedex 9, France.
4) Institut Fresnel UMR 7249, CNRS, Aix-Marseille Université, Centrale Marseille, 13013 Marseille, France.
5) LMA, CNRS UPR 7051, Aix Marseille Université, Centrale Marseille, F 13402 Marseille cedex 20, France.
6) Laboratoire d'Imagerie Biomédicale, Sorbonne Université UPMC Paris CNRS UMR 7371, INSERM U1146, Paris,
France.
Recently, properties of perfluorocarbons (PFC) have been used to improve contrast for ultrasound and
photoacoustic imaging as well as therapeutic purposes. The work presented herein deals with the design and
synthesis of sophisticated PFC/water nanoemulsions devoted to early detection of tumor development and
controlled/targeted chemotherapy. These nanoemulsions of liquid PFC dispersed in water are formed by
microfluidization and stabilized by tailor-made fluorinated surfactants called “F-TACs”.
Optimizing the hydrophilic-fluorophilic balance of the surfactants and the emulsification process, we
successfully developed nanoemulsions with interesting properties in terms of size evolution, cellular toxicity and
19F MRI detection1. However, the ultrasound echogenicity of such liquid nanodroplets is known to be poor in
comparison to conventional contrast agents. At this time, our strategy to improve echogenicity is to induce
vaporization of the PCF liquid core. To do so, we investigate the ability of gold nanoparticles coated at the
surface of our PFC nanodroplets to induce phase transition by photothermic activation.
We will present in this poster the preliminary results we obtained regarding the behavior of gold nanoparticles
(generated by femtosecond laser ablation process2) with the different constituents of our system (PFC core,
F-TACs micelles, F-TACs-PFC/water nanoemulsions) to figure out their affinity and localization (core and/or
shell). The cellular safety3 of nanoemulsions on human cell lines will also be presented.
References
1) K. Astafyeva, L. Somaglino, S. Desgranges, R. Berti, C. Patinote, D. Langevin, R. Salomir, A. Polidori, C. Contino-Pépin,
W. Urbach, and N. Taulier. J. Mater. Chem. B, 2015, 3, 2892-2907.
2) A. V. Kabashin, M. Meunier, C. Kingston, J. H. T. Luong J. Mater. Chem. B, 2003,107, 4527–4531.
3) F. Correard, K. Maximova, M.A. Estève, C. Villard, M. Roy, A. Al-Kattan, M. Sentis, M. Gingras, A.V. Kabashin, D.
Braguer. Int J Nanomedicine, 2014, 9, 5415-5430.
- 123 -
TA004
FRAGMENT-BASED SCREENING USING TANDEM MASS

SPECTROMETRY FOR THE DISCOVERY OF MYCOBACTERIUM
TUBERCULOSIS MABA INHIBITORS
Marion Flipo (1), Martin Moune (2), Ngoc Chau Tran (1), Catalin Pintiala (1), Alain Baulard (2), Nicolas
Willand (1), Benoit Deprez (1)
1) INSERM U1177, Drugs and Molecules for Living Systems, Univ. Lille Nord de France, Institut Pasteur de Lille, Lille
F-59006 France
2) INSERM U1019, CNRS UMR8204, Univ. Lille Nord de France, Institut Pasteur de Lille, Centre d'Infection et d'Immunité
de Lille, Lille F-59019 France
Tuberculosis remains a major cause of mortality and morbidity killing each year 1.4 million people. Although
the combined use of first line antibiotics is efficient to treat most patients, the rapid emergence of multidrug
resistant (MDR) strains of Mycobacterium tuberculosis stresses the need for alternative therapies. In this context
active molecules against unexploited targets are obviously needed.
Mycolic acids are very long-chain fatty acids playing an essential role in the architecture and permeability of the
envelope of M. tuberculosis. The mycolic acid biosynthetic machinery, which is the target of several
antitubercular drugs, still represents an important reservoir of attractive targets. The protein called MabA is
involved in mycolic acids biosynthesis. This enzyme has genetically been shown to be essential for M.
tuberculosis survival and it represents a target of choice to start a drug discovery program.
Our objective is to discover drug-like inhibitors of MabA active on sensitive and resistant M. tuberculosis strains
in order to propose a novel strategy to treat this disease. To enhance the chance to find low-molecular-weight
inhibitors, with adequate physicochemical properties to penetrate into the mycobacteria and reach their target,
we focused our strategy on a fragment based approach.
We have assembled a fragment library comprising 1280 compounds. This library has been designed based upon
the commonly accepted "Rule-of-Three". 1280 fragments were tested on MabA using a new enzymatic assay
which led to the discovery of several families of inhibitors. The optimization in drug-like compounds through
fragment evolution will be guided by X-ray crystallography and in silico modeling, combined with target-based
and cell-based activity assays performed at high throughput. The enzymatic assay based on tandem mass
spectrometry and the discovery of MabA inhibitors will be discussed.
- 124 -
TA005
DEVELOPMENT OF [18F]FLUORO-GLYCORGD FOR PET IMAGING

Charlotte COLLET (1,2), Fatiha MASKALI (1), Sylvain POUSSIER (1,2), Amel MOHAMADI (2,4),
Véronique REGNAULT (2,4), Patrick LACOLLEY (2,4), Yves CHAPLEUR (1,2,3), Pierre-Yves MARIE
(1,2,4), Gilles KARCHER (1,2), Sandrine LAMANDE-LANGLE (2,3)
1) Nancyclotep, CHU de Nancy-Brabois, F-54511 Vandoeuvre les Nancy - France

2) Université de Lorraine, F-54506 Vandoeuvre les Nancy – France
3) CNRS, UMR 7565, F-54506 Vandoeuvre les Nancy – France
4) INSERM U1116, 9 av. de la forêt de Haye, F-54500 Vandoeuvre-les-Nancy, France
PET1 is a radioactivity-based functional imaging technique requiring molecules radiolabelled with a

positron-emitting as fluorine-18 (18F). This imaging technique is used for diagnostic and gives also access to
pharmacodynamic and pharmacokinetic properties of injected labelled molecules.2 Peptides are the most
symbolic examples of bioactive entities that are today fully recognized as viable options for diagnostic and
therapy. However, the sensitivity of peptides does not allow their direct radiolabelling under harsh conditions. A
solution is to use a prosthetic group, an easily radiolabelled small molecule, subsequently coupled in mild
condition to the peptide.
We therefore proposed to develop new and easily accessible prosthetic groups based on carbohydrates
derivatives, functionalized with a good leaving group for easy substitution by fluorine-18. Some model peptides
containing a cysteine residue are radiolabelled, especially the Arg-Gly-Asp-Cys (RGDC) sequence. Indeed, the
high nucleophilicity of the thiol function can be exploited to prepare S-propargylated derivatives, prone to
cycloaddition reaction with the sugar prosthetic groups. The use of sugars as prosthetic groups is innovative and
would improve the bioavailability of peptides.
Biological activity of these glycoRGD was evaluated in vitro (platelet aggregation assay) and show that
introduction of a carbohydrate moiety on RGD peptides strongly enhances the inhibitory activity. The synthesis
and radiosynthesis of prosthetic groups and [18F]fluoro-glycoRGD will be presented.3 PET-scan images were
obtained in animals.4
References
1) Ametamey, S.M.; Honer, M.; Schubiger, P.A. Chem. Rev. 2008, 108, 1501-1516
2) Bhattacharyya, S., Biochem. Pharmacol. 2012, 1.
3) a) Vala, C.; Chrétien, F.; Balentova, E.; Lamandé-Langle, S.; Chapleur, Y. Tetrahedron Lett. 2011, 52, 17-20. b) Chapleur
Y., Lamandé S., Collet C., Chrétien F., PCT Int. Appl. (2014), WO2014006022 A120140109. c) Chapleur, Y.; Vala, C.;
Chrétien, F.; Lamandé-Langle, S.; Toward imaging glycotools by click coupling;
4) Lamandé-Langle, S. , Collet, C. Hensienne, R. , Vala, C. , Chrétien, F. , Chapleur, Y. , Mohamadi, A. , Lacolley, P. ,
Regnault. V., Bioorg. Med. Chem., 2014, 22, 6672-6683
- 125 -
TA006
GENE THERAPY FOR MELANOMA: THE EVALUATION OF rAAV

TRANSDUCTION EFFICIENCY OF B16-F10 CANCER CELLS
Milena Czajka (1), Magdalena Ducher (1), Joanna Skubis-Zegadlo (1), Malgorzata Wozniak (1),
Agnieszka Chodkowska-Gora (1), Edyta Banaczkowska-Duda (1), Izabela Kubrak (1), Krzysztof
Gawrychowski (2), Maciej Malecki (1)
1) Department of Applied Pharmacy and Bioengineering Medical University of Warsaw, Poland

2) Department of Gynecological Oncology and Oncology, Medicover Hospital, Poland
Melanoma is the one of the most aggressive cancer. It is known that incidences of skin melanomas are increasing
worldwide. Patients with metastatic melanoma have a very poor prognosis. In the last decades, several approved
drugs, such as tyrosine kinase inhibitors as well as experimental preparations have been described for malignant
melanoma. One of the novel therapeutic strategies for melanoma is recombinant adeno-associated vectors
(rAAV) based gene therapy. The rAAV vectors are non-pathogenic, small, in vitro propagated recombinant
viruses that represent the most promising therapeutic gene delivery vehicles to cancer cells. In our experiments
rAAV vectors were produced in a helper-free system using an AAV-293 packaging cells, and analyzed by
real-time PCR methods. The obtained viral vector preparations were used for in vitro and in vivo transduction
experiments. The transductions of malignant melanoma cells (B16-F10) at appropriate multiplicity of infection
range (MOI) were performed. We have tested the influence of various culture condition factors for transduction
efficiency of B16-F10 cells (e.g. growth factors, carbohydrates, lipids influence were taken into consideration).
Finally, we performed in vivo rAAV infection studies of B16-F10 tumors in C57BL/6 mice. Our studies reported
moderate infection of B16-F10 cancer cells by rAAV vectors, and the selected carbohydrates increase the
infectivity of rAAV. The expression of reporter genes (GFP and LacZ) attributable to the rAAV cell uptake was
dependent on the applied multiplicity of infection ratio (MOI). The highest infection efficiency was observed at
the highest rAAV doses. The in vivo infection efficiency was directly dependent on the state of tumor
development. The efficiency of infection was highest for relatively small B16-F10 tumors. This work documents
the ability of rAAV to infect of melanoma cells, and therefore it is worth mentioning the potential usefulness of
these recombinant viruses for further development of gene therapy of melanoma. This work was supported by a
grant from The National Centre for Research and Development (Strategmed1/233264/4/NCBR/2014,
MentorEYE).
- 126 -
TA007
COMPARISON OF HIT DISCOVERY APPROACHES CASE STUDY:

NIK INHIBITORS
Jean-Marie Contreras (1), Bo Svensson (2), Bjorn Walse (2), Salam Al-Karadaghi (2), Frank Totzke (3),
Michael H.G. Kubbutat (3), Christoph Schächtele (3), Christophe Morice (1), Thierry Langer (1,4)
1) Prestwick Chemical, Blvd Gonthier d'Andernach, 67400 Strasbourg-Illkirch, FRANCE

2) SARomics Biostructure, Scheelevägen 2, SE-223 63 Lund, SWEDEN
3) ProQinase, Breisacher Str. 117, 79106 Freiburg, GERMANY
4) University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, AUSTRIA
Identification of new chemical hits binding to a specific biological target is still one of the most challenging
steps within a drug discovery project. Whereas high-throughput screening (HTS) of large libraries of organic
compounds is still considered as a standard procedure in hit discovery, it remains a long and costly approach that
can be performed only by big pharma and mid-size biotech organizations. The use of smart and focused
chemical libraries nowadays represents a cost-effective and efficient alternative approach to the HTS accession.
Computer-aided drug design (CADD) has emerged in the past decades as powerful approach to limit the number
of compounds necessary to screen by skipping those predicted to be inactive. CADD tools such as virtual
screening using structure-based pharmacophore models and molecular modeling allow preselecting a smaller
number of molecules to be tested in vitro. In this presentation, we will describe the 3 previous strategies and
present experimental results obtained during TAKTIC (TrAnslational Kinase Tumor Inhibitor discovery
Consortium), a project funded within the FP7-SME-2012 framework, which aims to identify small molecule
inhibitors targeting NF-ĸB inducing kinase (NIK).
- 127 -
TA008
SYNTHESIS AND BIOLOGICAL EVALUATION OF

PYRAZOLYLMETHYLBENZENSULFONAMIDES AS T-TYPE
CALCIUM CHANNEL BOLCKERS
Ghilsoo Nam, Jung Hyun Kim, Jin Ri Hong, Seon Hee Seo, Eun Jeong Lim, Ae Nim Pae, Gyochang
Keum, Kyung Il Choi, Hyunah Choo
Senior Researcher, Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST),
Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea
Biophysical and pharmacological studies have identified five different subtypes of high-voltage activated (HVA)
calcium channel: L, N, P, Q, and R and one low-voltage activated channel (LVA): the T-type.1-2 The discovery
of specific blockers for different calcium channels types is focused on new drug development of calcium channel
related disease because each calcium channel subtypes contribute to different physiology of neuronal cells. 3
Recently, T-type calcium channels as a potential target for the treatment of chronic pain are interested in the
future drugs.4 Furthermore, the genetic study on the role of T-type calcium channel in pain suggest that the
thalamic control of visceral nociception mediates by T-type Ca2+ channels.5
As an effort to develop potent T-type calcium channel blockers, we have designed and synthesized novel series
of pyrazolylmethylbenzenesulfonamide derivatives. To examine their biological activities, compounds were
preliminary screened using cell-based FDSS6000 high-throughput screening (HTS) assay against CaV3.1 (α1G)
and CaV3.2 (α1H) calcium channels, and the compounds shown more than ~ 50% inhibition were evaluated for
metabolic stability, hERG channel inhibitory activity, and CYP liability. Here the detailed studies including
pharmacokinetic properties and in vivo efficacy will be presented
References
1) 1. Milizanich, J.; Ramachandran, J. Anun. Rev. Pharmacol. Toxicol. 1995, 35, 707-734
2) 2. W. A. Catterall. Annu. Rev. Cell. Dev. Biol. 2000, 16, 521-555
3) 3. K. S. Elmslie. J. Neurosci. Res. 2004, 75, 733-741
4) 4. J. L. Flatters, Sarah. Drugs of the future. 2005, 30 (6), 573-580
5) 5. D. S. Kim.; D. Park.; S Choi.; S. Lee.; M. Sun.; C. Kim.; H-S. Shin. Science, 2003, 302, 117-119
- 128 -
TA009
IN SILICO IDENTIFICATION, SYNTHESIS AND EVALUATION OF

TPH-3: AN ORIGINAL TIAM-1 INHIBITOR TARGETING
PH-DOMAIN TO PREVENT CANCER CELL INVASION
Arnaud Rives (1), Morgane Farge (2), Weixe Kong (3), Nicolas Caron (1), Vincent Cutillas (2), Julian
Nomme (2), Lu Chen (4), Michaël R. Paillasse (1), Shuxing Zhang (4), Emmanuelle J. Meuillet (2,3)
1) Affichem SA, Toulouse (FR)

2) ITAV-CNRS USR 3505, Toulouse (FR)
3) The University of Arizona Cancer Center, Tucson AZ (USA)
4) MD Anderson Cancer Center, Houston, TX (USA)
TIAM1 (T-lymphoma invasion and metastasis-inducing protein-1) is a highly conserved guanine nucleotide
exchange factor and contains an Dbl Homology (DH)/C-terminal Pleckstrin Homology (PH) domain. The crystal
structure of DH/PH of TIAM1 in complex with Rac-1 has been reported. TIAM1 has been found to be
over-expressed in cancers such as breast, colon and prostate cancers. An increase in TIAM1 expression has been
shown to be associated with increased metastatic potential of breast cancer cell lines and is also correlated with
poor prognosis of patients with prostate cancer. TIAM1 is thus a novel PH domain-containing drug target
directly related to cancer progression, metastasis and patient survival. We have identified and characterized
novel small molecule inhibitors targeting the phosphoinositide lipid binding PH domain of TIAM1 in order to
selectively inhibit cell migration, invasion and survival. An In Silico screen of our internal and Maybridge
libraries using the crystal structure of TIAM1 has identified 10 compounds that bind to the PH domain.
Innovative synthesis of TPH-3 is described here. in vitro assays, using surface Plasmon ressnance revealed that
compound significantly reduced the amount of active Rac1 in PC-3 prostate cancer cells and displaced
Phosphatidyl-Inositol-3,4,5-triphosphate. Molecular Modeling and docking studies confirmed the binding pocket
for TPH-3 in the PH domain. TPH-3 inhibited prostate and breast cancer cell proliferation with EC50 in the low
micromolar range (PC-3, LNCaP, MDA-MB-231 and MDA-MB-468). Target engagement was confirmed using
knock-in/out into MDA-MB-231 and PC-3 cell lines. Wound healing, colony & lamellipodia formation, relevant
of metastatic potential, were all inhibited by the compound. Finally, in vivo, early pharmacokinetic studies for
TPH-3 revealed a short half-life in the blood of C57BLJ6 mice injected with a single dose of 150mg/kg i.p.
Taken together, we have identified a novel compound with interesting chemical scaffold which exhibit the
ability to reduce prostate and breast cancer cell invasion by binding to the PH domain of TIAM1, an important
GEF in the process of metastasis. Alternative structural analogs of TPH-3 are being synthesized to improve the
in vivo efficacy and bioavailability.
This work was supported in part by the Toulouse Cancer Santé Foundation (Toulouse, FR)
- 129 -
NOTES
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BookRICT.indd 84 15/06/2015 12:12:23

POSTERS:
Understanding of the
Molecular Space
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BookRICT.indd 85 15/06/2015 12:12:23

- 132 -
BookRICT.indd 86 3/06/2015 09:45:58

UM001
INNOVATIVE HUMAN KINOME INHIBITION MODEL

Alina Bora (1,2), Sorin Avram (2), Stefana Avram (3), Ionel Ciucanu (1)
1) Department of Chemistry, West University of Timisoara, Faculty of Chemistry-Biology-Geography, 16 Pestalozzi Str.,

300115 Timisoara, Romania
2) Department of Computational Chemistry, Institute of Chemistry Timisoara of Romanian Academy, 24 Mihai Viteazul
Avenue, 300223 Timisoara, Romania
3) Victor Babes University of Medicine and Pharmacy Timisoara, Faculty of Pharmacy, Piata E. Murgu 2-4, 300034,
Timişoara, Romania
The human kinome comprises a wide range of therapeutic targets and many are available in extensive kinase
profiling panels. A challenge in drug discovery programs is the rapid and effective assessment of the kinase
selectivity properties to prioritize compounds in chemical libraries. In this study we propose an innovative
collection of kinase-inhibitors prediction models based on large-scale kinase activity data extracted from
publicly available sources. We used 2D‑pharmacophore fingerprints and random forest to generate a number of
107 kinase models which were externally validated. The prediction capabilities of the models were assessed in
terms of classification and virtual screening using adequate evaluation parameters, i.e., average accuracy of 0.89
(± 0.05) for classification, 84.65% (± 11.87) average of true positives retrieved within the 0.5% false positives
and average exponential receiver operating curve enrichment (eROCE) of 0.91 (± 0.08) for virtual screening.
Our approach provides a fast and efficient way to predict the kinase inhibitory profile of compounds in large
chemical libraries.
Acknowledgments: The work of Alina Bora was supported by the strategic grant POSDRU/159/1.5/S/137750,
Project "Doctoral and Postdoctoral programs support for increased competitiveness in Exact Science research"
co-financed by the European Social Fund within the Sectoral Operational Programme Human Resources
Development 2007-2013 and performed at West University of Timisoara.
- 133 -
UM002
RAPID TECHNIQUE FOR NEW SCAFFOLD GENERATION II: WHAT

IS THE BEST SOURCE OF INSPIRATION?
Tim Cheeseright, Susana Tomasio, Paolo Tosco, Mark Mackey, Ritesh Chauhan
Cresset, New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire, SG8 0SS
Scaffold hopping remains a central task in medicinal chemistry for generating and protecting intellectual
property. We have previously presented a technique for rapidly generating reasonable yet novel scaffold
replacements using molecular fields. We showed that our method, embodied in the scaffold hopping software
Spark, competes favorably with other published methods including those derived from quantum mechanics.
In this poster we explore how different data sources affect the results of scaffold hopping experiment. Common
data sources include small molecule crystal structures, screening compounds, available reagents and literature
reports of bioactive compounds. These data sources will be explored in relation to a set of Spark experiments
(e.g. core replacement, R-group exploration, fragment growing) to determine how they affect the quality of the
results.
- 134 -
UM003
VISUALIZING DESOLVATION IN THE FREE ENERGY OF BINDING

AND TORSIONAL SIGNIFICANCES: SeeSAR, A NEW TOOL FOR
MEDICINAL CHEMISTRY AND CRYSTALLOGRAPHY
Marcus Gastreich
BioSolveIT, An der Ziegelei 79, 53757 St. Augustin, Germany, mg@biosolveit.de
Medicinal Chemists are very much aware of avoiding torsional strain and the importance of water/desolvation
effects for ∆G. However, a concise and unparameterized estimation of these effects has been missing so far. And
consequently, there was no means to visualize these contributions during Lead Optimization.
We present a novel and unique software for the MedChem desktop that has been explicitly designed with the
Medicinal Chemist as target user groups in mind. As such, this tool ("SeeSAR") has three pronounced strengths:
● 3D Visualization of atom-based contributions (including enthalpy and entropy terms),
thus telling the user where there are strong and weak contributions to affinity [1]
● Torsional significance visualization based on crystal statistics [2]
● On-the-fly hypothesis checking (e.g., What if I changed this to fluorine?", "Would desolvation penalties still
allow me to have a nitrogen here?"), using an interactive editing facility.
The tool has been and is being written in very close collaboration with Hamburg University and BAYER [1];
parts of it rely on technology originally conceived in alliances with Big Pharma such as F.A. Hoffmann-LaRoche
[2] and BASF.
We will outline its applicability in the context of a Medicinal Chemist's everyday life and give several examples
of its usefulness that are partly already published in peer-reviewed journals by renown research groups globally.
These comprise selectivity questions (COX [2]), SAR elucidation (MAO-B [3]), optimization challenges
(dynamic combinatorial chemistry [4]), and crystallographic scrutineering.
References
1) Schneider et al., J.Comput.-Aided Des., 2013, 27(1) 15-29 and references therein.
2) Schärfer et al., J.Med.Chem. 2013 56 2016.
3) Tzvetkov et al., J. Med. Chem., 2014, 57(15), 6679.
4) Mondal et al., Angew.Chem.Int.Ed. 2014 53 1.
- 135 -
UM004
PALLADIUM-CATALYZED SYNTHESIS OF BRIDGED PHE-GLY

DIPEPTIDES TO ACCESS NOVEL LIGANDS OF TRANSLOCATOR
PROTEIN 18kDa (TSPO)
François Hallé (1), Imane Lejri (2), Irene Marginedas (3), Christelle Doebelin (1), Séverine Schneider (1),
Christian Klein (4), Michel Maitre (4), Martine Schmitt (1), Guy Mensah (4), Mariano Ostuni (3), Anne
Eckert (2), Frédéric Bihel (1)
1) CNRS, University of Strasbourg, UMR7200, Faculté de pharmacie, 74, route du Rhin, 67401 Illkirch
2) University of Basel, Dept of Biomedicine, Psychiatric University Clinics, Wilhelm Klein-Strasse 27, CH-4012 Basel
3) UMRS665 - Institut National de la transfusion sanguine, 6, rue Alexandre Cabanel, 75015 Paris
4) INSERM, University of Strasbourg, U1119, Faculté de medicine, 11 rue Humann, 67000 Strasbourg
We identified compound NCS1008 (1) as a good ligand of the Translocator Protein 18kDa (TSPO). As many
ligands of this protein, the druggability of NCS1008 is pretty poor as this compound is planar and contains a
high number of aromatic rings leading to low water solubility.
With the goal to improve druggability, we designed a bridged Phe-Gly dipeptide (2) which presents the same
pharmacophoric pattern as NCS 1008. This non-natural rigidified dipeptide constitutes a new unplanar scaffold
for TSPO. The bridged dipeptide is obtained through an intramolecular Buchwald-Hartwig cross-coupling
reaction starting from a 2-bromophenylalanine-glycine derivative (3), and we developed conditions that induce
chemoselectivity leading to either indoline (4) or 3,4-dihydroquinolinone (5) derivatives. Performed under mild
conditions, no racemization was observed during cyclization. A preliminary mechanistic study was performed to
identify the parameters leading to the cyclization chemoselectivity.
Following an unconventional strategy, we started from a planar heterocyclic compound to design a novel
unplanar bridged dipeptide, affording a new class of TSPO ligands.
- 136 -
UM005
MERIOLIN DERIVED HIGHLY POTENT PDK1 INHIBITORS

Timo Heinrich, Ulrich Graedler, Hans-Peter Buchstaller, Dieter Dorsch, Paul Czodrowski, Christina
Esdar, Margarita Wucherer-Plietker, Hartmut Greiner
Merck KGaA, MerckSerono, Frankfurter Str. 250, Darmstadt, Germany
The marine alkaloid variolin B, isolated from an Antarctic sponge in 1994,1 showed its kinase inhibitor potential
first against CDK. Four years later meridianins could be isolated from a tunicate also inhibiting kinases like
CDK or GSK-3.2 In 2007 the artificial hybrid scaffold of these natural products was called meriolin.3
3-Phosphoinositide-dependent protein kinase-1 (PDK1) is responsible for regulating the activity of related
kinases in the AGC kinase family by phosphorylating a specific threonine or serine residue within the activation
loop which is critical for kinase activation. Many of the kinases activated by PDK1 regulate cellular process such
as cell survival, differentiation, growth, and protein expression.4
In this poster we describe the synthesis and optimization of highly potent meriolin analogs, discuss the binding
mode and reflect on the topic of introducing selectivity into the putative multi-kinase inhibiting hinge-binding
element 7-Azaindole.
References
1) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G. Tetrahedron 1994, 50, 3987. (b) Trimurtulu, G.;
Faulkner, D. J.; Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994,
50, 3993
2) Hernandez Franco, L.; Bal de Joffe, E.; Puricelli, L.; Tatian, M.; Seldes, A. M.; Palermo, J. A. J. Nat. Prod. 1998, 61,
1130.
3) Bettayeb, K.; Tirado, O. M.; Marionneau-Lambot, S.; Ferandin, Y.; Lozach, O.; Morris, J. C.; Mateo-Lozano, S.; Drückes,
P.; Schächtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer
Res. 2007, 67, 8325.
4) Barile, E.; De, S. K.; Pellecchia, M. PDK1 inhibitors. Pharm. Pat. Analyst 2012, 1, 145-163. Raimondi, C.; Falasca, M.
Targeting PDK1 in Cancer. Current Medicinal Chemistry 2011, 18,2763-2769. Peifer, C.; Alessi, D. R. Small-molecule
inhibitors of PDK1. ChemMedChem 2008, 3, 1810-1838.
- 137 -
UM006
SAFAN-ISP: A NEW SMALL MOLECULE FRAGMENT

INFORMATICS APPROACH FOR IN-SILICO PROFILING
Luisa Pugliese (1), Marco Botta (2)
1) S.A.F.AN. BIOINFORMATICS. via Fulvio Croce 23/B 10137 Turin

Italy
2) Università degli Studi di Torino, Dipartimento di Informatica
Corso Svizzera 185, 10149 Turin - Italy
Background:
"Ligandability" describes a protein target's ability to bind small molecules with high affinity.
The pharmaceutical industry would be highly interested in any predictive tool that helps distinguish ligandable
from non-ligandable targets. Many known computational methods for predicting ligandability require knowing
the
3D structure of the protein target and/or understanding what ligand space is compatible with the target.
Fragments (molecules of low complexity) sample chemical space more effectively than drug-sized molecules.
Methods:
SAFAN-ISP combines fragment sampling capabilities and "revisited" publicly available ligand target
information concurrently predicting a compound's "ligandability" to 2900 protein targets belonging to 12
different classes, yielding binding constant as output.
Target prediction are coupled to diseases:target and disease:side effect data to output drug repositioning
information on selective drugs.
Results:
The method has been validated on the prediction of 18000 drug:target predictions that quantitatively correlate to
the experimental data yielding a Pearson correlation coefficient of 0.8.
The average error on the predicted binding constants, using a logarithmic scale is 0.5.
Conclusion:
SAFAN-ISP predictions are more precise than most of the other available methods and allow to find highly
selective drugs. Using molecular fragments the technology obtains reliable predictions where other methods fail:
using a unique weighted combination of whole-molecules and fragments match computations, consistently
outperforms other tools based only on either methods, as measured by correlation with known experimental
results. Using this ISP technology, molecules with lower similitude scores by either methods can be shown to
nonetheless adhere closely to experiments, unlocking their potential as active principles in drug repositioning
studies.
The developed SAFAN-ISP technology can be used for:
1. Drug repositioning using the target: disease database
2. Side Effect prediction using target: side effect database
3. Target identification in phenotypic screening outputs.
4- Potential therapeutic indications for natural compounds.
- 138 -
UM007
HOW ACCURATELY CAN WE PREDICT THE MELTING POINTS OF

DRUG-LIKE COMPOUNDS?
Igor V. Tetko (1,2,3,4), Yurii Sushko (3), Sergii Novotarskyi (3), Luc Patiny (5), Ivan Kondratov (6,7),
Alexander E. Petrenko (6), Larisa Charochkina (7), Abdullah M. Asiri (2,8)
1) Institute of Structural Biology, Helmholtz Zentrum Muenchen -German Research Center for Environmental Health,
Ingolstaedter Landstrasse 1, b. 60w, D-85764 Neuherberg, Germany
2) King Abdulaziz University, Faculty of Science, Chemistry Department, Jeddah, Saudi Arabia
3) eADMET GmbH, Garching, Germany
4) A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlyovskaya St. 18, 420008
5) EPFL, Lausanne, Switzerland
6) Enamine Ltd, Kyiv, Ukraine
7) Institute of Bioorganic and Petrochemistry, Kyiv, Ukraine
8) Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia
This article contributes a highly accurate model for predicting the melting points (MPs) of medicinal chemistry
compounds. The model was developed using the largest published dataset, comprising more than 47k
compounds. The distributions of MPs in drug-like and drug lead sets showed that > 90% of molecules melt
within [50,250]°C. The final model calculated an RMSE of less than 33°c for molecules from this temperature
interval, which is the most important for medicinal chemistry users. This performance was achieved using a
consensus model that performed calculations to a significantly higher accuracy than the individual models. We
found that compounds with reactive and unstable groups were overrepresented among outlying compounds.
These compounds could decompose during storage or measurement, thus introducing experimental errors. While
filtering the data by removing outliers generally increased the accuracy of individual models, it did not
significantly affect the results of the consensus models. Three analyzed distance to models did not allow us to
flag molecules, which had MP values fell outside the applicability domain of the model. We believe that this
negative result and the public availability of data from this article will encourage future studies to develop better
approaches to define the applicability domain of models. The final model, MP data, and identified reactive
groups are available online at http://ochem.eu/article/55638 and the model is already published.1
References
1) Tetko IV, Sushko Y, Novotarskyi S, Patiny L, Kondratov I, Petrenko AE, Charochkina L, Asiri AM. J Chem Inf Model.
2014 Dec 22;54(12):3320-9
- 139 -
UM008
USING BIOPHYSICS TO TARGET METHYL TRANSFERASES

(HKMTS) WITH SMALL MOLECULES
Oscar van Linden, Gregg Siegal
ZoBio BV, Einsteinweg 55, 2333CC Leiden, The Netherlands
DOT1L is a unique histone lysine methyl transferase that is an epigenetic regulator of gene transcription. The
substrate of DOT1L is H3K79 and it methylation is linked to various cancers. The crystal structure of the
DOT1L catalytic domain (CD) in complex with its cofactor SAM (S-Adenosyl methionine) and the product
SAH, as well as a number of related inhibitors, have been deposited in the PDB (e.g. 3SR4, 4HRA, 4EKG &
1NW3). We have expressed the CD in E. coli, shown its functionality and screened for weakly binding “drug
fragments”. The fragment hits have been validated using SPR (Biacore) and their affinities have been accurately
determined. In order to progress these weakly binding hits into “lead-like” compounds an important component
would be to have structural information on inhibitor-protein complexes. Structural biology is a critical part of the
modern process of drug design and obtaining structural information on the binding site location and orientation
of hit fragments at an early stage is particularly important in fragment based drug discovery. NMR based
structure elucidation of a target-ligand complex is a good alternative when determination of such a complex by
X-ray crystallography fails. We will demonstrate how biophysical techniques are used to determine the binding
characteristics of small molecules interacting with DOT1L.
- 140 -
UM009
IN SILICO MODELING OF HUMAN DOPAMINE TRANSPORTER

AND DESIGN OF NOVEL INHIBITORS
Yelekci Kemal, Djikic Teodora
Faculty of Engineering and Natural Sciences, Kadir Has University, Fatih 34083, Istanbul, Turkey, Fax: +90 212 533 6515,
yelekci@khas.edu.tr, Phone: +90 212 5336532
Parkinson’s disease is a common neurodegenerative disorder of the central nervous system. It is characterized by
the loss of dopamine-generating neurons in the substantia nigra and corpus striatum (which leads to the
decreasing level of dopamine) and accumulation of α-synuclein aggregates in the brain. Presently, commercial
drugs in market altogether do not provide complete treatment for neuronal degradation however only treats the
disease in a symptomatic way.
Dopamine transporter (DAT) plays an important role in the termination of neurotransmission by rapid reuptake
of dopamine (DA) from the synaptic cleft into presynaptic terminals where it will be degraded by monoamino
oxidase. With the blockade of DAT, level of dopamine in synaptic cleft as well as dopaminergic
neurotransmission will increase. We have modelled the human DAT based on a drosophila’s DAT X-ray crystal
structure, and minimized it in the environment of the lipid bilayer and solvent water. The transporter was
validated with known inhibitors downloaded from CHEMbl database, in Auto Dock 4.2. and GOLD 5 docking
software. The obtained results correlated positively with the existing experimental results. The binding free
energy for DA, according to preexistent experiments, is ΔGexperimental = -7,4 kcal/mol; while ΔGcalculated = -6,4
kcal/mol was obtained through our studies. The binding position of DA, also, coincides with previous literatures:
interaction with Phe320, Asp79, Ser149, Ser422, and Thr156 amino acids. Thus, with the results collected, a
new model was designed for potential inhibitors approached through De Novo and fragment based drug design.
Novel selective DAT inhibitors, when alone or in combination with levodopa, may improve the quality of life in
patients suffering from Parkinson’s disease.
- 141 -
NOTES
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- 142 -
BookRICT.indd 86 15/06/2015 12:13:40

POSTERS:
Case Studies
- 143 -
BookRICT.indd 87 15/06/2015 12:13:40

- 144 -
BookRICT.indd 88 3/06/2015 09:45:58

CS001
THE STRUCTURE-ACTIVITY RELATIONSHIP IN A SERIES OF

FUSED SELENOPHENO QUINOLINONES AND COUMARINS
Pavel Arsenyan, Ilona Domracheva, Jelena Vasiljeva
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia

pavel.arsenyan@lycos.com
The furoquinolinone alkaloids are widely distributed in nature. They can be primarily isolated from Rutaceae
species as angularly and linearly fused structures. For these compounds various biological activities such as
antimicrobial, antimalarial, insecticidal, antineoplastic, antidiuretic, antiarrhythmic and sedative, have been
reported. Also the coumarin system is found in the composition of many natural compounds and derivatives of
coumarin have drawn considerable attention because of their biological activity (for ex., medical preparations
Psoralen, Angelicin, Xanthotoxin, Bergapten, Nodakenetin). On the other hand, selenium has attracted great
interest as an essential element and certain diseases have been eradicated through dietary supplementation of this
element. Glutathione peroxidase and other enzyme systems proper function depends on selenium. There have
been attempts to prevent certain cancers by supplementation with selenium. We developed a straightforward
method for the preparation of a fused heterocyclic systems, namely selenophenoquinolinones[1] and
selenophenocoumarins[2], via reaction of in situ prepared selenium(IV) bromide with ethynyl quinolinones and
coumarins, respectively.
The structure-activity relationships of selenophenoquinolinones and selenophenocoumarins as inhibitors

malignant cell proliferation, inducers of apoptosis and not necrosis, activators of human caspases (1–10), as well
as modulators of enzyme activities (superoxide dismutase, glutathione peroxidase, thioredoxin reductase) will be
discussed.
The financial support for this work provided by the Latvian Council of Science (593/2014) is gratefully
acknowledged.
References
1) Arsenyan et al. Chem. Heterocycl. Comp., 2014, 49, 1674-1680.
2) Arsenyan et al. Comptes Rendus Chimie, 2015, 118, 399-409.
- 145 -
CS002
PRMT5 INHIBITORS AS NOVEL TREATMENT FOR CANCERS

Ian P. Street (1), Hendrik Falk (1,2,3), Ylva E. Bergman (1,4), Scott R. Walker (1,4), Stefan E.
Sonderegger (1,8), Elizabeth Allan (1,2), Michelle A. Camerino (1,4), Susan A. Charman (1,6), Melanie de
Silva (1,2), Mark Devlin (1,9), Richard C. Foitzik (1,4), Danny Ganame (1,2), Julian Grusovin (1,7), Stefan
J. Hermans (1,5), Catherine F. Hemley (1,4), Ian P. Holmes (1,4), Wilhelmus J.A. Kersten (1,2), H. Rachel
Lagiakos (1,4), Romina Lessene (1,2,3), Gillian E. Lunniss (1,4), Benjamin J. Morrow (1,4), Anthony
Natoli (1,9), Michael W. Parker (1,5), Thomas S. Peat (1,7), Jo-Anne Pinson (1,4), Patricia Pilling (1,7),
Alex E. Stupple (1,4), Alison Thistlethwaite (1,6), Emma Toulmin (1,8), Karen L. White (1,6), David J.
Curtis (1,8), Stephen M. Jane (1,8), Brendon J. Monahan (1,2), Marica Nikac (1,4), Matthew Chung (1,5),
Hong Yang (1,2), Paul A. Stupple (1,4)
1) Cancer Therapeutics CRC (CTx), Parkville, Australia

2) Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
3) Department of Medical Biology, The University of Melbourne, Parkville, Australia
4) Monash Institute of Pharmaceutical Sciences, Parkville, Australia
5) St Vincent's Institute, Fitzroy, Victoria, Australia
6) Centre for Drug Candidate Optimisation, Parkville, Australia
7) Materials Science and Engineering Division, CSIRO, Parkville, Australia
8) Australian Centre for Blood Diseases, Monash University
9) The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
Increased expression or dysregulation of protein arginine methyltransferase 5 (PRMT5) activity is associated

with poor prognosis in many cancers. Through increased methylation of epigenetic and non-epigenetic targets,
the aberrant activity of PRMT5 has been associated with many pro-tumourigenic cellular changes such as,
increased levels of protein synthesis, dysregulation of cell cycle, cellular adaptation to hypoxic conditions, and
suppression of normal cell death pathways. Genetic studies suggest that suppression of PRMT5 activity can
reverse many of these pro-tumourigenic effects making PRMT5 an attractive drug discovery target.
We screened a library of 350,000 lead-like compounds with a biochemical assay measuring the methylation of a
histone H4 peptide by the recombinant human PRMT5/MEP50 complex. Biochemical and biophysical profiling
of the inhibitory compounds indicated that several distinct binding modes were exhibited by the different
chemical scaffolds. Inhibitors displayed competitive, noncompetitive or uncompetitive interactions with respect
to S-adenosyl methionine and the peptide substrate. Medicinal chemistry developed several classes of potent,
highly selective inhibitors of PRMT5 methyltransferase activity from the hit set. The optimised tool compound,
CTx-034, is a potent inhibitor of PRMT5 methyl transferase activity (KD = 2 nM), which is highly selective
(>100-fold) versus a panel of 18 methyltransferases (including 6 PRMT family members), 11 lysine
demethylases, and 15 safety related targets (GPCRs, ion channels, enzymes). Treatment of cancer cell lines with
CTx-034 reduces cellular levels of symmetrically dimethylated H4 Arginine 3 (H4R3me2s), in a dose dependent
manner (IC50 = 4 nM) to levels undetectable by Western blot. Furthermore, within this chemical series the ability
of compounds to reduce cellular levels of H4R3me2s closely correlates with PRMT5 inhibitory activity
supporting PRMT5 as the cellular target of these compounds, and suggesting that PRMT5 is the major writer of
this histone mark in many cancer cell lines. CTx-034 also inhibits the symmetric dimethylation of arginine on
other histone and non-histone cellular substrates of PRMT5, including H3R2me2s and SmD1. Conversely,
CTx-034 treatment does not reduce levels of H4R3 asymmetric dimethylation, a histone mark catalysed by
PRMT1.
Finally, CTx-034 has good oral bioavailability and pharmacokinetic properties in rodents and twice-daily dosing
(10 - 100 mg/kg) over 10-14 days produces a dose dependent reduction of the H4R3me2s mark in bone marrow
cells and peripheral white blood cells. This treatment is well tolerated by the mice, with no significant reduction
in body weight or changes in haematological parameters observed.
CTx-034 provides an excellent tool compound for cellular and in vivo proof of concept studies.
- 146 -
CS003
DISCOVERY OF DONECOPRIDE A NOVEL MULTI-TARGET

DIRECTED LIGANDS FOR ALZHEIMER'S DISEASE
Christophe Rochais (1), Cédric Lecoutey (1), Thomas Freret (2), Céline Ballandonne (1), Valentine Bouet
(2), Patrizia Giannoni (3), Florence Gaven (3), Sylvie Claeysen (3), Michel Boulouard (2), Patrick
Dallemagne (1)
1) Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN) - UPRES EA 4258 - FR CNRS INC3M -
SFICORE, Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques - Bd Becquerel
F-14032 Caen, France
2) Groupe Mémoire et Plasticité comportementale (GMPc) - EA4259 - Université de Caen Basse-Normandie, UFR
desSciences Pharmaceutiques - Bd BecquerelF-14032 Caen, France
3) CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 MONTPELLIER
Complex pathologies such as Alzheimer's disease (AD) would benefit from a combination of actions targeting,
in the same time, several molecular causes implied in the pathogenesis. Our aim was to design a multi
target-directed ligand (MTDL) gathering two properties: acetylcholinesterase (AChE) inhibition and 5-HT4
receptor activation. AChE inhibition is the action mechanism of donepezil, the current available drug for AD.
Activation of 5-HT4 receptors promotes the non-amyloidogenic cleavage of the amyloid precursor protein (APP)
and the release of the neuroprotective soluble APPalpha fragment.
Combining a dual-binding site pharmacophore of AChE inhibitors with a pharmacophore of 5-HT4R ligands, we
isolated a candidate compound and performed pharmacomodulation of this hit to optimize its properties. We
selected donecopride1 as a druggable lead able to inhibit AChE (IC50 = 16 nM) and to induce sAPPalpha release
(EC50 = 11.3nM) upon 5-HT4R activation (Ki = 10.4 nM; 48.3% of serotonin response). In vivo properties of
this new compound in the 5XFAD mouse model of AD (acute and chronic administration) will be presented.
References
1) Lecoutey, C. et al. PNAS, 2014, 111 (36), E3825-E3830.
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CS004
REVERSIBLE MAO-B INHIBITORS WITH SUB-NANOMOLAR

POTENCY: DISCOVERY OF PROMISING DRUG CANDIDATES FOR
THE TREATMENT OF PARKINSON'S DISEASE
Nikolay T. Tzvetkov (1), Sonja Hinz (1), Petra Küppers (1), Christa E. Müller (1), Marcus Gastreich (2)
1) University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany

2) BioSolveIT, An der Ziegelei 79, 53757 St. Augustin, Germany, mg@biosolveit.de
Despite the fact that Parkinson's Disease (PD) was first diagnosed already two centuries ago, the “gold standard”
for its treatment still remains levodopa – a prodrug of monoamine neurotransmitter dopamine [1,2]. We
discovered very selective, sub-nM inhibitors acting through a different mechanism of action [3].
The enzyme monoamine oxidase B (MAO-B) catalyzes the oxidative degradation of monoamine
neurotransmitters and biogenic amines. Selective inhibition of MAO-B in the human brain is considered an
attractive concept for treatment of several neurodegenerative conditions, including PD and AD. We report on a
series of novel indazole-5-carboxamides (designated class I), indole-5-carboxamides (class II) and
(indazol-5-yl)methanimine derivatives (class III) as highly potent, selective and reversible MAO-B inhibitors
[3]. The most potent derivatives were compounds which belong to the best balanced MAO-B inhibitors reported
to date [3].
Structural optimization and SAR analyses further led to the discovery of remarkably potent competitive and
reversible MAO-B inhibitors with sub-nanomolar potency. Moreover, these compounds are highly useful as
pharmacological tools for in vitro and in vivo studies, and may be suitable for the development of radioligands,
including diagnostics for positron emission tomography (PET). One compound can be highlighted because of its
remarkable in vitro MAO-B inhibitory activity and selectivity - combined with a well-balanced physicochemical
profile which is predictive of CNS bioavailability.
To rationalize the SAR detected and investigate further exploration steps, we analyzed the binding mode of
selected C5- versus C6-substituted indazole-carboxamide derivatives within the binding pocket of the human
MAO-B enzyme [3] using a novel Free Energy approximation concept ("HYDE"), originally published by Bayer
and collaborators.[4]
References
1) Hopkins et al. Future Med. Chem., 2009, 1(3), 501–513.
2) Malek and Grosset J. Exp. Pharmacol., 2012, 4, 85–90.
3) Tzvetkov et al. J. Med. Chem., 2014, 57(15), 6679–6703.
4) Schneider et al., J.Comput.-Aided Des., 2013, 27(1) 15-29 and references therein.
- 148 -
CS005
PHENOXYMETHYL 1,3-OXAZOLES AND 1,2,4-OXADIAZOLES AS

POTENT AND SELECTIVE AGONISTS OF FREE FATTY ACID
RECEPTOR 1 (GPR40)
Ihor Zahanich, Ivan Kondratov, Vasyl Naumchyk, Yuri Kheylik, Maxim Platonov, Sergey Zozulya,
Mikhail Krasavin
Enamine Ltd, Chervonotkatska, 78, 02094 Kyiv, Ukraine
A screening hit that showed a weak (EC50 = 18 uM), partial agonistic effect on GPR40 was used a prototype for
expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles
and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 uM). The lead compounds in
each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal
stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds
reported are significant new starting points for further preclinical development of future diabetic agents with a
mechanism of action for which a first-in-class agent is yet to be approved.
- 149 -
CS006
SIGNALLING PATHWAY-BASED SCREENING FOR DRUG

DISCOVERY: AN APPLICATION IN MULTIPLE SCLEROSIS
Dimitris E Messinis (1,2), Vicky Pliaka (2), Sophia Stamatatou (2), Theodore Sakellaropoulos (1),
combiMS consortium (3), Leonidas G Alexopoulos (1,2)
1) National Technical University of Athens, Greece

2) ProtATonce Ltd, Athens, Greece
3) combiMS consortium (http://www.combims.eu) is: IDIBAPS Hospital Clinic of Barcelona, Spain / Department of
Neurology and Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden / University of
Zurich, Switzerland / NeuroCure Clinical Research Center, Charité University Medicine Berlin, Berlin, Germany / European
Molecular Biology Laboratory, European Bioinformatics Institute, UK / ProtATonce Ltd, Athens, Greece / Anaxomics
Biotech, Barcelona, Spain / Bionure Farma SL, Barcelona, Spain
Multiple Sclerosis (MS) is an autoimmune disease affecting the brain and spinal cord. There is not yet a cure for
the disease while 2,5 million people around the world have MS. Several pathological mechanisms for MS have
been described, involving alterations in multiple processes and signalling pathways.
Our goal is to evaluate how current MS drugs and compounds with a therapeutic potential work at the signalling
level in different patient populations. By understanding how current MS drugs work on patient-specific
biological networks, more effective therapies can be designed that take into account the uniqueness of each
patient’s response in treatment and biomarkers can be developed to stratify patients.
For the production of this dataset, we used High-Throughput Screening (HTS) with custom cell signalling assays
(by ProtATonce), that allow screening of thousands of samples at the proteomic and phosphoproteomic level at a
very small fraction of the cost compared to off-the-shelf reagents. Strict quality control check points were
embedded to the collection-to-measurement pipeline in order to evaluate errors in sample collection, sample
preparation, ELISA procedure and instrument variation.
Collection kits were prepared and shipped to 4 clinical centres across EU in order to collect peripheral blood
mononuclear cells (PBMCs) from 255 donors. The cells were plated and stimulated at 3 time points with 20
compounds and drugs. We collected cell lysates and cell supernatants to simultaneously quantify in the samples
17 phosphoproteins and 22 secreted proteins respectively.
This dataset was analysed with pathway optimization tools for the construction of detailed signalling pathway
maps for each donor which can help reveal the drugs’ mode of action and efficacy in correlation with differences
in the patient population. The therapeutic potential of compounds that their phosphoproteomic signature matches
that of existing drugs will be evaluated and the data will be combined with SNP data and clinical profiles in an
attempt to develop biomarkers to distinguish between responder and non-responder to treatment patients.
- 150 -
CS007
INSIGHT INTO BINDING MODE AND SELECTIVITY OF

HETEROCYCLIC INHIBITORS OF JNK KINASES USING
STRUCTURE BASED DRUG DESIGN APPROACH
Abdellah Messoussi (1,2), Gwenael Cheve (1), Khalid Bougrin (2), Aziz Yasri (1)
1) OriBasePharma,1682 Rue de la Valsière, 34000 Montpellier, France.

2) Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23,Mohammed V University, Faculty
of Sciences,Rabat, Morocco.
In mammals, the JNK kinase family includes three closely related members: JNK1, JNK2 and JNK3.
Overexpression of JNK was detected in a wide range of human cancers(1). Generally kinases can exist in two
forms, the active form called DFG-in and the DFG-out representing the inactive form. The latter is the most
therapeutically interesting to design type II inhibitors. Until today, the most of the available 3D structures of
JNKs concern the active form, whereas for the inactive form, only one 3D crystal structure is published, JNK2
with the ligand BIRB 796(2). The elucidation of the 3D structures of the inactive forms of JNK1 and JNK3 is
required for the understanding of JNKs active sites that allows a rational design of JNK1, JNK2 and JNK3 type
II selective heterocyclic inhibitors using various techniques of structure based drug design (SBDD).
This study shows how SBDD techniques, like homology modeling and docking were used to obtain 3D
structures of JNK1 and JNK3 in the DFG-out forms. This allows us to performa rational design and chemical
synthesis of potential heterocyclic JNKs inhibitors (Figure 1).
References
1) C. Bubici et S. Papa, Br. J. Pharmacol., vol. 171, no 1, p. 24‑37, janv. 2014.
2) A. Kuglstatter, M. Ghate, S. Tsing, A. G. Villaseñor, Bioorg. Med. Chem. Lett., vol. 20, no 17, p. 5217‑5220, sept. 2010.
- 151 -
CS008
HYDANTOINS AS A NOVEL SCAFFOLD FOR SIRT INHIBITION:

FROM VIRTUAL SCREENING TO ACTIVITY ASSAYS
Lucie Lucie Ryckewaert (1), Lionel Sacconnay (1), Giuseppe Marco Randazzo (1), Charlotte Petit (1),
Carolina Dos Santos Passos (1), Asta Zubrien (2), Matulis Daumantas (2), Pierre-Alain Carrupt (1),
Claudia Simoes-Pires (1), Alessandra Nurisso (1)
1) School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211, Geneva
4, Switzerland
2) Laboratory of Biothermodynamics and Drug Design, Institute of Biotechnology, LT-02241 Vilnius, Lithuania
Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation activity of N-acetyl lysines of both
histone and non-histone substrates. Their catalytic inhibition was recently reported in the literature as beneficial
in aging-related diseases such as cancer and neurodegeneration [1-3]. By coupling a structure-based virtual
screening approach with enzymatic and cellular assays, we identified hydantoins as a new scaffold for SIRT2
catalytic inhibition. Compound 97, active against SIRT2 in the low µM range, showed optimal physiochemical
properties for passive adsorption and low cytotoxicity in vitro. Further studies revealed a non-competitive and
mixed-type kinetics towards acetyl-lysine substrates and NAD+, respectively, and a non-selective mechanism of
action for SIRT inhibition. A binding mode, consistent with the experimental evidences, was finally proposed by
molecular modelling. The collected results encourage further investigation of hydantoin derivatives as tools for
exploring novel SIRT-related physiological and therapeutic effects.
References
1) Sebastián C., Satterstrom F.K., Haigis M.C., Mostoslavsky R. From sirtuin biology to human diseases: an update. The
Journal of Biological Chemistry (2012) 287(51), 42444-42452
2) de Oliveira R.M, Sarkander J., Kazantsev A.G., Fleming Outeiro T. SIRT2 as a therapeutic target for age-related disorders.
Frontiers in Pharmacology (2012) 3, 82
3) Donmez G., Outeiro T.F. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Molecular Medicine (2013) 5,
344-352
- 152 -
CS009
STRUCTURE-BASED DESIGN OF NOVEL HUMAN DNA

TOPOISOMERASE IIα INHIBITORS
Barbara Pogorelcnik, Matej Janezic, Matjaz Brvar, Andrej Perdih, Tom Solmajer
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
Human DNA topoisomerases II are validated targets for the development of novel anticancer agents. [1]
Inhibitors targeting human DNA topoisomerase IIα generally fall into two groups: an established group of
poisons which stabilize the covalent cleavable complex and convert this enzyme into a cellular toxin, and an
emerging group of catalytic inhibitors that act by interfering with a single step of the topo II catalytic cycle. [2, 3
] We have used a well established structure-based design approach to identify novel inhibitors that interfere with
the catalytic cycle of the human topoisomerase IIα by blocking the ATP binding on its ATPase domain. Based
on the available structural information about the binding mode of the AMP-PNP molecule to human topo IIα [4],
we designed a two-stage virtual screening campaign combining structure-based pharmacophore models and
molecular docking calculations. This screening led to the discovery of three classes of DNA topoisomerase IIα
inhibitors in lower micromolar range: monocyclic 4-amino-6-(phenylamino)-1,3,5-triazines, mono and
bi-substituted 1H-pyrazolo[3,4]pyrimidines and 9H-purines. These inhibitors were subsequently extensively
characterized by biophysical techniques (differential scanning fluorimetry, surface plasmon resonance and
microscale thermophoresis) and their binding mode in the ATPase active site characterized by molecular
dynamics. Selected compounds showed promising anticancer activities in hepatocellular carcinoma cell line
(HepG2) and breast cancer cell line (MCF-7). Discovered compounds represent a starting point for further hit to
lead development in the discovery of novel anticancer agents.
References
1) Wang, J.C., Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Bio, 2002, 3, (6), 430-440.
2) Pogorelcnik, B.; Perdih, A.; Solmajer, T., Recent Advances in the Development of Catalytic Inhibitors of Human DNA
Topoisomerase IIa As Novel Anticancer Agents. Curr Med Chem, 2013, 20, (5), 694-709.
3) Pogorelcnik, B.; Perdih, A.; Solmajer, T., Recent developments of DNA poisons--human DNA topoisomerase IIa
inhibitors--as anticancer agents. Curr Pharm Des, 2013, 19, (13), 2474-2488.
4) Wei, H.; Ruthenburg, A.J.; Bechis, S.K.; Verdine, G.L., Nucleotide-dependent domain movement in the ATPase domain
of a human type IIa DNA topoisomerase. J Biol Chem, 2005, 280, (44), 37041-37047.
5) Pogorelcnik, B.; Brvar, M.; Zajc, I.; Filipič, M.; Solmajer, T.; Perdih A. Monocyclic 4-amino-6-(phenylamino)-1,3,
5-triazines as inhibitors of human DNA topoisomerase IIa. Bioorg. & Med. Chem. Lett., 2014, 24, 5762-5768
6) Pogorelcnik, B.; Brvar, M.; Zegura, B.; Filipič, M.; Solmajer, T.; Perdih A. Discovery of mono- and disubstituted
1H-pyrazolo[3,4]pyrimidines and 9H-purines as catalytic inhibitors of human DNA topoisomerase IIa. ChemMedChem,
2015, 10, 345-359.
- 153 -
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POSTERS:
Others
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BookRICT.indd 91 15/06/2015 12:15:26

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BookRICT.indd 90 3/06/2015 09:45:58

OT001
SYNTHESIS AND CHARACTERIZATION OF PHOTOACTIVATABLE

PROBES FOR LABELING OF THE HUMAN CHEMOKINE
RECEPTOR CXCR3
Tizita Haimanot Admas, Nuska Tschammer
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University,
Schuhstrasse 19,91052
Erlangen, Germany
The chemokine receptor CXCR3, which belongs to a family of rhodopsin like G protein-coupled receptors, is
upregulated in various autoimmune and inflammatory diseases. Despite the fact that CXCR3 is an attractive
pharmacological target, there is no adequate knowledge about the receptor-ligand interactions responsible for the
high affinity and noncompetitive (allosteric) antagonism. In contrast to chemokines, small molecules bind to the
distinct (allosteric) binding site. The main goal of this work is structural and functional characterization of
CXCR3 allosteric binding pocket used by AMG487 (a negative allosteric modulator of CXCR3) by photoaffinity
labeling followed by mass spectrometry.
Photoaffinity labeling is one of the most commonly used techniques for the determination of structural elements
in the binding pocket of a receptor. This method involves design and synthesis of ligands, which incorporate an
appropriate photoactivatable functional group (such as azide, diazirine or benzophenone). Here we report the
synthesis and biological validation of photoactivatable ligands with diazirine and benzophenone groups as
photoreactive moieties. The probes were developed based on a known scaffold with the CXCR3 antagonist
activity. The possibility to irradiate these probes at a longer wavelength (365nm) is an advantage to avoid cell
damage. The diazirine containing compound to give the corresponding reactive carbene intermediate was proved
by carbene trapping reaction.
Synthesized photoactivatable ligands have shown micromolar affinity towards CXCR3 receptor as determined
by radioligand displacement assay using RAMX31, a radiolabeled negative allosteric modulator of CXCR3. The
ligands were shown to be negative allosteric modulators of CXCR3 with an IC50 value in micromolar range as
assessed with the bioluminescence resonance energy transfer (BRET)-based cAMP assay using CAMYEL
biosensor. CXCL11 served as an endogenous agonist. Labeling of CXCR3 with the photoactivatable probes,
isolation of labeled receptor and consequent mass spectrometry analyses are undergoing.
References
1) Bernat, V.; Heinrich, M.; Buschauer, A.; Baumeister, P.; Tschammer, N. ChemMedChem. 2010, 7(8): 1481-1489.
- 157 -
OT002
DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF SOFT ROCK

INHIBITORS BASED ON THE ISOQUINOLINE SCAFFOLD
Jo Alen, Sandro Boland, Arnaud Bourin, Pieter Schroeders, Jacques Geraets, Dirk Leysen, Olivier Defert
Amakem Therapeutics, Agoralaan A bis, B-3590 Diepenbeek, Belgium
ROCK1 and ROCK2 play a key role in various cellular functions, via the phosphorylation of Myosin Light
Chain (MLC), MLC phosphatase and LIM kinases. Inhibition of ROCK induces several effects of
pharmacological interest, such as relaxation of vascular smooth muscles or anti-inflammatory effects.
A well-known side effect resulting from systemic exposure to ROCK inhibitors is a marked decrease in blood
pressure, limiting their usefulness for the systemic treatment of non-cardiovascular indications.
Recently, we reported the design, synthesis and in vitro/in vivo proof of concept of two novel series of soft
ROCK inhibitors.1,2 These compounds contain ester functions, facilitating their rapid conversion by
blood/plasma esterases into predefined, functionally inactive metabolites, in order to minimize side effects.
Herein, we present the rational design and evaluation of a series of soft ROCK inhibitors, based on the
isoquinoline scaffold. Following encouraging initial data, the crystal structure of a representative compound in
complex with ROCK2 was solved to confirm the binding mode of the isoquinoline-based soft ROCK inhibitors
and to identify favorable substitution sites. Structure-activity and structure-property relationship studies were
focused on varying the saturated heterocyclic linker, modifying the substitution pattern on the aromatic linker,
reversing the amide bond, changing the nature and position of the ester function and lastly, varying the ester side
chain.
The most active compounds exhibit single-digit nanomolar to subnanomolar potency against ROCK2 and low
nanomolar functional activity in a (cellular) MLC phosphorylation assay. The compounds’ stability was assessed
in human plasma, to verify their ‘softness’.
References
1) Boland, S.; Bourin, A.; Alen, J.; Geraets, J.; Schroeders, P.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Fransen,
S.; Vanormelingen, J.; Leysen, D.; Defert, O.; Design, synthesis and biological evaluation of novel, highly active soft ROCK
inhibitors; J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00308.
2) Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.;
Stalmans, I.; Leysen, D.; 3-[2-(aminomethyl)-5-[(pyridin-4-yl) carbamoyl]phenyl] benzoates as soft ROCK inhibitors;
Bioorg. Med. Chem. Lett. 2013, 23 (23), 6442-6446.
- 158 -
OT003
ENZYMATIC SYNTHESIS OF ACYCLIC NUCLEOSIDE

THIOPHOSPHONATE DIPHOSPHATES: EFFECT OF THE
α-PHOSPHORUS CONFIGURATION ON HIV-1 RT ACTIVITY
Stéphane PRIET (1), Loic ROUX (2), Magali SAEZ-AYALA (2), François FERRON (1), Bruno CANARD
(1), Karine ALVAREZ (2)
1) Laboratoire d’Architecture et Fonction des Macromolécules Biologiques, Université Aix-Marseille, UMR CNRS 7257,
Team "Viral Replicases : Structure, Mechanism and Drug-Design ", Parc scientifique de Luminy, Marseille, France
2) Laboratoire d’Architecture et Fonction des Macromolécules Biologiques, Université Aix-Marseille, UMR CNRS 7257,
Team "Antiviral Medicinal Chemistry ", Parc scientifique de Luminy, Marseille, France
The Human Immunodeficiency Virus type 1 and type 2 (HIV-1 and HIV-2) and Hepatitis B (HBV) are of special
interest in public health. Indeed, it is estimated that more than 40 million people infected with HIV worldwide
and 350 million with HBV. Reverse transcriptase (RT) is an enzyme required for their replication and is
therefore a target of choice in current antiviral therapies. Among the NRTI marketed, nucleotide analogues like
nucleoside acyclic phosphonates (ANP), such as adefovir (Hepsera ®, Gilead) and Tenofovir (VIREAD ®,
Gilead) as a prodrug form, have revolutionized the treatment against HBV and HIV. Given the emmergence of
resistant viruses, there is a real need developing new powerful antiviral compounds active against these strains to
optimize antiviral combination therapies.
In an effort to reach this goal, we have designed and synthesized thiophosphonate analogs of Adefovir and
Tenofovir, named Adethiovir (S-PMEA, 1) and Tenothiovir (S-PMPA, 2)1,2,3. These nucleoside acyclic
thiophosphonates (S-ANP) are active against HIV-1, HIV-2 and HBV in infected cells culture. Prodrug forms,
synthesized and evaluated, display also improved and potent antiviral activity. Their diphosphate forms
S-PMEApp (5) and S-PMPApp (6), synthesized as stereoisomeric mixture, are potent inhibitors of wild-type
(WT) HIV-1 RT. Understanding HIV-1 RT stereoselectivity, however, awaits resolution of the diphosphate
forms into defined stereoisomers. To this aim, thiophosphonate monophosphates S-PMEAp and S-PMPAp were
synthesized and used in a stereocontrolled enzyme-catalyzed phosphoryl transfer reaction involving either
nucleoside diphosphate kinase (NDPK) or creatine kinase (CK) to obtain thiophosphonate diphosphates as
separated isomers. We then quantified substrate preference of recombinant WT HIV-1 RT toward pure
stereoisomers using in vitro steady-state kinetic analyses. The crystal structure of a complex between
Dictyostelium NDPK and S-PMPApp at 2.32 Å allowed to determine the absolute configuration at the
a-phosphorus atom in relation to the stereo-preference of studied enzymes. The RP isomer of S-PMPApp and
S-PMEApp are the preferred substrate over SP for both NDPK and HIV-1 RT4.
Figure 1 : (a) Structure of acyclic nucleoside phosphonates PMEA (Adefovir), PMPA (Tenofovir),
thiophosphonates S-PMEA (1, Adethiovir) and S-PMPA (2, Tenothiovir) and their diphosphate forms
S-PMEApp (5) and S-PMPApp (6). (b) Crystallographic structure of the H122G mutant of Dictyostelium NDPK
in complex with S-PMPApp (6)
References
1) K. Alvarez, K. Barral, J. Balzarini, B. Canard, J. Neyts, JL Romette. WO/2008/056264. novel nucleotide analogues as
precursor molecules for antivirals ».
2) K. Barral, C. Weck, N. Payrot, L. Roux, C. Durafour, F. Zoulim, J. Neyts, J. Balzarini, B. Canard, S. Priet and K. Alvarez.
Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication. Eur. J. Med. Chem. 2011, 46(9),
4281-4288
3) Roux L., Priet S., Payrot N., Weck C., Fournier M., Zoulim F., Balzarini J., Canard B. and Alvarez K. Ester prodrugs of
acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study. Eur. J.
Med. Chem. 2013, 63, 869-81.
4) Priet S., Roux L., Saez-Ayala M., Ferron F., Canard B., and Alvarez K.. Enzymatic synthesis of acyclic nucleoside
thiophosphonate diphosphates: effect of the α-phosphorus configuration on HIV-1 RT activity. Antiviral Research. 2015. In
press. - 159 -
OT004
BIKINS, INNOVATIVE KINASE INHIBITOR LIBRARIES

Claire Amiable (1), Guillaume Bollot (2), Cyril Bauvais (2), Dominique Surleraux (1)
1) BCI Pharma
Cap Alpha - Avenue de l'Europe
34830 Clapiers
France
2) Synsight
Bâtiment Maupertuis
rue du Père Jarlan
91000 Evry
France
Kinases are one of the largest and promising class of potential new drug targets. Indeed, deregulation of kinase
function is involved in many disorders including cancer, immunological, neurological, metabolic and infectious
diseases. With more than 500 different kinases, protein kinase inhibitors represent an attractive and booming
market.
We have developed three innovative kinase inhibitor libraries, called BiKin 1-3. Our libraries explore a new and
large chemical space with good chemical properties and show both good activity and selectivity against diverse
kinases. While small modifications on the scaffold of BiKin 1 enable to reach different targets of the kinome,
BiKin 2 exhibits a strong and selective inhibitory potency against FLT3, a valid therapeutic target in human
acute myeloid leukaemia. The biochemical and biological results of these latters will be discussed.
- 160 -
OT005
COPPER-FREE CLICK CHEMISTRY IN TARGETED DELIVERY OF

ANTICANCER DRUG USING B SUBUNIT OF SHIGA TOXIN
Vesela KOSTOVA , Michel AZOULAY , Frédéric SCHMIDT , Estelle DRANSART , Ludger
JOHANNES
Institut Curie/UMR 3666, CNRS/U1143 INSERM, Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France
The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a
major challenge in anticancer therapy. We report an attractive, versatile and modular copper-free click-based
method for the preparation of STxB-conjugates. We select STxBa as a targeting moiety able to recognize Gb3
positive cells. Gb3 is the natural ligand of STxB and is overexpressed in most human tumorsb. Furthermore, we
introduce the use of click chemistry for the easy and efficient covalent coupling of adequately functionalized
STxB with an ad hoc azido-biotin or azido-prodrugs. The strategy is outlined below. Firstly, the carrier (STxB)
was functionalized by attachment of bifunctional linker (1) that contains “clickable” handles (e.g., MFCO).
Then, the carrier was linked to an azido-biotin (2) or two different azido-prodrugs (3, 4) with a bio-cleavable
spacer. Finally with the two last STxB-conjugates obtained via Cu-free click chemistry, we demonstrated and
validated in vitro the efficacy of this Gb3-targeting delivery system.
Simplified scheme of Gb3-targeting delivery system via Cu-free click chemistry:

A- Bifunctional linker coupling, B- Cu-free click chemistry with azido-biotin or azido-prodrugs, C-
Tumor-specific drug delivery in positive Gb3 cells induced by STxB.
*Correspondence: michel.azoulay@curie.fr
References
a) L. Johannes, W. Römer, Shiga toxin-from cell biology to biomedical applications, Nat. Rev. Microbiol. 2010, 8(2),
105-16.
b) A. El. Alaoui, F. Schmidt, M Amessou, M. Sarr, J.-C. Florent, L. Johannes, Shiga Toxin-mediated Retrograde Delivery of
a topoisomerase I Inhibitor Prodrug, Angew. Chem. Int. Ed., 2007, 46, 6469-6472.
c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew Chem Int Ed Engl 2002, 41, 2596.
- 161 -
OT006
NEW PALLADIUM-CATALYZED METHOD TO SYNTHESIZE

N-HYDROXYSUCCINIMIDE ESTERS AND ITS APPLICATION THE
PREPARATION OF CENTRAL ACETYLCHOLINESTERASE
INHIBITORS
Anaïs Barré (1,2), Mihaela-Liliana Ţînţaş (1), Florent Alix (2), Vincent Gembus (2), Cyril Papamicaël (1),
Vincent Levacher (1,2)
1) Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, 76821 Mont
Saint Aignan Cedex, France.
2) VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl,
benzyl, vinyl and allyl halides with the unusual N-hydroxysuccinimidyl (NHS) formate to afford the
corresponding NHS esters.(1) High conversion to the coupling products was achieved with up to 98% yield by
means of Pd(OAc)2/Xantphos catalyst system.
This coupling offers an alternative to the classical preparation of NHS esters through the conversion of
carboxylic acids via DCC activation.(2) While DCC is allergenic and produces urea as byproduct making
difficult the isolation of the pure product, our method is easy to apply, uses nontoxic reagents, employs an
environmentally friendly solvent, and affords easily pure products.
This methodology was developed as part of our ongoing research program aimed at developing potent central
cholinesterase inhibitors. To this end, highly functionalized NHS esters were needed to implement
post-functionalization strategies under mild conditions. Known acetylcholinesterase inhibitors(3) were indeed
successfully synthesized using the developed carbonylative coupling reaction as the key step.
References
1) A. Barré, M.-L. Ţînţaş, F. Alix, V. Gembus, C. Papamicaël, V. Levacher, Unprecedented Palladium-Catalyzed
Carbonylation of (Hetero)Aryl, Alkenyl and Allyl Halides by means of N-Hydroxysuccinimidyl Formate as an unusual CO
Surrogate, J. Org. Chem. 2015, submitted.
2) L. A. Paquette, Encyclopedia of Reagents for Organic Synthesis, Ed. Wiley New York 1995, 2430.
3) P. Bohn, V. Levacher et al., Organic & Biomolecular Chemistry 2009, 7, 2612.
- 162 -
OT007
FFAR1/GPR40 TARGETING FLUORESCENT PROBE FOR BETA

CELL IMAGING
Romain Bertrand (1,2), Andrea Wolf (1), Yuri Ivashchenko (1), Matthias Löhn (1), Mark Brönstrup (3),
Martin Gotthardt (2), Volker Derdau (4), Oliver Plettenburg (1)
1) Diabetes Division, Research & Translational Medicine, Sanofi GmbH, Frankfurt am Main, 65926, Germany
2) Department of Nuclear Medicine - Radboud UMC, Nijmegen, 6525, The Netherlands
3) Helmholtz Centre for Infection Research, Braunschweig, 38124, Germany
4) DSAR / Drug Disposition, Sanofi GmbH, Frankfurt am Main, 65926, Germany
Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare
expenses. Imaging of β-cells contributes to an improved understanding, diagnosis and development of new
treatment options for diabetes. Here we describe the first small molecule fluorescent probe targeting the free
fatty acid receptor 1 (FFAR1/GPR40). This receptor is specifically and highly expressed on ß-cells1, and was up
to now unexplored for imaging purposes. We designed a novel probe by modification of the selective and potent
FFAR1 agonist TAK-8752. Effective and specific binding of the probe was demonstrated using FFAR1
overexpressing cells. We also successfully detected the presence of FFAR1 on widely used β-cell models MIN6
and INS1E cells. Finally, we showed that the probe is capable of inducing insulin secretion in a
glucose-dependent fashion, thus demonstrating that functional activity of the probe was maintained. These
results suggest that our probe should be useful for ß-cells imaging by targeting FFAR1.
References
1) Itoh, Y. et al. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature, 422,
173-176
2) Negoro, N. et al. (2012) Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty
Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent
Insulinotropic Agent. Journal of Medicinal Chemistry, 55, 3960−3974
- 163 -
OT008
STUDY OF THE THERAPEUTIC POWER OF THE CRUDE EXCRACT

OF LEAVES FROM MARRUBIUM VULGARE L. AGAINST
HEPATOTOXICITY INDUCED BY CCL4 AND AN INSECTICIDE IN
MOUSES
Ouahiba BORDJIBA, Ali Boutlelis DJAHRA, Salah benkherara
BADJI Mokhtar Annaba University – Faculty of Sciences – Department of Biology

Laboratory of Plant Biology and Environment
P.O.Box 12-23000 Annaba - Algeria
Ouahiba_bordjiba@yahoo.fr
Among the medicinal plants endowed a good therapeutic reputation and which should be the subject for
extensive research in order to prove its efficiency and clarify their biological properties and validate their use,
the Marrubium vulgare. In this context, a study was conducted on the antihepatotoxic activity of crude extract of
leaves.
The phytochemical screening of leaves of Marrubium vulgare has revealed several compounds of secondary
metabolism (terpenes, sterols, cardinolides, saponin, polyphenols). The chromatographic analysis by HPLC
revealed the richness of leaf extracts with natural substances. The chromatograms profiles have highlighted the
presence of two major compounds, flavonoids and tannins.
The efficiency of crude extract of leaves was demonstrated through testing of the hepatotoxicity induced by
carbon tetrachloride CCl4 and the insecticide Decis Expert. A decrease in the concentration of serum
biochemical parameters GOT,GPT) and transaminases was observed in treated mice compared to untreated
controls. This antihepatotoxic effect is also confirmed through histological study. The observation of liver cuts
showed damages in the hepatic organ that were less widespread among intoxicated mouses treated and healing
occured earlier than at the untreated intoxicated mouses.
Keywords: Marrubium vulgare L., antihepatotoxicity, leaf crude extract, CCL4, insecticide, therapeutic power
- 164 -
OT009
THE USE OF VARIOUS SELECTIVITY SCORES IN KINASE

RESEARCH
Nicolas Bosc, Pascal Bonnet
Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d'Orléans 7311, Université d'Orléans BP 6759,
45067 Orléans Cedex 2, France
So far 518 protein kinases (PKs) have been identified in the Human genome.[1] They share a common
mechanism of protein phosphorylation and are involved in many vital biological processes of eukaryotic cells.
Impaired kinase phosphorylation function is recognized to play a role in diseases like cancer, diabetes or
inflammation. As a result, considerable efforts were made to identify potent and selective protein kinase
inhibitors (PKIs) as new potential drugs. Selectivity of PKIs is a major objective in drug development and it may
help to distinguish promiscuous candidates from those more discriminating.
With the emergence of rapid and affordable techniques to screen compounds of interest on large panels of PKs,
pharmaceutical companies and academic research institutions are generating broad kinase activity profiles of
PKIs. From these large data sets, selectivity of the compounds can be easily computed. However, the whole
concept of compound selectivity rest upon several definitions.[2-4] The metrics already developed may present
advantages and drawbacks, some are intuitive and others are difficult to interpret such as the selectivity score
and Gini score respectively. Here we introduce two new metrics named window score and ranking score. Both
metrics can be seen as an improved selectivity scores in which the highest inhibition of a compound tested on a
panel of proteins is taken as a reference. While the window score counts the number of compound activities
between this reference and a compound activity threshold chosen by the user, the ranking score compare directly
the highest activity to the activity threshold. Depending on the threshold, all these metrics provide different
results and offer additional interpretations of the data.
In conclusion, the two metrics presented here are complementary to those already published. They offer new
information for decision-making, are easily computable and are not limited to the size of the dataset.
References
1) Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human
genome. Science 298, 1912–1934 (2002).
2) Uitdehaag, J. C. & Zaman, G. J. A theoretical entropy score as a single value to express inhibitor selectivity. BMC
Bioinformatics 12, 94 (2011).
3) Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1046–1051 (2011).
4) Graczyk, P. P. Gini Coefficient: A New Way To Express Selectivity of Kinase Inhibitors against a Family of Kinases.
Journal of Medicinal Chemistry 50, 5773–5779 (2007).
- 165 -
OT010
NUCLEOSIDE-2',3'/3',5'-BIS(THIO)PHOSPHATE ANALOGUES ARE

PROMISING ANTIOXIDANTS AND AGENTS FOR DISASSEMBLY OF
AMYLOID BETA(1-42)-Zn(II)/Cu(II) AGGREGATES
Bosmat Levi Hevroni, Bilha Fischer
Bar-Ilan University, 52900 Ramt-Gan, Israel
In a quest for biocompatible metal-ion chelators potentially useful for Alzheimer’s disease (AD) therapy, we
synthesized adenine(A)/guanine(G) 2′,3′- or 3′,5′-bisphosphate(P) or –bisthiophosphate(PS) analogues, 1−6, and
studied them as potential antioxidants in Cu(I)/Fe(II)-H2O2 systems and agents for dissolution of amyloid
beta-Zn(II)/Cu(II) aggregates.
First, we explored analogues 1-6 as potential Cu(I)/Fe(II) chelators. Indeed, dA/G3'5'P and A2'3'P, 1, 3 and 5
inhibited OH radicals production in Fe(II)-H2O2 system (IC50 36, 24 and 40 mM, respectively), more effectively
than EDTA. dA/G3'5'PS and A2'3'PS 2, 4 and 6 (IC50 92, 50 and 80 mM, respectively), exhibited a dual
antioxidant activity, acting as both Fe(II)-chelators and radical scavengers (established by ABTS assay). Only
2’-dA3’,5’PS 2, exhibited good inhibition of Cu(I)-induced H2O2 decomposition (IC50 78 vs 224 mM for
EDTA). 1H- and 31P-NMR monitored Cu(I) titration of 2’-dA3’5’PS, 2, showed that Cu(I) was coordinated by
both 3’5’PS groups and N7, while A2’3’PS 6 coordinated Cu(I) only by 2’3’PS groups.1
We evaluated these analogues also for their ability to dissolve Aβ42–Zn(II)/Cu(II) aggregates. Using EPR we
established a ML2 complex between 2’-dG3’5’PO, 3, and Cu(II), with 4O or 1N3O as equatorial ligands. Using a
turbidity assay, we found that A2’3’PS, 6, was as effective as EDTA dissolving 45% of Aβ42–Zn(II) aggregates.
2’-dG3’5’PS, 4, and A2’3’PS, 6, dissolved 56% and 50% of Aβ42–Cu(II) aggregates, and were 2.5-fold more
effective than EDTA. Based on Tyr10 fluorescence measurements we found that analogues 4 and 6 compete
with Aβ42 on Cu(II). Furthermore, 2’-dG3’5’PS and A2’3’PS reverted the Aβ42–Cu(II)/Zn(II) structure (mostly
b-sheet), back to that of free Aβ42 as observed by CD. Finally, cryo-TEM and TEM images confirmed the
re-solubilization of Aβ42 and Aβ42–M(II) aggregates by A2’3’PS, 6. Hence, (d)A3’5’/2’3’P(S) may serve as
promising scaffolds for the development of drug candidates for the treatment of AD, acting both as highly
effective antioxidants and agents for re-solubilization of Aβ42-Cu(II)/Zn(II) aggregates.
References
1) B. Levi Hevroni, A. H. Sayer, E. Blum, and B. Fischer, Inorg. Chem. 2014, 53, 1594−1605
- 166 -
OT011
DESIGN, SYNTHESIS AND APPLICATION OF NOVEL MORPHOLINE

SURROGATES
M. Bossert, O. Denisenko, O. Datcenko, R. Martirosov, A. Artemenko, G. Tkachuk, A. Parhomenko, O.
Gorulia, O. Andrushko, P. Mykhailiuk, I. Kondratov, O. Shyshlyk, V. Yarmolchuk, A. Shcherbatiuk, A.
Tolmachev
Enamine Ltd., 78 Chervonotkatska Street, Kyiv (Ukraine).
Morpholine is an established building block in drug discovery – more than 20 FDA-approved drugs contain
its residue. In this work, therefore, we have rationally designed and synthesized a library of novel/previously
scarcely available bicyclic morpholine surrogates. Details of the synthesis and application of this library will be
discussed.1,2
References
1) A. Scherbatiuk et al. Tetrahedron 2013, 69, 3796.
2) 95% of these results are not published.
- 167 -
OT012
AZO DYES AS POTENTIAL DRUGS: SYNTHESIS AND IN VITRO

ANTIMICROBIAL EVALUATION OF A SERIES OF 5-ARYL AZO-4, 6-
DIHYDROXYPYRIMIDINE DERIVATIVES.
Leila Boukenna (1), Soumaya Benmohamed (1), Djamila Oukacha (1), Françoise Dumas (2), Samira
Merabtene (3), Yahia Rachedi (1)
1) Laboratory of Applied Organic Chemistry, Faculty of Chemistry, USTHB, BP 32, El-Alia, Algiers, Algeria.
2) Bimolecular laboratory, Design, Insulation and Synthesis Bio CIS UMR CNRS 8076, Faculty of Pharmacy, Paris sud
University, France.
3) Laboratory of quality control of the culture media, Pasteur Institute, Algiers, Algeria.
E-mails: [1] lboukenna15@gmail.com, [1] yrachedi@gmail.com

Abstract:
Azo dyes are an important class of organic colorants which contain at least a conjugated azo chromosphere
(N=N). They are also considered as the largest and the most versatile class of dyes [1]. Azo compounds are the
most widely used class of dyes, having applications in various fields, such as dyeing textiles, as biomedical
agents, and in advanced applications in organic synthesis.
In this work, a bioactive series of 5-aryl azo-4, 6-dihydroxypyrimidine derivatives were prepared by classical
method of azo coupling reaction via one pot multicomponent green reaction between aromatic amine, chloridric
acid and pyrimidine 4, 6-dione in sodium hydroxide in ice aqueous media. Environment friendly procedure,
green solvent and excellent yields, are the advantages of this procedure.
All synthesized compounds were characterized by IR, 1HNMR and UV spectral data. The antimicrobial
activities of all the target synthesized compounds were tested against various microorganisms such as
Escherichia coli; Staphylococcus aureus (Bacteria) and Candida albicans (Yeast fungus) by disc diffusion and
streak dilution methods. In general, the synthesized compounds showed a good antimicrobial activity against the
previously mentioned microorganisms.
Keywords: Antimicrobial activity, Azo compounds, Green synthesis.
References
1) H. Zollinger, Color Chemistry: Syntheses, Properties, and Applications of Organic Dyes Pigments, Wiley-VCH,
Weinheim, 2003. .
- 168 -
OT013
SYNTHESIS OF SELECTIVE INHIBITORS OF NAGZ, AN ENZYME

INVOLVED IN THE ANTIBIOTIC RESISTANCE OF THE PATHOGEN
PSEUDOMONAS AERUGINOSA
Jaufret BOUQUET (1), Thibault LEGIGAN (1), Grishma VADLAMANI (2), Brian L. MARK (2), Jérôme
DÉSIRÉ (1), Yves BLÉRIOT (1)
1) Université de Poitiers, IC2MP, UMR CNRS 7285, 4 Rue M. Brunet, 86073 Poitiers cedex, France.
2) Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Patients with cystic fibrosis have a pulmonary environment that promotes chronic infection by pathogens such as
Pseudomonas aeruginosa, a Gram negative bacteria that plays a key role in the morbidity and mortality of these
patients.1 Unfortunately, more and more antibiotherapies are compromised by the emergence of resistant strains
to b-lactam antibiotics. This intrinsic resistance is due to the production by the pathogen of AmpC enzyme, a
b-lactamase that metabolizes antibiotics. The production of this enzyme involves a glycosylhydrolase, NagZ,
which catalyzes the formation of the enzyme inducer of AmpC, the tripeptide 1,6-anhydro-MurNac.2 By
repressing the expression of AmpC, the inhibition of NagZ should restore the effectiveness of antibiotic therapy
based on penicillins and cephalosporins against resistant strains.
We recently synthesized a selective inhibitor of NagZ, showing a polyhydroxylated azepane core, that mimics
the transition state of the enzyme. This azepane also induces a decrease of 50% of antibiotic resistance (against a
relevant mutant of P. aeruginosa) when co-administrated with the β-lactam ceftazidime.3
We will present herein our recent results regarding the synthetic access, the biological and the synthetic potential
of seven-membered iminosugars.
References
1) Oliver, A. ; Cantón, R. ; Campo, P. ; Baquero, F. ; Blázquez, J. Science 2000, 288, 1251-1253.
2) a) Stubbs, K. A. ; Balcewich, M. ; Mark, B. L. ; Vocadlo, D. J. J. Biol. Chem. 2007, 282, 21382-21391. b) Yamaguchi, T. ;
Blazquez, B. ; Hesek, D. ; Lee, M. ; Llarrull, L. I. ; Boggess, B. ; Oliver, A. G. ; Fisher, J. F. ; Mobashery, S. ACS Med.
Chem. Lett. 2012, 3, 238-242. c) Stubbs, K. A. ; Bacik, J.-P. ; Perley-Robsertson, G. E. ; Whitworth, G. E. ; Gloster, T. M. ;
Vocadlo, D. J. ; Mark, B. L. ChemBioChem 2013, 14, 1973-1981.
3) Mondon, M. ; Hur, S. ; Vadlamani, G. ; Rodrigues, P. ; Tsybina, P. ; Oliver, A. ; Mark, B. L. ; Vocadlo, D. J. ; Blériot, Y.
Chem. Commun. 2013, 49, 10983-10985.
- 169 -
OT014
IN SILICO KINASE PLATFORM (ISKP): A TOOL FOR THE

IDENTIFICATION OF SELECTIVE KINASE INHIBITORS.
Stéphane Bourg, Emilie Pihan, Baptiste Canault, Rohit Arora, Felipe Golib, José-Manuel Gally, Nicolas
Bosc, Samia Aci-Sèche, Pascal Bonnet
Institut de Chimie Organique et Analytique, ICOA, UMR 7311, Université d'Orléans et CNRS, rue de Chartres, BP 6759,
45067 Orléans France
Protein Kinases (PK) are involved in a number of distinct signaling pathways and are crucial in several aspects
of cellular regulation, making them attractive therapeutic targets in the treatment of cancer. Currently, the PK
conformations are classified as catalytically active or inactive broadly based upon the visual orientation of the
highly conserved DFG and alphaC-helix motifs. The design of PK inhibitors, such as Type I, Type II and
allosteric, is dependent of the specific PK conformation.
After the identification of important structural descriptors of the PK conserved motifs using over 4000 crystal
structures of human PK, a novel classification scheme was developed using protein clustering method. The
results of this study reveal 3 well separated clusters each representing a different conformation of the PK. This
improved understanding of the conformational plasticity of PK will help in inception and designing of novel
kinase inhibitors. Here, we take these new data into account to build a multi-conformation representation of the
entire human kinome. An elaborated workflow containing Schrödinger Knime nodes was developed to
automatically retrieve crystal structures or generate homology models of three representative conformations of
each protein kinase.
A validation approach was performed using DUD-E dataset, which contains 26 protein kinase domains. The
comparison between the results obtained from the DFG-in/DFG-out common classification and the new
Hierarchical Clustering classification shows that we can improve the identification of active kinase inhibitors.
Moreover, we have also enhanced the prediction by using an appropriate consensus score.
This large scale virtual screening kinase platform can be used to identify selective kinase inhibitors with broad
pharmacological profiles.
- 170 -
OT015
DISCOVERY OF NEW INDAZOLE DERIVATIVES AS SOFT ROCK

INHIBITORS: DESIGN, SYNTHESIS AND IN-VITRO EVALUATION
Arnaud Bourin, Sandro Boland, Jo Alen, Pieter Schroeders, Jacques Geraets, Dirk Leysen, Olivier Defert
Amakem Therapeutics, Agoralaan A bis, B-3590 Diepenbeek, Belgium
The serine/threonine protein kinases ROCK play an important role in numerous cellular functions, including
smooth muscle cell contraction, cell proliferation, adhesion and migration. Consequently, ROCK inhibitors are
of potential interest for the treatment of multiple disorders including cardiovascular diseases, inflammatory and
autoimmune diseases or eye diseases. However, systemic inhibition of ROCK leads to strong biological effects
which are considered side effects for the treatment of most diseases. Therefore, the development of locally acting
ROCK inhibitors, which are designed to be rapidly inactivated once they enter the systemic circulation, might
represent an attractive therapeutic approach.
We have recently reported new series of soft ROCK inhibitors, structurally related to Y-27632, which contain
ester functions allowing their rapid hydrolysis by esterases and resulting in a functionally inactive metabolite.1,2
Moreover, these series showed promising results both in vitro and in vivo.3,4
In a continuing effort to identify new soft ROCK inhibitors, we applied a similar strategy to a structurally
unrelated chemical series displaying isoquinoline or indazole as hinge binder. Over 100 compounds have been
synthesized and profiled. These compounds have been prepared in ca. 4-8 steps following a straightforward
synthesis.
In this poster, we report the structure activity relationships against ROCK for a selection of indazole derivatives.
ROCK inhibitors with low to sub-nanomolar potency were identified. As required for a soft drug approach, large
differences of functional activity (MLC phosphorylation) were found between parent compounds and expected
metabolites. Further work on the cyclic linker “L” led to identification of non-chiral alternatives to the initial
piperidin-3-yl structure.
References
1) Boland, S. et al. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg.
Med. Chem. Lett. 2013, 23, 6442−6446.
2) Boland, S. et al. Design, synthesis and biological evaluation of novel, highly active soft ROCK inhibitors. J. Med. Chem.
2015; DOI: 10.1021/acs.jmedchem.5b00308.
3) Van de Velde, S. et al. AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in
New Zealand white rabbits with minimal hyperemia. Invest. Ophthalmol. Visual Sci. 2014, 55, 1006− 1351.
4) Hollanders, K. et al. The effect of AMA0428, a novel and potent ROCK inhibitor, in a model of neovascular age-related
macular degeneration. Invest. Ophthalmol. Visual Sci. 2015, 56, 1335−1348.
- 171 -
OT016
SULFOXIMINE ANALOGS OF S-ADENOSYL-L-METHIONINE

Laura Buglioni, Matyas Juhasz, Elmar Weinhold, Carsten Bolm
Institute of Organic Chemistry, RWTH Aachen University

Landoltweg 1, 52074 Aachen (Germany)
S-Adenosyl-L-methionine (AdoMet, 1) is one of the most important cofactors for enzyme catalysis in all phyla
of life. As a building block, it is involved in several transformations, acting, for example, as a donor for the
adenosyl, the ribosyl or the aminocarboxypropyl group.[1] Moreover, AdoMet is the main methylating agent[2] in
nature. The methyl group is transferred to various substrates and S-Adenosyl-L-homocysteine (AdoHcy, 2) is
formed as a powerful methyltransferases product inhibitor.[3]
In the last decades, a variety of analogs of 1 and 2 have been synthesized.[4] In this context, AdoHcy has been
oxidized, yielding the corresponding sulfoxide and sulfone analogs,[5] which are considered bioisosters of
AdoMet. In this work, we present the synthesis of new sulfoximine-containing analogs (3), and first results from
inhibition studies with the DNA methyltranferase M.TaqI.
References
1) a) G. F. Liou, S. Yoshizawa, P. Courvalin, M. Galimand, J. Mol. Biol. 2006, 359, 358-364; b) R. K. Slany, M. Bösl, P. F.
Crain, H. Kersten, Biochemistry 1993, 32, 7811-7817; c) S. Nishimura, Y. Taya, Y. Kuchino, Z. Ohashi, Biochem. Biophys.
Res. Commun. 1974, 57, 702-708.
2) a) G. F. Liou, S. Yoshizawa, P. Courvalin, M. Galimand, J. Mol. Biol. 2006, 359, 358-364; b) R. K. Slany, M. Bösl, P. F.
Crain, H. Kersten, Biochemistry 1993, 32, 7811-7817; c) S. Nishimura, Y. Taya, Y. Kuchino, Z. Ohashi, Biochem. Biophys.
Res. Commun. 1974, 57, 702-708.
3) R.T. Borschardt, The Biochemistry of S-Adenosylmethionine, Columbia University Press, New York, 1977, 151-171.
4) a) R. C. Greene, Biochemistry 1969, 6, 2255-2265; b) M. Pignot, G. Pljevaljcic, E. Weinhold, Eur. J. Org. Chem. 2000,
549-555; c) D. F. Iwig, S. J Booker, Biochemistry 2004, 43, 13496-13509.
5) a) R. T. Borchardt, Y. S. Wu, J. Med. Chem. 1974, 17, 862-868; b) C. Guerard, M. Breard, F. Courtois, T. Drujon, O.
Ploux, Bioorg. Med. Chem. Lett. 2004, 14, 1661-1664.
- 172 -
OT017
DESING AND SYNTHESIS OF DUAL PI3K/mTOR IN THE

TREATMENT OF BREAST CANCER
Frédéric Buron (1), Nuno Rodrigues (1), Thibault Saurat (1,2), Marie-Ludivine de Tauzia (2), Lionel
Colliandre (1), Stéphane Bourg (1,2), Pascal Bonnet (1), Anne Corlu (3), Christiane Guillouzo (3), Pauline
Berthier (4), Pascale Rio (4), Marie-Lise Jourdan (4), Hélène Bénédetti (2), Sylvain Routier (1)
1) Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067
OrléansCedex 2, France
2) Centre de Biophysique Moléculaire, CNRS Orléans, Rue Charles Sadron, 45071 Orléans, France
3) Hôpital de Pontchaillou, Université de Rennes 1, INSERM, UMR-991, 65033 Rennes Cedex, France
4) Faculté de Médecine, Centre Hospitalier Universitaire (CHU) Tours, INSERM U1069, 10 Boulevard Tonnellé, 37032
Tours Cedex, France
Kinases are enzymes that catalyse reactions in the cell, they are indispensable to the cellular mecanism such as
cell proliferation, survival, growth and angiogenesis. According to various studies, it has been observed in cancer
patients, activating mutations of enzyme genes that lead to elevated pathway activities. In order to cure cancer,
research on combined therapies (radio and chemio therapy) was strongly developed within those last years as it
has proven to be much more beneficial for the patient. We chose to inhibit the PI3K/Akt/mTOR pathway in
particular, often mutated in various types of cancers, and thus is a promising target in therapeutic research.[1-5]
The design, synthesis and screening of pyridopyrimidines as dual PI3K/mTOR inhibitors is described that gave
nanomolar enzymatic and cellular activities on both targets with acceptable kinase selectivity profile.[6-8] A
docking study was performed to understand the binding mode of the compounds and to explain the differences in
biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines
and compared to a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer
cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular
effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast
cancer cells and trigger apoptosis. These compounds show interesting kinase profile as dual PI3K/mTOR tool
compounds or as chemical series for further optimization to progress into in vivo experiments.
References
1) Jiang, B. H.; Liu, L. Z. Biochimica et Biophysica Acta 2008, 1784, 150-158.
2) Knight, Z. A.; Gonzalez, B.; Feldman, M.; Zunder, E.; Shokat, K. Cell 2006, 125, 733-744.
3) Jackson, S.; Schoenwaelder, S.; Gonclaves, I.; Nesbitt, W. Nature Medecine 2005, 11, 507-514.
4) Camps. M.; Ruckle, T.; Ji, H.; Aridssonne, V. Nature Medecine 2005, 11, 936-943.
5) Ali, K., Camps M., Pearce, W. Journal of Immunology 2008, 180, 2538-2544.
6) Buron, F.; Mérour, J.Y.; Akssira, M.; Guillaumet, G.; Routier, S. European J. Med. Chem. 2015, 95, 76-95.
7) Saurat, T.; Buron, F.; Rodrigues, N.; de Tauzia, M.-L.; Colliandre, L.; Bourg, S.; Bonnet, P.; Guillaumet, G.; Akssira, M.;
Corlu, A.; Guillouzo, C.; Berthier, P.; Rio, P.; Jourdan, M.-L.; Bénédetti, H.; Routier, S. J. Med. Chem. 2014, 57, 613–631.
8) Routier, S.; Benedetti, H.; Buron, F.; Hiebel, M.-A.; Saurat, T.; Guillaumet, G. WO/2014/027081.
- 173 -
OT018
SYNTHETIC PEPTIDES AS ELICITORS OF PLANT DEFENSE

RESPONSES
Cristina Camó (1), Esther Badosa (2), Emilio Montesinos (2), Marta Planas (1), Lidia Feliu (1)
1) LIPPSO, Department of Chemistry, University of Girona, Campus Montilivi, E-1707, Girona, Spain
2) CIDSAV, University of Girona, Campus Montilivi, E-17071 Girona, Spain
Plant diseases produced by bacteria and fungi are responsible for considerable economic losses [1]. Among
them, fire blight, caused by Erwinia amylovora, is the most serious bacteriosis that affects fruit trees and plants
of the family Rosaceae. Nowadays, antibiotics are the most effective products to control fire blight, but they are
not authorized in the European Union and some bacterial strains have developed resistance to them. In fact, in
Europe, the only strategy to combat this phytopathology is based on the use of copper derivatives. Due to the
lack of available products to control fire blight there is a great need for new compounds and strategies to treat it.
Our current research is centered on the development of peptides as an alternative to traditional antimicrobial
agents. In recent decades, antimicrobial peptides have been shown to be promising candidates for plant disease
control [2]. Moreover, several peptides have been described as plant defence elicitors [3]. These sequences
promote molecular mechanisms in plants that lead to an alkalinisation of the medium, an increase of the
concentration of intracellular calcium, the production of reactive nitrogen intermediates and reactive oxygen
species (ROS) or the synthesis of salicylic acid, jasmonic acid and ethylene.
In this work, we have prepared a set of peptides potentially useful to combat plant diseases. Their antimicrobial
activity, hemolysis and ability to induce plant defences will be presented.
References
1) G. N. Agrios, Plant pathology, Academic Press, San Diego, California, 5th edn, 2005.
2) Montesinos, E., Badosa, E., Cabrefiga, J., Planas, M., Feliu, L., Bardají, E., 2012. Antimicrobial peptides for plant disease
control. From discovery to application. In: Rajasekaran, K., Cary, J., Jaynes, J., Montesinos, E. (EDs.). Small Wonders:
Peptides for Disease Control. American Chemical Society, Washington, DC-Oxford University Press, Inc.
3) Markus, A. 2013. Peptids as triggers of plant defence. J. Exp. Bot., 64, 17, 5269-5279
- 174 -
OT019
SYNTHESIS OF ALFA-ALKYLIDEN-GAMMA-LACTONES AS FAS

INHIBITORS
Marina Zacchigna (1), Francesca Cateni (1), Giuseppe Procida (1), Tiziano Altieri (2), Patrizia Nitti (1),
Chiara Florio (3), Marco Pelin (3)
1) Department of Chemical and Pharmaceutical Sciences, University of Trieste, P.zle Europa 1, 34127, Trieste, Italy
2) School of Advanced Studies 'G. D’Annunzio', University of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti Scalo, Italy
3) Department of Life Sciences, University of Trieste, Via Weiss, 2, 34128, Trieste, Italy
4)
a-Methylenelactones have received much attention due to the biological activity exhibited by natural products
containing this structural moiety [1]. Cytotoxic, anti-inflammatory, phytotoxic, allergenic and antimicrobial
properties are shown not only by highly functionalized, complex sesquiterpene lactones but also simple
representatives were studied for their biological effects. Besides, compared to normal human tissues, many
common human cancers, express high levels of fatty acid synthase (FAS), the primary enzyme responsible for
the synthesis of fatty acids. This differential expression of FAS between normal tissues and cancer has led to the
notion that FAS is a target for anticancer drug development [2].
A new series of a-methylene-g.butyrolactones has been synthesized with an alkylidene moiety in 3 position and a
substution in 5 position.
All the compounds were tested against PANC-1, HCT-116, Lovo, MCF-7 and MDA-231-MB tumor cell lines by
MTT assay to different concentrations of the above compounds (4.1x10-7-3.0x10-4 ) after a 48 h exposition. The
compound with R=H and R'= 3',5'- dimethoxyphenyl exhibited a pharmacological interesting cell toxicity profile
in all cell lines with EC50 values similar to the reference compound cerulenine.
References
1) F. Cateni et al. , European Journal of Medicinal Chemistry 41, (2006), 192-200.
2) F.P. Kuhajda et al. , Proc. Natl. Acad. Sci. USA 7, (2000), 3450-4.
- 175 -
OT020
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF P.

FALCIPARUM AMINOPEPTIDASE M17 INHIBITORS
Bérénice Chaillou (1), Sébastien Albrecht (1), Marjorie Schmitt (1), Céline Tarnus (1), Isabelle Florent (2)
1) Laboratoire de Chimie Organique et Bioorganique, EA4566, UHA - ENSCMu, 3 rue Alfred Werner, Mulhouse 68093
Cedex, France
2) CNRS/MNHN, UMR7245, Molécules de Communication et Adaptation des Micro-organismes, F-75231 Paris, France
Malaria is an infectious disease caused by Plasmodium parasites, mainly P. falciparum, and widely-observed in
the intertropical areas of America, Asia and Africa. Various ways of fighting against this disease already exist.
However the problem of parasite resistance to current drugs and the high cost of therapies for the most affected
populations make urgent the discovery of novel P. falciparum molecular targets and search for original
therapeutic agents to expand the antimalarial drug library.
Among these new targets, the metallo-aminopeptidase PfA-M17, involved in the hemoglobin degradation by
Plasmodium, has recently emerged as a potential and attractive target.1 Indeed, its inhibition by metal chelating
peptides prevents the parasite growth.2 However, those compounds suffer from several drawbacks, notably low
in cellulo activity and low bioavailability. Thus, the development of new PfA-M17 inhibitors with better
pharmacological properties represents an attractive therapeutic approach.
Previous work at the laboratory enabled to point out an aminobenzosuberone-based scaffold inhibiting
specifically the two-zinc aminopeptidase family (compound I).3
Their challenging synthesis and in vitro evaluation will be discussed in the poster.
References
1) T.S. Skinner-Adams et al., Trends Biochem. Sci. 2010, 35, 53-61
2) For Example : S. McGowan et al., J. Med. Chem. 2013, 56, 5213-5217
3) M. Al-Lakkis-Wehbe et al., Bioorg. Med. Chem. 2013, 21, 6447-6455
- 176 -
OT021
RIMANTADINE ANALOGUES - SYNTHESIS, CHEMICAL STABILITY

AND INFLUENZA VIRAL ACTIVITY
Radoslav Chayrov (1), Vesela Veselinova (1), Vasilka Markova (1), Angel Galabov (2), Ivanka Stankova
(1)
1) Departament of Chemistry, South-West University “Neofit Rilski”, 66 Ivan Mihailov str., Blagoevgrad, 2700, Bulgaria
2) Angeloff Institute of Microbiology, Bulgarian Academy of Science, Sofia, 1113, Bulgaria
Amantadine is a drug both as an antiviral and an antiparkinsonian drug.

It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane
backbone that has an amino group substituted at one of the four methine positions. Rimantadine is a closely
related derivative of adamantane with similar biological properties.
In order to improve the efficacy of amantadine and rimantadine we synthesized, studied the antiviral activity and
the chemical stability of their analogues with the following amino acids: valin, leucine and isoleucine.
We are grateful to the South-West University ”Neofit Rilski”, Bulgaria (Contract SRP A19/15).
- 177 -
OT022
SYNTHESIS OF IMIDAZOQUINOXALINE DERIVATIVES WITH

ANTICANCER POTENTIAL ACTIVITIES
Cindy Patinote (1,3), Adrien Chouchou (1), Pierre Cuq (1), Anne Aubert-Pouessel (2), Sylvie Begu (2),
Pierre-Antoine Bonnet (1), Carine Deleuze-Masquefa (1)
1) Oncopharmacochimie et Pharmacotoxicologie cutanee, equipe F16, UMR 5247 IBMM, UFR Pharmacie, Universite
Montpellier
2) Equipe MACS, UMR 5253 ICGM, UFR Pharmacie, Universite Montpellier
3) SATT AxLR Montpellier
Heterocyclic systems containing quinoxaline moiety exhibit important biological activities. Among the
derivatives annulated at bond a, Imidazoquinoxalines, also called Imiqualines, hold a special place since many
pharmaceuticals have been developed. Changing substituents nature and/or positions affect the manifestation of
one or the other kind of properties. We are particularly working on imidazo[1,2-a]quinoxaline compounds, that
have been protected by a patent since 2008(a) and recently granted in the USA on February 2013(b). Among the
prepared series, EAPB0503 derivative has been identified as a lead compound thanks to its in vitro activities
against human melanoma, lymphoma and colon cancer cell lines(c).
Compound EAPB0503 showed very low water-solubility, which was critical for further preclinical studies. In
order to get around this problem, two strategies were developed. Firstly, the formulation of lipid nanocapsules
(d-e) containing EAPB0503 aimed to a parenteral administration was tested. Secondly, a chemical modulation on
the lead was considered. Substitutions on the imidazole ring, using for example Suzuki cross-coupling reactions,
permit the introduction of a large variety of aromatic and alkyl groups.
We present herein the total synthesis of imidazoquinoxaline derivatives. These compounds are evaluated for
their in vitro activities against human melanoma cancer cell lines (A375) and compared to our lead.
References
a) Deleuze-Masquefa C. and al, Patent PCT WO 2008/063290
b) Deleuze-Masquefa C. and al, Patent US 2013, 8,378,098 B2,
c) Deleuze-Masquefa C. and al, Eur. J. Med. Chem. 2009, 44(9):3406-11,
d) Heurtault B. and al, Pharm. Res. 2002, 19(6): 875-880,
e) Khier S. and al, Drug Metab Dispos. 2010, 38(10):1836-47
- 178 -
OT023
TUMOR-TARGETED ZWITTERIONIC POLYDIACETYLENE

MICELLE
Damien Clarisse (1), Anilkumar Parambath (1), Ioanna Theodorou (3), Anaelle Doerflinger (1), Benoit
Lelandais (2,3), Edmond Gravel (1), Frédéric Ducongé (2,3), Eric Doris (1)
1) CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif-sur-Yvette, France

2) CNRS, Unité de Recherche Associée CEA-CNRS2210, Université Paris Sud, 18 route du panorama, BP n°6, F-92265,
Fontenay-aux-Roses, France.
3) CEA, I2BM, Molecular Imaging Research Center (MIRCen), 18 route du panorama, BP n°6, F-92265,
Fontenay-aux-Roses, France.
The challenge of nanomedicine consists in carrying active molecules through the different biological barriers and
reaching specific targets in an efficient and nontoxic way. With the advent of nanotechnologies, a whole range of
new carriers with different properties and functionalities are now available. However, the development of small
biocompatible carriers with high loading capacity, extended circulation time and favourable biodistribution has
several unanswered issues.
In this regard, we recently reported photo cross-linked polydiacetylene micelles (PDA-micelles) as robust
carriers. The polymerized micelles were loaded with active compounds and used for tumor imaging and drug
delivery, after intravenous injection.1,2 In the course of our investigations, we demonstrated that micelles with an
outer shell made of polyethyleneglycol chains of rather high molecular weight (2000 Da) were well suited for in
vivo applications.
In the present study, polymerized polydiacetylene-micelles (size ca. 8 nm) with “stealth” zwitterionic surface
coatings are assembled (Figure 1) and tested for their ability to passively target tumor through the enhanced
permeability and retention effect. Intravenous injection of micelles in a murine xenograft model of breast cancer
indicated accumulation of the micelles in the tumor area as visualized by in vivo fluorescence imaging.
Fluorescence diffuse optical tomography and histological studies revealed a predominant uptake of the micelles
at the margins of the tumor. Our findings show the potential of zwitterionic-micelles for delimiting the tumor
volume which could find applications in fluorescent imaging-guided surgery.
References
1) J. Ogier, T. Arnauld, G. Carrot, A. Lhumeau, J. M. Delbos, C. Boursier, O. Loreau, F. Lefoulon and E. Doris, Org.
Biomol. Chem., 2010, 8, 3902.
2) E. Gravel, J. Ogier, T. Arnauld, N. Mackiewicz, F. Ducongé and E. Doris, Chem. Eur. J., 2012, 18, 400.
- 179 -
OT024
SYNTHESIS AND BIOLOGICAL EVALUATION OF A NEW

CATHEPSIN C INHIBITOR (XPZ-01)
Cécile Croix (1), Yveline Hamon (2), Sandrine Dallet Choisy (2), Marie-Claude Viaud-Massuard (1), John
Pedersen (3), Francis Gauthier (2), Baris Korkmaz (2)
1) UMR CNRS 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, UFR des Sciences Pharmaceutiques,
Université de Tours 31 Avenue Monge 37200 Tours - FRANCE
2) Centre d'Etude des Pathologies Respiratoires, INSERM U-1100, Faculté de Médecine de Tours, Université François
Rabelais, Bât 47C 10 Bld, Tonnellé, 37032 Tours - FRANCE
3) CEO, CSO, M.Sc., UNIZYME Laboratories A/S, Dr. Neergaards Vej17, DK2970 Hörsholm, Denmark
Neutrophil serine proteases (NSPs) contribute to the destruction of lung tissue in several inflammatory lung
diseases, especially cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Attempts to inhibit
these proteases in situ still remain not convincing due to the protective environment made of mucus and DNA in
bronchial secretions. These compounds compromise the efficient inhibition of proteases by exogenous
therapeutic inhibitors. An alternative way is to control the activity of NSPs before they are delivered on
inflammatory sites. This can be done by inhibiting cathepsin C (CatC), a cysteine protease that activates
pro-NSPs in the bone marrow.
In this work, we describe the large scale synthesis (~5g) and the biological evaluation of a CatC inhibitor ((S
)-2-amino-N-((1R,2R)-1-cyano-2-(4’-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopro-pyl)butanamide)
first described as XPZ-01 by Unizyme Laboratories.
This inhibitor will be first tested on CatC extracted from the neutrophil of macaques since the animal model is
the most relevant for preclinical studies on the fate of CatC during neutrophil-dominated inflammatory diseases.
- 180 -
OT025
SAR STUDY ON GHRELIN RECEPTOR TRISUBSTITUTED

1,2,4-TRIAZOLE ANTAGONISTS
Séverine Denoyelle, Mathieu Maingot, Céline M’Kadmi, Marjorie Damian, Sophie Mary, Didier Gagne,
Jacky Marie, Jean-Louis Banères, Jean Martinez, Jean-Alain Fehrentz
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS - Université Montpellier, Faculté de Pharmacie,
15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France
Ghrelin, the natural ligand of the Growth Hormone Secretagogue Receptor type 1a (GHS-R1a), has been
intensively studied for its various biological activities such as stimulation of both growth hormone release and
food intake. Ghrelin also regulates the metabolic balance by decreasing fat use, affecting body weight and
adiposity. Thus, ghrelin functions as an orexigenic hormone and it is of interest to find agonists and antagonists
of its receptor.
In our effort to find new ghrelin receptor ligands, we explored families of peptidomimetics based on the
1,2,4-triazole scaffold that led to potent agonists and antagonists of GHS-R1a.1-3 These compounds were
synthesized from (d)tryptophan residue and present in their final structure only one asymmetric carbon atom,
whose configuration was controlled during the synthetic process. One of our leading compound, JMV 2959
(compound 1), was found to be a potent GHS-R1a antagonist exhibiting a large range of interesting properties
such as antagonizing either ghrelin-induced food intake or fasting food intake, and decreasing fat mass
accumulation.4 In order to improve the pharmacokinetic profile of compound 1, we explored structural
modifications on its N-terminal part by replacing the glycine residue with various substitutes and found out a
very potent antagonist (compound 2) bearing a picolinic moiety. We then extended our SAR study by first
modulating the pyridinyl ring5 and then by introducing a second asymmetric carbon with a controlled
configuration.
In this study, we report on the consequences of these structural modifications on both the affinity and the
biological activity of the new ligands targeting the ghrelin receptor.
References
1) Demange, L.; Boeglin, D.; Moulin, A.; Mousseaux, D.; Ryan, J.; Berge, G.; Gagne, D.; Heitz, A.; Perrissoud, D.;
Locatelli, V.; Torsello, A.; Galleyrand, J. C.; Fehrentz, J. A.; Martinez, J. Journal of Medicinal Chemistry 2007, 50, 1939.
2) Moulin, A.; Demange, L.; Berge, G.; Gagne, D.; Ryan, J.; Mousseaux, D.; Heitz, A.; Perrissoud, D.; Locatelli, V.;
Torsello, A.; Galleyrand, J. C.; Fehrentz, J. A.; Martinez, J. Journal of Medicinal Chemistry 2007, 50, 5790.
3) Moulin, A.; Demange, L.; Ryan, J.; Mousseaux, D.; Sanchez, P.; Berge, G.; Gagne, D.; Perrissoud, D.; Locatelli, V.;
Torsello, A.; Galleyrand, J. C.; Fehrentz, J. A.; Martinez, J. Journal of Medicinal Chemistry 2008, 51, 689.
4) Salome, N.; Hansson, C.; Taube, M.; Gustafsson-Ericson, L.; Egecioglu, E.; Karlsson-Lindahl, L.; Fehrentz, J. A.;
Martinez, J.; Perrissoud, D.; Dickson, S. L. Journal of Neuroendocrinology 2009, 21, 777.
5) Blayo, A.-L.; Maingot, M.; Aicher, B.; M'Kadmi, C.; Schmidt, P.; Müller, G.; Teifel, M.; Günther, E.; Gagne, D.;
Denoyelle, S.; Martinez, J.; Fehrentz, J.-A. Bioorg. Med. Chem. Lett. 2015,25, 20
- 181 -
OT026
SYNTHESIS AND DOCKING SIMULATION STUDY OF NEW

TETRACYCLIC TACRINE ANALOGS CONTAINING
PYRANO[2,3-C]PYRAZOLE FOR THE TREATMENT OF
ALZHEIMER’S DISEASE
Chamseddine Derabli (1,2), Raouf Boulcina (2), Ahmed bakr Abdelwahab (1), Abdelmadjid Debache (2),
Gilbert Kirsch (1)
1) Université de Lorraine, SRSMC, 01 Boulevard Arago, 57070 Metz, France.

2) Laboratoire de Synthèse des Molécules d’intérêts Biologiques, Université Constantine 1, 25000 Constantine, Algeria.
Alzheimer’s disease (AD) is a progressive neurological disease leading to impairment in memory, language
skills, judgment and orientation.1 Despite the huge effort and resources invested in the development of drugs
which could treat AD, the most widely used palliative treatment is still based on the well-established cholinergic
process in which the concentration of acetylcholine (ACh) neurotransmitters in the brain and central nervous
system (CNS) is increased using cholinesterases inhibitors(ChEIs).2 In addition to acetylcholinesterase (AChE)
which hydrolyzes about 80% of acetylcholine in the healthy brain, attention has also focused on
butyrylcholinesterase (BChE), whereas the function of this enzymes less clearly defined due to its ability to
hydrolyze ACh and other esters.3 Various anti-AChE agents such as tacrine, donepezil, rivastigmine,
galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist, memantine have shown to cause a slight
improvement in cognitive and memory disorders.
As an integration of the above mentioned approaches and in a continuation of previous study concerning the
development of new AChE inhibitors 4, the current project reporting an efficient synthesis of
tacrine-pyrano[2,3-c]pyrazole hybrids through multi-components reaction and subsequent Friedländer reaction
between the obtained pyrano[2,3-c]pyrazoles and cyclohexanone to produce novel ChEIs of
tacrine-pyrano[2,3-c]pyrazole scaffold. The effectiveness of obtained molecules were theoretically investigated
by application of 3-D molecular modelling technique to determine the best candidates for planned biological
studies.
References
1) Goedert, M.; Spillantini, M. G. Science 314, 2006, 777-781.
2) Ballard, C.G.; Greig, N.H.; Guillozet-Bongaarts, A.L.; Enz, A.; Darvesh, S. Curr.Alzheimer Res. 2, 2005, 307–318.
3) Darvesh, S.; Hopkins, D.A.; Geula, C. Nat. Rev. Neurosci. 4, 2003, 131–138.
4) Khoobi, M.; Ghanoni, F.; Nadri, H.; Moradi, A.; Pirali Hamedani, M.; Homayouni Moghadam, F.; Emami, S.; Vosooghi,
M.; Zadmard, R.; Foroumadi, A.; Shafiee, A. Eur. J. Med. Chem. 89, 2015, 296-303.
- 182 -
OT027
SYNTHESIS OF NEW DERIVATIVES COMPOUNDS FROM

SUBSTITUTED ACETYL-COUMARINES
Delel Dridi (1,2), Gilbert Kirsch (1), Faouzi Meganem (2)
1) Université de Lorraine, Laboratoire de Synthèse et Réactivité des Systèmes Moléculaires Complexes UMR-SRSMC
7565,Equipe Hécrin, 1 boulevard Arago, 57070 Metz Technopôle-France
2) Laboratoire de Synthèse Organique, Faculté des Sciences de Bizerte, Jarzouna 7021-Bizerte-Tunisie
Acetyl coumarine 1 and chalcone 2 derivatives are well known to have pharmacophic elements. In 2010, Valente
et al reported the design and synthesis of novel coumarin-based small molecules as cdc25 phosphatases
inhibitors. 3
Therefore, we reported the synthesis of new molecules with combined coumarine/chalcone scaffold, which are
expected to act as cdc25 phosphatases inhibitors. Different 3-acetyl coumarine derivatives have been condensed
with urea, hydrazine and isatin. 4
References
1) Abidi.H, Mojarrad.JS, Asghaloo.H; Zarrini.G;2011; Synthesis, in vitro anticrobial and antioxidant activities of chalcone
and flavone derivatives having allylic sabstitutions. Medicinal Chemistry Research; 20(8), 1318-1324.
2) Aboraia A.S, Hamdy M, RahmanA, Mahfouz,M., Mahmoud A,E L Gendy Synthesis characterization and antibacterial
activities of oxadiazole derivatives. Bioorganic & medicinal chemistry letter; 2006:14: 1236-46.
3) Valente.S, Bana.E, Viry.E, Bagrel.D,Kirsch.G;2010; Synthesis and biological evaluation of novel coumarin-based
inhibitors of Cdc25 phosphatases; Bioorganic and Medicinal Chemistry Letters;20;5827-5830.
4) Charles-Adolphe Wurtz;(1872) ;Ueber einen Aldehyd-Alkohol ; J. Prakt. Chemie, vol. 5(1) ,457-464
- 183 -
OT028
DESIGN OF AMPHIPHILIC NITRONES WITH IMPROVED

SPIN-TRAPPING AND ANTIOXIDANT PROPERTIES
Marie Rosselin (1), Béatrice Tuccio (2), Frederick A. Villamena (3), Grégory Durand (1)
1) Université d'Avignon, Avignon, France; Institut des Biomolécules Max Mousseron, UMR 5247, Montpellier, France
2) Aix-Marseille Univ.-CNRS, UMR 6264, Equipe SACS, 13390 Marseille
3) Department of Pharmacology and The Davis Heart and Lung Research Institute, College of Medicine, The Ohio State
University, Columbus, USA
To prevent oxidative stress-mediated damage, the use of synthetic antioxidants is attractive as it allows to tune
their physical-chemical properties as well as their targeting specificity. Of particular interest is the linear
α-phenyl-N-tert-butylnitrone (PBN), which exhibits pharmacological activity against radical-mediated
pathophysiological conditions.1
In the first part of my PhD work, we improved the intrinsic antioxidant properties of PBN by grafting various
substituents either onto the aromatic ring2 or the N-tert-butyl-group.3 Electron paramagnetic resonance and
UV-vis. competitive kinetics experiments were conducted in order to compare their ability to trap free radicals.
Then, the cytoprotective properties of these agents against H2O2–induced cell death were investigated in vitro
using bovine aortic endothelial cells.
With optimized nitrone derivatives in hand, the second part of my project consisted in improving the bioactivity
and bioavailability of our nitrone agents using amphiphilic carriers.4 The amphiphilicity of the carrier is
expected to confer to the antioxidant good solubility in water and sufficient lipophilicity to reach cellular
membranes. Amino acids were used as central linkers allowing multi-functionalization with different
antioxidants.
References
1) Floyd R. A. et al. Mech. Ageing Dev., 2002, 123, 1021
2) Durand G. et al. J. Phys. Chem., 2008, 112, 12498
3) Rosselin M. et al. J.Org.Chem., 2014, 79, 6615
4) Durand G. et al. Chem. Res. Tox., 2009, 22, 1570
- 184 -
OT029
APPLICATION OF THE MSAS APPROACH IN THE DISCOVERY OF

POTENT AND SELECTIVE INHIBITORS OF UROKINASE
Rafaela Gladysz (1), Hans De Winter (1), Jurgen Joossens (1), Anne-Marie Lambeir (2), Koen Augustyns
(1), Pieter Van der Veken (1)
1) Medicinal Chemistry-UAMC, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610

Antwerp, Belgium
2) Laboratory for Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp
Fragment-Based Drug Discovery (FBDD) has evolved into an established methodology for ‘hit’ identification.
Nonetheless, the approach still faces a number of fundamental challenges.[1] One of these relates to the need for
specialized cost- and time-intensive biophysical techniques to detect and study weak binding fragments. The
Substrate Activity Screening (SAS) approach has been proposed as a relatively cheap and straightforward
alternative for the identification of fragments for enzyme inhibitors.[2] In spite of some promising results, it has
so far only seen limited investigation by the group of Ellman and, more recently, by Seebach et al.[3]
In this study, we applied SAS to the discovery of inhibitors of oncology target urokinase (uPA).[4] During our
investigation, a number of unreported limitations of the SAS approach were uncovered. In response, we
developed a modified, more efficient alternative method: MSAS (Modified Substrate Activity Screening).
MSAS not only circumvents the limitations of SAS but also broadens its scope by providing additional
fragments and more coherent SAR data.
The MSAS strategy was validated by identifying several fragment-sized ligands of uPA’s S1 pocket.[4] We
assumed, that an S1-binding fragment can be transformed into a druglike uPA inhibitor by grafting it onto a
suitable scaffold and by further decorating this scaffold with additional affinity-conferring substituents. A
comparison of the IC50-values of the separate and the scaffolded fragment (~250 µM vs. ~10 µM) indicated the
imidazopyridine system to be a novel, potentially useful scaffold for uPA inhibitors. Consequently, following the
Groebke-Blackburn-Bienaymé (GBB) reaction protocol, we prepared a set of scaffold-based inhibitors where the
S1-binding fragment was grafted onto the 3-position of an imidazopyridine central core. Optimization of the
initial hit compound provided reversible uPA inhibitors of nanomolar potency and high selectivity against the
related trypsin-like serine proteases. Additionally, a number of inhibitors carrying a warhead function were
prepared and served as a proof-of-concept for the substrate-based identification of uPA inhibitors.
References
1) C. W. Murray, M. L. Verdonk, D. C. Rees, Trends Pharmacol. Sci. 2012, 33, 224-232.
2) W. J. L. Wood, A. W. Patterson, H. Tsuruoka, R. K. Jain, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, 15521-15527.
3) J. Chapelat et al. Eur. J. Med. Chem. 2012, 57, 1-9.
4) R. Gladysz, M. Cleenewerck, J. Joossens, A.-M. Lambeir, K. Augustyns, P. Van der Veken, ChemBioChem 2014, 15,
2238-2247.
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OT030
THIAZOLE-PHENOTHIAZINE DYADS WITH ANTITUMOR

ACTIVITY
Adriana Grozav(Ignat) (1), Ciprian Ionut Tomuleasa (2), Eva Fischer-Fodor (3), Valentin Zaharia (1),
Castelia Cristea (4)
1) Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, Organic Chemistry Laboratory, Victor
Babes 4, Cluj-Napoca, RO-400012, ROMANIA
2) Tumor Biology Department, “I. Chiricuta” Oncology Institute, 34-36 Republicii Street, RO-400015, Cluj Napoca,
ROMANIA
3) Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and
Pharmacy, Marinescu 23, RO-400337, Cluj Napoca, ROMANIA
4) Faculty of Chemistry and Chemical Engineering, “Babes Bolyai” University, Chemistry Department, RO-400028, Arany
Janos 11, Cluj-Napoca, ROMANIA
Phenothiazine and thiazole occur independently as pharmacophore groups in derivatives with widespread
therapeutic applications. The thiazole-phenothiazine dyads described in this work (scheme 1) contain the
heterocyclic units either joint (3), or directly condensed (5). The target compounds were obtained by multistep
synthetic pathways starting with a phenothiazine derivative (1) and by progressively building the thiazole unit
either by Hantzsch condensation of thiosemicarbazone (2), or by Jacobson cyclization of thiobenzanilide (4)
respectively.
Scheme 1
The cytotoxic potential of a series of thiazole-phenothiazine dyads was evaluated and compared with the
antitumor activities of the corresponding phenothiazine based intermediates. In vitro antiproliferative activity
was determined by MTT colorimetric assay. The tested compounds show promising antitumor activity in THP-1
and HL-60 tumor cells and selectivity towards normal peripheral blood mononuclear cells (PBMC's).
Acknowledgments: “This paper was published under the frame of European Social Found, Human Resources
Development Operational Programme 2007-2013, project no. POSDRU/159/1.5/136893.”
References
1) Valentin Zaharia, Adriana Ignat, Nicolae Palibroda, Bathélémy Ngameni, Victor Kuete, Charles N Fokunang, Marlyse L
Moungang, Bonaventure T Ngadjui, European journal of medicinal chemistry, 2010 45 (11), 5080-5085.
2) A.Ignat, T. Lovasz, M. Vasilescu, E.Fischer‐Fodor, C. Bianca Tatomir, C. Cristea, L. Silaghi‐Dumitrescu, V. Zaharia,
Archiv der Pharmazie, 2012, 345 (7), 574-583
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OT031
THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS WITH

ANTIOXIDANT ACTION
Adriana Grozav(Ignat) (1), Daniela Hanganu (2)
1) Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, Organic Chemistry Laboratory, Victor
Babes 4, Cluj-Napoca, RO-400012, ROMANIA
2) Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, Pharmacognosy
Laboratory, 12 Ion Creanga, Cluj-Napoca, RO-400012, ROMANIA
Oxidative stress is responsible for the appearance of inflammatory processes, metabolic diseases,[i] rheumatic
diseases, neurodegenerative diseases,[ii]of the different types of cancer,[iii] cell aging,[iv] etc. This is caused by
an increase in the biosynthesis of free radicals resulting from aerobic and anaerobic processes in the body or by a
decrease in the antioxidant potential of the cell. Arene ruthenium complexes are well known for their anti-tumor
activity and more recently it has been discovered that they also have antioxidant activity.[v]The objective of this
study is to assess the antioxidant activity of a number of ten ruthenium complexes (II) whose general structure is
shown in Figure 1.
Figure 1
The antioxidant activity of these compounds towards various radicals generated in different systems was
evaluated using DPPH bleaching method, Ferric reducing antioxidant capacity (FRAP) and Electron
Paramagnetic Resonance (EPR) spectroscopic methods.
The results obtained by the three methods show a promising antioxidant activity of arene ruthenium complexes
(II) included in the study.
Acknowledgments: This work was supported by the Swiss Enlargement Contribution in the framework of the
Romanian-Swiss Research Programme.
References
1) Cazzola R, Cestaro B. Antioxidant Spices and Herbs Used in Diabetes. In: Victor Preedy. Diabets. Oxidative Stress and
Dietary Antioxidants. 1st edition. London:Elsevier; 2013.
2) Mekha MS, Shobha RI, Rajeshwari CU, Andallu B. Aging and Arthritis: Oxidative Stress and Antioxidant Effects of
Herbs and Spices. In: Victor Preedy. Aging. Oxidative stress and Dietary Antioxidant. 1 st edition. London: Elsevier; 2014
3) Jacob KD, Hooten NN, Trzeciak AR, Evans MK. Markers of oxidant stress that are clinically relevant in aging and
age-related disease. Mech Ageing Dev. 2013;134:139–157. Christensen LP, Christensen KB. The Role of Direct and Indirect
Polyphenolic Antioxidants in Protection Against Oxidative. In: Ronald Watson, Victor Preedy, Sherma Zibadi. Polyphenols
in Human Health and Disease. 1 st edition. London: Elsevier; 2013
4) Christensen LP, Christensen KB. The Role of Direct and Indirect Polyphenolic Antioxidants in Protection Against
Oxidative. In: Ronald Watson, Victor Preedy, Sherma Zibadi. Polyphenols in Human Health and Disease. 1 st edition.
London: Elsevier; 2013
5) Bing-Jie Han, Guang-Bin Jiang, Jun-Hua Yao, Wei Li, Ji Wang, Hong-Liang Huang, Yun-Jun Liu, DNA interaction,
antioxidant activity, and bioactivity studies of two ruthenium (II) complexes, Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy, Volume 135, 25 January 2015, Pages 840–849
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OT032
NEW METHOD OF MODULATION OF QUINAZOLIN-4(3H)-ONES:

DIRECT C-H ARYLATION
Marine Harari, Sylvain Laclef, Julien Godeau, Vincent Levacher, Corinne Fruit, Thierry Besson
COBRA UMR 6014

Batiment IRCOF - 1 Rue Tesniere - 76821 Mont St Aignan Cedex
An objective of our group is the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives
as potential kinase inhibitors.1 Preliminary interesting biological results led us to intensively study the
thiazoloquinazolin-4-one scaffold. Modulations of positions 1 and 3 were especially examinated to create a
library of 143 molecules.2 These thiazoloquinazolin-4-one products were tested for their inhibition of DYRK1A
(Dual Specificity tYrosine-phospholylation Regulated Kinase 1A) kinase with IC50 up to 60 nM. To pursue this
work we wanted to develop a method of fonctionnalization of the position 2. As an efficient and versatile access
to complex molecules, palladium-catalyzed C–H functionalization of heteroarenes3 is an attractive approach for
our laboratory. Therefore we used easily accessible quinazolin-4(3H)-ones to develop a microwave-assisted
method for the direct C2-arylation of quinazolin-4(3H)-ones (position 2) using a palladium catalysis with aryl
iodides as coupling partners.4
This innovative methodology tolerates a broad range of aryl iodides substituted by electronically different
groups. Thus it provides an efficient, versatile, and rapid access to 2-arylquinazolin-4-one backbone and will be
extended to our thiazoloquinazolin-4-one derivatives.
References
1) Loidreau, Y.; Deau, E.; Marchand, P.; Nourrisson, M.-R.; Logé, C.; Coadou, G.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J.
Med. Chem. 2015, 92, 124.
2) Foucourt, A.; Hédou, D.; Dubouilh-Benard, C.; Girard, A.; Taverne, T.; Désiré, L.; Casagrande, A.-S.; Leblond, B.; Loaëc,
N.; Meijer, L.; Besson, T. Molecules 2014, 19, 15546.
3) (a) El Kazzouli, J.; Koubachi, J.; El Brahmi, N.; Guillaumet, G. RSC Adv. 2015, 5, 15292 (b) Rossi, R.; Bellina, F.; Lessi,
M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17. (c) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (d)
Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960. (e) Ackermann, L. Chem. Rev. 2011,
111, 1315.
4) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, E.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org.
Lett. 2015, 17, 1700.
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OT033
PENTAFLUOROSULFANYL-SUBSTITUTED MOLECULES
Christine M. M. Hendriks, Carsten Bolm
Institute of Organic Chemistry, Landoltweg 1, 52074 Aachen, Germany

carsten.bolm@oc.rwth-aachen.de
Today, organofluorine compounds are increasingly applied as drugs and tools in biochemistry.1 Due to their
unique properties, aromatic pentafluorosulfanyl (SF5) compounds are of special interest, and the synthesis of
medically relevant SF5-containing building blocks is an important field of research.2,3 The incorporation of SF5
groups − also known as 'supertrifluoromethyl' groups − into drugs can lead to significant changes of the
electronic and steric properties, bioavailability and pharmacokinetics.3,4 In this context, the exchange of CF3 to
SF5 groups is especially attractive, often coming along with higher metabolic stability, increased polarity in
combination with superior lipophilicity in the corresponding pharmaceuticals.5-7
As a result of limited industrially applicable synthetic routes, only few functionalized SF5-containing building
blocks are commercially available, and the number of SF5-based drugs is limited.
Following our interest in the chemistry of SF5 groups and their pharmaceutical applications, we herein report
straight-forward syntheses of unprecedented SF5-containing building blocks,8 and chemical and biological
studies on SF5-containing bioactives.
References
1) Kirsch, P. In Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2013.
2) Sheppard, W. A. J. Am. Chem. Soc. 1960, 82, 4751.
3) Savoie, P. R.; Welch, J. T. Chem. Rev. 2015, 115, 1130.
4) Altomonte, S.; Zanda, M. J. Fluorine Chem. 2012, 143, 57.
5) Wipf, P.; Mo, T.; Geib, S. J.; Caridha, D.; Dow, G. S.; Gerena, L.; Roncal, N.; Milner, E. E. Org. Biomol. Chem. 2009, 7,
4163.
6) Welch, J. T.; Lim, D. S. Biorg. Med. Chem. 2007, 15, 6659.
7) Lim, D. S.; Choi, J. S.; Pak, C. S.; Welch, J. T. J. Pestic. Sci. 2007, 32, 255.
8) Hendriks, C. M. M.; Reball, J.; Bolm, C. Synlett 2015, 26, 73.
- 189 -
OT034
NEW APPROACH FOR THE DEVELOPMENT OF A REDOX

CHEMICAL DELIVERY SYSTEM TO TARGET
META-IODOBENZYLGUANIDINE INTO THE BRAIN
Axelle Henry (1), Cyril Papamicaël (1), Delphine Patin (2), Fabienne Gourand (2), Louisa Barré (2),
Vincent Levacher (1)
1) Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesniere, 76821 Mont
Saint Aignan Cedex, France
2) CEA/DSV/I2BM, UMR ISTCT 6301, LDM-TEP Group, GIP Cyceron, Bd Henri Becquerel, BP 5229, 14074 Cedex Caen,
France
Keywords: chemical delivery system, m-iodobenzylguanidine

The blood brain barrier (BBB) is a selective physiological barrier that protects the brain and prevents the passage
of some drugs. To improve the transport of drugs into the brain, the redox-based chemical delivery system
(CDS) based on a NADH/NAD+ model1 appears as an appealing chemical tool to reach this goal.
[123I/131I]MIBG (m-Iodobenzylguanidine) is widely used for scintigraphic imaging studies of peripheral
adrenergic tumors.2 However, the latter does not cross the BBB. In this context, we focused our research work
on the use of bio-oxidizable 1,4-dihydroquinoline carriers as CDS to [123I/131I]MIBG.3 A series of carrier-MIBG
systems were synthesized and labeled with carbon-11. In vivo studies into rats have finally shown a moderate
brain penetration and a previous peripheral oxidation. A carrier-linker-MIBG system was then envisaged to
improve the efficiency of this CDS approach. The present work describes the synthesis of a new
carrier-linker-MIBG system by means of a coupling reaction with a quinolinium salt having an N
-hydroxysuccinimidyl ester. The difficulties encountered during the syntheses used and the strategies to
overcome these difficulties will be discussed.
References
1) Prokai, L., et al., Med Res Rev. 2000, 20, 367. Bodor, N.; Buchwald, P., Drug Discovery Today. 2002, 7, 766. Bodor, N.;
Buchwald, P., Adv. Drug Delivery Rev. 1999, 36, 229.
2) Raffel, D. M., et al., J. Med. Chem. 2007, 50, 2078.
3) Gourand, F., et al., Journal of Medicinal Chemistry. 2010, 53, 1281.
- 190 -
OT035
THE DISCOVERY AND OPTIMIZATION OF A ORALLY

BIOAVAILABLE PORCUPINE INHIBITOR
Soo Yei Ho (1), Athisayamani Jeyaraj Duraiswamy (1), May Ann Lee (1), Babita Madan (2), Shi Hua Ang
(1), Eldwin Sum Wai Tan (1), Vivien Wei Wen Cheong (1), Zhiyuan Ke (1), Vishal Pendharkar (1), Lijun
Ding (1), Yun Shan Chew (1), Vithya Manoharan (1), Kanda Sangthongpitag (1), Anders Poulsen (1),
David M. Virshup (2), Thomas H. Keller (1)
1) Experimental Therapeutics Centre, 31 Biopolis Way, #03-01 Nanos, Singapore 138669

2) Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857
Wnt proteins are secreted glycoproteins acting as growth factors that regulate various cellular functions,
including proliferation, differentiation, death, migration and polarity, by activating multiple intracellular
signalling cascades, including the β-catenin-dependent and –independent pathways. Wnt signaling is
dysregulated in a wide spectrum of diseases including degenerative diseases, inflammatory and fibrotic diseases,
metabolic diseases, and a variety of cancers.
Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoylates the Wnts, hence is essential for
their secretion and function. The inhibition of PORCN could serve as a therapeutic approach for the treatment of
a number of Wnt-dependent cancers. Herein, we describe the identification of a Wnt secretion inhibitor from
cellular high throughput screening. Using classical SAR based cellular optimization, we developed a potent and
orally bioavailable PORCN inhibitor with nanomolar activity that has demonstrated efficacy in a Wnt-driven
murine tumor model. Finally, we also discovered that enantiomeric PORCN inhibitors show very different
activity in our reporter assay, suggesting that such compounds may be useful for mode of action studies on the
PORCN O-acyltransferase.
References
1) WNT pathway modulator. PCT/SG2014/000183
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OT036
FLEXIBLE DOCKING STUDY AND STRUCTURE-ACTIVITY

RELATIONSHIPS OF TRPV1 ANTAGONISTS FOR NEUROPATHIC
PAIN DRUG DISCOVERY
Sunhye Hong (1), Minghua Cui (1), Jeewoo Lee (2), Peter M. Blumberg (3), Sun Choi (1)
1) National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate
School of Pharmaceutical Sciences, and Global Top 5 program,
Ewha Womans University, Seoul 120-750, Korea
2) College of Pharmacy, Seoul National University, Seoul 151-742, Korea
3) Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD
20892, USA
The transient receptor potential vanilloid subtype 1 (TRPV1) is a member of the ligand-gated nonselective cation
channel superfamily which is highly permeable to Ca2+. TRPV1 plays a significant role in chronic pain; thus, it
is the important therapeutic target for pain relief. Especially, TRPV1 antagonists have drawn a lot of attention as
promising drug candidates for inhibiting the transmission of nociceptive signals from the periphery to the central
nervous system (CNS) and for relieving other pathological states associated with this receptor.
Based on the dibenzyl thiourea analogue as a lead compound, the diarylalkyl amide and furan-linked amide
analogues were designed and synthesized as rat TRPV1 (rTRPV1) antagonists. We performed flexible docking
study of the tested compounds by using our rTRPV1 homology model. And our results were consistent with the
rTRPV1 activities of the synthesized compounds. Even though the binding mode of the diarylalkyl amide did not
fit perfectly, the furan-linked amide analogue as well as the dibenzyl thiourea fitted nicely into the binding site.
The rigidity of B-region could contribute to the appropriate positioning of the C-region for the hydrophobic
interactions.
Furthermore, as human TRPV1 (hTRPV1) antagonists, the 4-methylsulfonamide derivatives were designed and
synthesized. The bulky hydrophobic group was added to the C-region and this led to a prominent increase of the
hTRPV1 activity. In order to investigate the structure-activity relationships, we built the hTRPV1 tetramer
homology model and performed the flexible docking study. The tested compounds fitted well in the binding site
and made tight interactions through the hydrophobic and H-bonding interactions with the residues of binding
site. Moreover, the additional hydrophobic group formed another hydrophobic interaction with the hydrophobic
regions, consisted of Met514 and Leu515 or Leu547 and Thr550. That might explain why the
4-methylsulfonamide derivative with an additional hydrophobic group had much more potent activity.
- 192 -
OT037
SYNTHESIS AND KINETIC STUDIES OF CYCLISATION-BASED

SELF-IMMOLATIVE SPACERS
Steve Huvelle (1,2), Ahmed Alouane (1,2), Ludovic Jullien (2), Frédéric Schimdt (1)
1) UMR 3666 CNRS/Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France
2) Ecole Normale Supérieure, Département de Chimie, UMR 8640 PASTEUR CNRS-ENS-UPMC Paris 06, 24 rue Lhomond,
75231 Paris Cedex 05, France.
Some active compounds know actually several limits for therapeutic using; like low solubility in biological
liquids, toxicity or weak selectivity (critical point in cancers). In this case, prodrugs are useful: it permits to
increase failing parameters by introducing one (or more) chemical group. In certain cases, it’s possible to connect
it directly with the drug; but sometimes not, because of many reasons (lost of activity, stearic encombrement).
So, it’s mandatory to introduce a spacer between the additional group and the bioactive molecule; and also, this
spacer must be able to release it easily and quickly.
That is why we synthesized and studied known cyclisant self-immolative spacers a,b, on the base of previous
work done at the Curie Institutec.
References
a) ) F. Schmidt, J.C. Florent, C. Monneret*, R. Straub, J. Czech, M. Gerken, K. Bosslet, Glucuronide Prodrugs of Hydroxy
Compounds for Antibody Directed Enzyme Prodrug Therapy (ADEPT) : A Phenol Nitrogen Mustard Carbamate, Bioorganic
& Medicinal Chemistry Letters, 1997, 7 (8), 1071-1076
b) ) Levine MN., Raines RT. Trimethyl lock: A trigger for molecular release in chemistry, biology, and pharmacology. Chem
Sci., 2012, 2412-2420
c) Labruère R., Alouane A., Le Saux T., Aujard I., Pelupessy P., Gautier A., Dubruille S., Schmidt F.*, Jullien L.*,
Angewandte Chemie International Edition, 2012, 124, 9478 –9481
- 193 -
OT038
DESIGN AND SYNTHESIS OF NOVEL FLUORINATED AMINES:

ADVANCED BUILDING BLOCKS FOR MEDICINAL CHEMISTRY
O. Artamonov, S. Trofymchuk, A. Shсherbatyuk, V. Ivanov, V. Yarmolchuk, R. Iminov, A. Tkachenko, I.
Kondratov, P. Mykhailiuk, A. Tolmachev, V. Kubyshkin
Enamine Ltd, 78 Chervonotkatska Street, Kyiv (Ukraine)
Modern drug discovery is hard to imagine without fluorine: ca. 20% of all pharmaceuticals contain this
element. To date, however, only a tiny part of the theoretically possible building block structures are
synthesized. Many simple combinations of fluorine with carbon and nitrogen atoms are still unknown.
Commercially accessible fluorinated cyclic amines are mostly limited to pyrrolidines and piperidines. The
latter are quite popular in medicinal chemistry.
In this work, we synthesized a library of novel aliphatic saturated amines.1-5 Details of their design and
synthesis will be reported.
References
1) V. Kubyshkin et al. J. Fluorine Chem. 2015, submitted.
2) A. Artamonov et al. Eur. J. Org. Chem. 2014, 3592.
3) V. Yarmolchuk et al. Eur. J. Org. Chem. 2013, 3086.
4) A. Shcherbatiuk et al. Tetrahedron 2013, 3796.
5) O. Artamonov et al. Synthesis 2013, 225.
- 194 -
OT039
SYNTHESIS OF NOVEL UNIQUE PYRROLIDINES BY

[3+2]-CYCLOADDITION OF AZOMETHINE YLIDES WITH
ELECTRON-DEFICIENT ALKENES
V. Yarmolchuk, I. Ivanov, V. Mikhalchuk, V. Savich, I. Komarov, P. Mykhailiuk, A. Tolmachev
Enamine Ltd, 78 Chervonotkatska Street, Kyiv (Ukraine)
Pyrrolidine is one of the most frequently used aliphatic amines in medicinal chemistry: its residue can be
found in at least ten FDA-approved drugs. Therefore, elaboration of practical synthetic approaches to novel
substituted pyrrolidines is important.
In this work, we synthesized a library of novel unique pyrrolidine building blocks using [3+2] cycloaddition
between electron-deficient alkenes and azomethine ylides.1-4 Some synthesized structures are mimics of
morpholine, β-proline derivatives, and fluorinated pyrrolidines.
References
1) V. Yarmolchuk et al. Tetrahedron 2014, 3011.
2) V. Yarmolchuk et al. Eur. J. Org. Chem. 2013, 69, 3086.
3) V. Yarmolchuk et al. Tetrahedron Lett. 2011, 52, 1300.
4) V. Yarmolchuk et al. J. Org. Chem. 2011, 76, 7010.
- 195 -
OT040
FLUORINATED DIAZOALKANES IN THE SYNTHESIS OF BUILDING

BLOCKS FOR MEDICINAL CHEMISTRY
V. Ivanov, P. Mykhailiuk, E. Slobodyanuk, A. Artamonov, I. Komarov, A. Tolmachev
Enamine Ltd., 78 Chervonotkatska Street, Kyiv (Ukraine).
Hardly can one imagine modern organic chemistry without diazo compounds. Their found numerous
applications not limiting only to cyclopropanation of alkenes, carbene insertions, [3+2]-cycloadditions,
Arndt-Eistert synthesis.
By far N2CHCO2Et is probably the most popular diazo compound in chemistry.1 Although some other
conceptually attractive low-molecular reagents exist they still remain in shadow of this reagent.
In this work, we studied the [2+1]- and [3+2]-cycloadditions of CF3CHN2 and previously unknown
CF2HCHN2, C2F5CHN2:2-9 These reagents proved to be efficient in synthesis of diverse fluorinated compounds
not accessible by other methods.
References
1) Y. Zhang et al. Chem. Commun. 2009, 5359.
2) P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2015, accepted (DOI: 10.1002/anie.201501529).
3) P. Mykhailiuk et al. Org. Biomol. Chem. 2015, in press (DOI: 10.1039/C4OB02670E).
4) P. Mykhailiuk et al. Beilstein JOC 2015, 11, 16.
5) P. Mykhailiuk et al. Chem. Eur. J. 2014, 17, 4942.
6) E. Slobodyanuk et al. Eur. J. Org. Chem. 2014, 2487.
7) A. Artamonov et al. Eur. J. Org. Chem. 2014, 3592.
8) A. Artamonov et al. Synthesis 2013, 225.
9) A. Artamonov et al. Synthesis 2010, 443.
10) P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 47, 5765.
- 196 -
OT041
NOVEL ANTIFUNGAL ACETYL COENZYME-A CARBOXYLASE

INHIBITORS
Stephane Jeanmart, Francesca Perruccio
Syngenta Crop Protection AG

Schaffhauserstrasse
4332 Stein
Switzerland
With a limited arsenal of modes of action to control fungal infection, it is not a surprise to encounter resistance
problems as an issue in controlling fungi. This statement applies to both human and plant pathogens. There is a
clear need for molecules that are not affected by the current known resistances. One way to avoid the resistance
problems is to find active ingredients acting by novel modes of action.
We report the findings on novel antifungal compounds inhibiting the Acetyl Coenzyme-A Carboxylase
(ACCase). This mode of action has never been used as commercial solutions to fight fungal infections. Therefore
the novel ACCase inhbitors represent a promising option to provide development compounds not affected by
current known resistance strains.
The investigations reported are focused on agrochemical application and on the binding modes at a molecular
level to explain selectivity between various pathogens.
- 197 -
OT042
NEW SYNTHETIC APPROACH TO DIVERSE HETEROCYCLIC

SULFONYL CHLORIDES
Pavlo Sokoliuk, Ivan Kondratov, Andrey Tolmachov
Enamine Ltd., Chervonotkatska, 78, 02094 Kyiv, Ukraine,
Sulfonyl chlorides are an important class of building blocks which are widely used in medicinal and
combinatorial chemistry, mostly for the preparation sulfonamides - compounds exhibiting a broad spectrum of
biological activities. The significant number of the marketed sulfonamide drugs is prepared from heteroaromatic
sulfonyl chlorides. These building-blocks are widely used in drug discovery therefore easy access to diverse
heteroaromatic sulfonyl chlorides is very important for modern medicinal chemistry.
Nowadays different synthetic approaches to plenty of hetaryl sulphonyl chlorides are described in the literature.
However often the described methods require comparatively forced conditions and cannot be considered as
convenient and effective synthetic methods in many cases.
We developed a novel synthetic approach (presented on the general scheme below) starting from 2-benzylthio
malonaldehyde which can be used for the multi-gram scale synthesis of diverse heteroaromatic sulfonyl
chlorides. Lots of obtained compounds scarcely can be obtained by other methods.
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OT043
SEARCH FOR NEW DRUGS STRUCTURALLY RELATED TO

MARSANIDINE, A HIGHLY SELECTIVE ALPHA2-ADRENOCEPTOR
AGONIST WITH HYPOTENSIVE ACTIVITY
Anita Kornicka (1), Aleksandra Wasilewska (1), Franciszek Sączewski (1), Apolonia Rybczyńska (2), Alan
L. Hudson (3), Mika Scheinin (4), Jonne M. Laurila (4), Jarosław Sączewski (5), Konrad Boblewski (2),
Artur Lehmann (2), Mehnaz Ferdousi (3), Maggie Lalies (3)
1) Department of Chemical Technology of Drugs, Medical University of Gdańsk, 80-416 Gdańsk, Poland
2) Department of Pathophysiology, Medical University of Gdańsk, 80-416 Gdańsk, Poland
3) Department of Pharmacology, University of Alberta, Edmonton T6G 2H7, Canada
4) Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Turku University Hospital,
Fl-20014 Turku, Finland
5) Department of Organic Chemistry, Medical University of Gdańsk, 80-416 Gdańsk, Poland
Our previous investigations on α2-AR ligands led to the discovery of a highly selective imidazoline-based
partial α2-AR agonist, marsanidine (Fig. 1, structure A, R = H, 1-[(imidazolidin-2-yl)imino]indazole), from
which 7-Me-marsanidine and 7-Cl-marsanidine have emerged with hypotensive, diuretic and cytoprotective
activities (Fig. 1, structure A, R = 7-Me or 7-Cl).1,2
The above results prompted us to prepare several new series of marsanidine analogues shown in Figure 1:
series B in which indazole -N-N= moiety is replaced with –N-CH= grouping; series C in which indazole and
imidazoline ring systems are connected with CH2 moiety; and series D resulting from translocation of the
iminoimidazolidine moiety from position N1 to C3 of the indazole ring.3,4
All synthesized compounds were tested for their in vitro binding affinities to α1- and α2-ARs as well as
imidazoline I1 and I2 receptors. Then, the in vitro intrinsic activities at α2A-ARs (functional [35S]GTPγS binding
experiments) of the most active analogues and their in vivo circulatory effects (intravenous infusion in
anesthetized rats) were evaluated. As a result of these investigations, 1-[(imidazolidin-2-yl)imino]indoles (B)
and 3-[(imidazolidin-2-yl)imino]indazoles (D) have been identified as selective α2-AR ligands with promising
hypotensive properties. For example, the following results were obtained for analogue B (R = 7-Me): α2Ki =
12.09 nM and ΔMAP = -40.6 mmHg at a dose of 0.01 mg/kg. Moreover, the analogue of type D (R =4-Me), a
partial α2A-AR agonist with high α2-AR affinity (Ki = 22.6 nM) and α2/I1 selectivity ratio of 1438, elicited
pronounced cardiovascular effects at doses as low as 0.1 mg/kg (ΔMAP = -53.5 mmHg). On the other hand, the
methylene analogue of type C (R = 7-Cl) showed high activities at both α1- and α2-ARs (Ki = 14.1 nM and 6.4
nM, respectively) and behaved as a potent hypotensive peripherally acting α1-AR antagonist. Of special interest
was the fluorinated analogue of general structure A (R = F, 7-F-marsanidine), which displayed a high affinity
and selectivity for α2-ARs (Ki = 30.97 nM; α2/α1 = 52, α2/I1 = 250, α2/I2 = 11263). The in vivo brain
microdialysis with use of 7-F-marsanidine showed that this analogue was able to cross the blood-brain barrier
and administered i.p. at a dose of 1 mg/kg reduced extracellular noradrenaline level in rat frontal cortex by 73%.5
References
1) Sączewski F., Kornicka A., Rybczyńska A., Hudson A.L., Miao S.S., Gdaniec M., Boblewski K., Lehmann A. J. Med.
Chem. 2008, 51, 3599.
2) Sączewski F., Rybczyńska A., Kornicka A., Sączewski J., Ma D., Maze M. PCT/GB2008/004024.
3) Sączewski J., Hudson A., Scheinin M., Rybczyńska A., Ma D., Sączewski F., Laird S., Laurila J.M., Boblewski K.,
Lehmann A., Gu J., Watts H. Bioorg. Med. Chem. 2012, 20, 108.
4) Sączewski F., Kornicka, A., Hudson A.L., Laird S., Scheinin M., Laurila J.M., Rybczyńska A., Boblewski K., Lehmann
A., Gdaniec M. Bioorg. Med. Chem. 2011, 19, 321.
5) Ferdousi M., Lalies M., Wasilewska A., Sączewski F., Hudson A. Neuroscience Lett. 2015, 590, 47.
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N-ACYLATED POLYAMINE DERIVATIVES AS

ANTIKINETOPLASTID AGENTS
Elodie JAGU (1), Sébastien POMEL (2), Florence RAMIANDRASOA (1), Stéphanie PETHE (1), Raphaël
LABRUERE (1), Philippe LOISEAU (2), Casimir BLONSKI (1)
1) Laboratoire de Chimie Bioorganique et Bioinorganique, LabEx LERMIT, Institut de Chimie Moléculaire et des Matériaux
d'Orsay (ICMMO, UMR 8182 ), Bâtiment 420, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay cedex –
France
2) Groupe Chimiothérapie Antiparasitaire, LabEx LERMIT, Faculté de Pharmacie, UMR 8076 (BioCIS), Université
Paris-Sud, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry - France
Kinetoplastids are responsible for around 120,000 deaths per years mostly in region of the world least able to
deal with the associated economic burden. The drugs available in clinic present several problems such as
toxicity, resistance, and cost. Therefore, there is an urgent requirement for alternative chemotherapies. In a
previous studies, bisubstrate inhibitors of Lysine acetyl transferase (KAT) have been developed as anticancer
agents.[1] KAT has been validated as a therapeutic target for kinetoplastids[2] and we were interested in testing
these compounds against these parasites (leishmania/trypanosome). Among the most potent antikinetoplastid
agents, a polyamine moiety was predominantly found. We therefore decided to synthesize new compounds
against these parasites based on our polyamine derivatives. These structures could display their activities
resulting from KAT inhibition, perturbation of the polyamine metabolism or blocking the polyamine transport
system. The poster will present the synthesis and the in vitro antikinetoplastid evaluation of the new polyamine
derivatives.
References
1) Kwie FH, Blonski C, Lherbet C, Baudoin-Dehoux C. Chem Biol Drug Des. 2011, 77(1), 86-92.
2) Maity AK, Saha P. FEMS Microbiol. Lett. 2012, 336, 57-63.
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OT045
DISCOVERY OF SAR623, A NOVEL, POTENT AND SELECTIVE

INHIBITOR OF VPS34 FOR CANCER TREATMENT
Jean-Philippe Letallec (1), Baptiste Ronan (1), Benoit Pasquier (1), Youssef El-Ahmad (1), Bruno
Filoche-Rommé (1), Christine Dureuil (1), Florence Fassy (1), Pierre-Yves Abecassis (2), Magali Mathieu
(3), Thomas Bertrand (3), Tsiala Benard (4), Cédric Barrière (1), Anne Caron (5), Jérôme Arigon (6),
Jean-Robert Labrosse (6), Laurent Schio (1), Gary McCort (1), Carlos Garcia-Echeverria (1)
1) Sanofi, Oncology Drug Discovery, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
2) Sanofi, Drug Disposition and Safety, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
3) Sanofi, Structure Design Informatics and Structural Biology, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
4) Sanofi, Pharmaceutical Sciences Operations, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
5) Sanofi, Global Biotherapeutics, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
6) Sanofi, Lead Generation Candidate Realization, 371 rue du professeur Joseph Blayac, 34184 Montpellier, France
Autophagy is a lysosome-dependent mechanism of intracellular degradation that recycles protein aggregates,

damaged organelles and lipids. This process occurs at baseline level in all cells, allowing clearance of misfolded
proteins, damaged organelles... Autophagy is upregulated in cancer to promote cell survival in response to
starvation, hypoxia, oxidative damage… Autophagy can be induced during drug treatment (with
chemotherapeutic agents, ionizing radiations..). It is therefore postulated to be a key resistance mechanism in
cancer treatment.
Vps34 (the class III phosphatidylinositol 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy
and thefore constitute an interesting target for cancer treatment. We aimed to identify Vps34 inhibitors to
validate the role of this lipid kinase in cancer maintenance and progression.
In the development of autophagy inhibitors, a cell-based high-throughput phenotypic screening identified
tetrahydropyrimidopyrimidinone derivatives as Vps34 inhibitors. We screened additional
tetrahydropyrimidopyrimidinone analogs from Sanofi chemical library and this led to the identification of
SAR470. The medicinal chemistry program focused on exploring SAR and improving ADME properties and
selectivity profile of this compound. The Vps34 co-crystal structure of some compounds in the series was
solved and revealed the crucial receptor-ligand interactions and guided the optimization process. This led to the
identification of (2S)-8-[(3R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro
-2H-pyrimido[1,2-a]pyrimidin-6-one (SAR623), a potent inhibitor of Vps34. It displayed exquisite selectivity in
a broad kinase panel and exhibited good ADME and physico-chemical properties. SAR623 was a good candidate
for further evaluation.
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OT046
NOVEL ASPECTS OF CHIRAL QSPR ANALYSIS

Piotr F. J. Lipinski
Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warszawa, Poland
Chirality is a property of a large number of chemical compounds. It plays an important role in all areas of
modern chemistry, especially in medicinal chemistry, since majority of drugs currently on market is chiral. On
the other hand, chirality seems not properly represented in Chemoinformatics, especially in Quantitative
Structure-Property (Activity) Relationship analysis (QSPR/QSAR). In my research, I undertook to add some
bricks to filling this gap. First of all, sinister-rectus chirality measures (SRCM), which are quantitative
descriptors of chirality, have been introduced into QSAR equations modeling affinity of steroids towards a
sex-hormone binding globulin. [1] The pilot study was then extended using a large descriptor pool and Genetic
Function Approximation to demonstrate unbiased application of chirality measures in QSAR. [2] In the next
step, I demonstrated existence of substituent effect in the spectra of Vibrational Circular Dichroism (VCD) – an
important analytical technique of modern chiral chemistry. [3] Finally, it has been shown that there is a
relationship between local chirality measures and the spectral parameters of vibrational spectroscopy. [4]
The study was supported by National Science Centre in Poland (NCN, Grant 2012/05/N/NZ7/01952).
References
1) M. H. Jamróz, J. E. Rode, S. Ostrowski, P. F. J. Lipiński, and J. C. Dobrowolski, J. Chem. Inf. Model., 2012, 52, 1462–79.
2) P. F. J. Lipiński, I. Tuvi-Arad, J. Cz. Dobrowolski, sent to RSC Adv., 2015
3) P. F. J. Lipiński J. Cz. Dobrowolski, RSC Adv., 2014, 4, 27062-27066
4) P. F. J. Lipiński, J. Cz. Dobrowolski, RSC Adv., 2014, 4, 47047–47055
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OT047
EVALUATION OF AURONES WITH TAU AGGREGATES IN

ALZHEIMER'S DISEASE
Laurent Lunven (1,2,3), Sabine Chierici (1,2), Ahcène Boumendjel (1,3), Marine Peuchmaur (1,3)
1) Université Grenoble-Alpes, Grenoble, F-38041

2) Centre National de la Recherche Scientifique, UMR 5250, Département de Chimie Moléculaire, I2BM
3) Centre National de la Recherche Scientifique, UMR 5063, Département de Pharmacochimie Moléculaire, EPSON
Alzheimer’s disease (AD) is the largest unmet medical need in neurology. The two hallmarks of AD in the brain
are senile plaques composed of extracellular deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles
formed by filaments of abnormally phosphorylated tau protein. As abnormal tau accumulation in the brain
precedes the outbreak of senile plaques1, the study of tau filaments formation has become an increasingly
attractive focus over the past few years. Herein we investigate a way to selectively interact with tau aggregates
by using aurone - peptide hybrid compounds.
We used short sequences of tau as models of tau fibres2 to assess the in vitro inhibitory effect of our compounds
by means of thioflavin dye fluorescence assays, circular dichroism and AFM techniques. With a 22 amino acid
sequence (R3 model), we were able to obtain fibres similar to native tau fibres in AFM. We then screened a
small library of aurones3 on our models that highlighted the importance of hydroxyl groups for interaction with
fibres. We used these data to build our hybrid compounds constituted of both hydroxylated aurone and a short
sequence from tau.
References
1) Delacourte et al. Neurology 1999, 52 (6), 1158-1158
2) Mohamed et al. ACS chemical neuroscience 2013, 4 (12), 1559-70
3) Boumendjel et al. Current Medicinal Chemistry 2012, 19 (18), 2861-2875
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OT048
DISCOVERY OF (IMIDAZO[1,2-a]PYRAZIN-6-YL)UREAS AS
ANTIPROLIFERATIVE AGENTS TARGETING HEF1 GENE IN
NON-SMALL CELL LUNG CANCER CELL LINES
Marc-Antoine Bazin (1), Bénédicte Rousseau (2), Sophie Marhadour (1), Christophe Tomasoni (2),
Christos Roussakis (2), Pascal Marchand (1)
1) Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, IICiMed EA 1155 Cibles et
Médicaments des Infections et du Cancer, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035
Nantes (France)
2) Université de Nantes, Nantes Atlantique Universités, Département Cancer du Poumon et Cibles Moléculaires, IICiMed EA
1155 Cibles et Médicaments des Infections et du Cancer, UFR des Sciences Pharmaceutiques et Biologiques, 9 rue Bias,
44035 Nantes (France)
E-mail: pascal.marchand@univ-nantes.fr - E-mail: marc-antoine.bazin@univ-nantes.fr
The non-small cell lung carcinomas (NSCLC) represent 80% of all cases of lung cancer [1] but remain very
resistant to all therapies currently in use such as chemotherapy, radiotherapy and surgery [2]. The gene HEF1
was discovered in 1996 [3] but, in recent years, an increasing number of studies concerning this gene have been
published. HEF1 belongs to a family of docking adapter proteins, including p130Cas and Efs, named the Cas
family [4]. HEF1 is involved in many different cellular functions, including migration, mitosis, differentiation
and apoptosis [5,6]. HEF1 is a ubiquitous gene, present in many healthy tissues as well as in cell lines at
different levels of expression. It is particularly expressed in lung tissue and pulmonary cell lines [7]. In this
context, HEF1 constitutes a very promising target for cancer therapy [8].
Research groups have reported the synthesis of imidazo[1,2-a]pyrazines and have evaluated them for various
biological activities [9]. Considering the interest of such scaffold and in the frame of our research line of
imidazo[1,2-a]azine series, we wish to report the synthesis of novel (imidazo[1,2-a]pyrazin-6-yl)ureas and their
biological activity towards HEF1 gene expression.
In parallel, the antiproliferative activity of these analogues against NSCLC-N6-L16 and A549 human lung
cancer cell lines will be highlighted.
References
1) Lilenbaum, R. C.; Herndon, J. E. 2nd; List, M. A.; Desch, C.; Watson, D. M.; Miller, A. A.; Graziano, S. L.; Perry, M. C.;
Saville, W.; Chahinian, P.; Weeks, J. C.; Holland, J. C.; Green, M. R. J. Clin. Oncol. 2005, 23, 190-196.
2) Ettinger, D. S. Oncology Williston Park N.Y. 2004, 18, 3-9.
3) Law, S. F.; Estojak, J.; Wang, B.; Mysliwiec, T.; Kruh, G.; Golemis, E. A. Mol. Cell Biol. 1996, 16, 3327-3337.
4) Law, S. F.; Zhang, Y. Z.; Klein-Szanto, A. J.; Golemis, E. A. Mol. Cell Biol. 1998, 18, 3540-3551.
5) Law, S. F.; O'Neill, G. M.; Fashena, S. J.; Einarson, M. B.; Golemis, E. A. Mol. Cell Biol. 2000, 20, 5184-5195.
6) O'Neill, G. M.; Seo, S.; Serebriiskii, I. G.; Lessin, S. R.; Golemis, E. A. Cancer Res. 2007, 67, 8975-8979.
7) Singh, M. K.; Dadke, D.; Nicolas, E.; Serebriiskii, I. G.; Apostolou, S.; Canutescu, A.; Egleston, B. L.; Golemis, E. A.
Mol. Biol. Cell 2008, 19, 1627-1636.
8) Rousseau, B.; Jacquot, C.; Le Palabe, J.; Malleter, M.; Tomasoni, C.; Boutard, T.; Sakanyan, V.; Roussakis, C. Sci. Rep.
2015, 5:10356, doi: 10.1038/srep10356.
9) Goel, R.; Luxami, V.; Paul, K. Org. Biomol. Chem. 2015, 13, 3525-3555. Review article
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OT049
DIFFERENTIAL TARGETING OF TOPOISOMERASE II ISOFORMS

WITH SMALL MOLECULES
Angelica Mariani (1), Alexandra Bartoli (1), Mandeep Atwal (2), Ka C. Lee (2), Caroline A. Austin (2),
Raphael Rodriguez (1,3)
1) Institut de Chimie des Substances Naturelles (ICSN-CNRS), Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
2) Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
3) Institut Curie Research Centre, Organic Synthesis and Cell Biology Group, 26 rue d’Ulm, 75248 Paris Cedex 05, France.
Etoposide (VP-16) is a topoisomerase II (TOP2) poison clinically used in the treatment of diverse human
cancers. Importantly, TOP2 poisons have been implicated in the generation of therapy related leukemia
following treatment of primary malignancies. TOP21 consists of two isoforms, namely TOP2A and TOP2B,
differentially expressed in mammalian cells throughout the cell cycle. Recent studies2 implicate TOP2B in the
occurrence of VP-16-related secondary malignancies, while the desired toxicity towards cancer cells has been
linked to TOP2A poisoning. Small molecules capable of targeting TOP2 in an isoform-selective manner would
represent powerful probes to elucidate cellular events relying on individual isoforms. Yet, structural similarities
between these proteins challenge the rational design of specific poisons. We report the synthesis of a library of
VP-16 analogues where chemical diversity was achieved by varying the nature of the moiety in close proximity
to a key polar residue recently identified in the complex with TOP2B.3 The small molecules were evaluated for
their ability to stabilize TOP2-DNA complexes in cells, to promote the formation of DNA double-strand breaks
(DSBs) and to inhibit growth of TOP2-depleted cells. We have identified two novel analogues, AM-371 and
AM-387 exhibiting a TOP2B-dependent toxicity, reversed in comparison with VP-16.4 The current study paves
the way towards studying isoform-specific cellular processes by means of small molecule intervention.
References
1) Vos, S. M.; Tretter, E. M.; Schmidt, B. H.; Berger, J. M. Nat. Rev. Mol. Cell Bio. 2011, 12, 827 – 841
2) a) Azarova, A. M.; Lyu, Y. L.; Lin, C.-P.; Tsai Y.-C.; Lau, J. Y-N.; Wang, J. C.; Liu L. F. Proc. Natl. Acad. Sci. USA,
2007, 104, 11014 – 11019; b) Cowell, I. G.; Sondka, Z.; Smith, K.; Lee, K. C.; Manville, C. M.; Sidorczuk-Lesthuruge, M.;
Rance, H. A.; Padget, K.; Jackson, G. H.; Adachi, N.; Austin, C. A. Proc. Natl. Acad. Sci. USA 2012, 109, 8989 – 8994
3) Wu, C.-C.; Li, T.-K.; Farh, L.; Lin, L.-Y.; Lin, T.-S.; Yu, Y.-J.; Yen, T.-J.; Chiang, C.-W.; Chan, N.-L. Science 2011, 333,
459–462.
4) Mariani A.; Bartoli A.; Atwal M.; Lee K. C.; Austin C. A.; Rodriguez R. J. Med. Chem. 2015, DOI:
10.1021/acs.jmedchem.5b00473
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OT050
DESIGN OF A CRYPTOPHANE-BASED BIOSENSOR FOR THE

DETECTION OF NON-SMALL CELL LUNG CANCER USING
HYPERPOLARIZED 129Xe MAGNETIC RESONANCE IMAGERY
Gaelle Milanole (1), Bo Gao (1), Christophe Dugave (1), Patrick Berthault (2), Thierry Brotin (3), Sofia
Rivera (4), Bernard Rousseau (1)
1) CEA Saclay, 91191 Gif sur Yvette, iBiTec-S/SCBM, LabEx LERMIT

2) CEA Saclay, 91191 Gif sur Yvette, IRAMIS, NIMBE, Laboratoire Structure et Dynamique par Résonance Magnétique
3) Laboratoire de Chimie, CNRS, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07
4) Institut Gustave Roussy, 94805 Villejuif Cedex
A fine detection and monitoring of tumor response to therapy through imaging techniques is critically important
in the treatment of cancer, in particular non-small cell lung cancer (NSCLC) which is the leading cause of lung
cancer-related mortality. Among all diagnostic techniques, magnetic resonance imaging (MRI) offers several
advantages owing to its low invasiveness, its harmlessness and its spatial in-depth resolution. However, it suffers
from poor sensitivity. Different strategies can be used to improve MRI detection threshold including the use of
hyperpolarized gases. In this context, laser-polarized 129Xe spectroscopy is a highly attractive tool for in vitro
and in vivo MRI.1
Good candidates for 129Xe biosensing are cryptophanes,2 molecular cages which exhibit outstanding properties
for xenon encapsulation, in particular a high affinity and an optimal rate of in and out exchange of xenon.3
Herein, we propose the synthesis of the first cryptophane-based biosensor for the detection of NSCLC. The
biosensor was constructed by highly specific chemical conjugation of a water-soluble cryptophane to Cetuximab,
a therapeutic antibody directed towards the epithelium growth factor receptor (EGFR) which is overexpressed in
NSCLC. A fluoresceine moiety was required for the in vitro experiments and proved the capacity of our
biosensor to bind cancer cells specifically in a concentration-dependant manner. Finally, the 129Xe NMR
spectrum of the biosensor was extremely encouraging for future in vitro and in vivo imaging.
References
1) a) M. S. Albert, G. D. Cates, B. Driehuys, W. Happer, B. Saam, C. S. Springer, A. Wishnia, Nature 1994, 370, 199; b) P.
Berthault, G. Huber, H. Desvaux, Prog. Nucl. Magn. Reson. Spectrosc. 2009, 55, 35.
2) a) T. Brotin, J.-P. Dutasta, Chem. Rev. 2009, 109, 88; b) N. Kotera, N. Tassali, E. Léonce, C. Boutin, P. Berthault, T.
Brotin, J.-P. Dutasta, L. Delacour, T. Traoré, D.-A. Buisson, F. Taran, S. Coudert, B. Rousseau, Angew. Chem. Int. Ed. 2012,
51, 4100; c) E. Dubost, N. Kotera, S. Garcia-Argote, Y. Boulard, E. Léonce, C. Boutin, P. Berthault, C. Dugave, B.
Rousseau, Org. Lett. 2013, 15, 2866; d) N. Tassali, N. Kotera, C. Boutin, E. Léonce, Y. Boulard, B. Rousseau, E. Dubost, F.
Taran, T. Brotin, J.-P. Dutasta, P. Berthault, Anal. Chem. 2014, 86, 1783.
3) a) R. M. Fairchild, A. I. Joseph, K. Travis Holman, H. A. Fogarty, T. Brotin, J.-P. Dutasta, C. Boutin, G. Huber, P.
Berthault, J. Am. Chem. Soc. 2010, 132, 15505; b) E. Dubost, J.-P. Dognon, B. Rousseau, G. Milanole, C. Dugave, Y.
Boulard, E. Léonce, C. Boutin, P. Berthault, Angew. Chem. Int. Ed. 2014, 53, 9837.
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OT051
SYNTHESIS AND BIOLOGICAL EVALUATION OF

1-METHYL-1,6-NAPHTHYRIDIN-2(1H)-ONE DERIVATIVES AS
POTENT Hsp90 C-TERMINAL INHIBITORS
David Montoir (1), Eléonore Lepvrier (2), Alain Tonnerre (1), Cyrille Garnier (2), Sophie Barillé-Nion (3),
Muriel Duflos (1), Marc-Antoine Bazin (1)
1) Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des
Infections et du Cancer, IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil 44035
Nantes Cedex - France
2) Université de Rennes 1, Institut de Génétique et Développement de Rennes, UMR-CNRS 6290, Campus Beaulieu Bâtiment
13, 263 avenue du Général Leclerc 35042 Rennes Cedex - France
3) CRCNA, UMR 892 INSERM / 6299 CNRS / Université de Nantes, Team 8 ‘‘Cell survival and tumor escape in breast
cancer’’, Institut de Recherche en Santé de l’Université de Nantes, IRS-UN, 8 quai moncousu, 44000 Nantes Cedex - France
E-mail : david.montoir@univ-nantes.fr
The 90-kDa Heat shock protein (Hsp90) is an ATP-dependent chaperone known to play a crucial role in protein
homeostasis. Hsp90 is directly involved in the conformational stability of numerous oncogenic proteins (e.g.,
Her2, Raf1, Akt, etc.), many of which are associated with cancer cell survival.(1), (2)
Novobiocin, an aminocoumarin antibiotic, was reported as the first Hsp90 C-terminal inhibitor. However, due to
its low antiproliferative activity (IC50 = 700 μM in SKBr3 breast cancer cell line), it was considered unsuitable
for therapeutic application. Subsequently, many studies have led to the development of novobiocin analogues
which manifest low micromolar activity.(3)
Prior studies have shown that attachment of a benzamide side chain to the 3-position of the coumarin ring
resulted in a significant enhancement in antiproliferative activity while noviose at the 7-position could be
replaced by hydrophilic moiety maintaining or increasing the biological activity.(4)
In this context, we focused our work on the synthesis of new analogues of novobiocin derived from the
1-methyl-1,6-naphthyridin-2(1H)-one scaffold. The target compounds were obtained in two steps from a key
amine intermediate, the 3-amino-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one, which was converted into
amide at position 3, and functionalized with amines at position 7.
Newly synthesized compounds were evaluated against two breast cancer cell lines and selected regarding their
ability to bind the mammalian Hsp90.
References
1) Garcia-Carbonero, R. et al. Lancet Oncol. 2013, 14, 358−369
2) Zhao, H. et al. Eur. J. Med. Chem. 2015, 89, 442-466
3) Kusuma, B. R. et al. Bioorg. Med. Chem. 2014, 22, 1441–1449
4) Zhao, H. et al. ACS Med. Chem. Lett. 2014, 5, 84−88
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OT052
SYNTHESIS AND APPLICATION OF PROLINE ANALOGUES:

V. Bilenko, V. Dolovanyuk, O. Grygorenko, Y. Ivon, I. Komarov, I. Kondratov, V. Kubyshkin, E.
Leychenko, O. Michurin, P. Mykhailiuk, T. Savchuk, O. Tereshenko, A. Tolmachev, S. Trofymchuk, A.
Tymtsunik, V. Vilchinskiy
Enamine Ltd., Chervonotkatska 78, Kyiv 01103 (Ukraine).
L-Proline is a natural amino acid playing an important role in drug discovery as a cheap chiral bifunctional
building block. In this context, over the past decade unnatural analogues of L-Proline became extremely popular.
For example, in 2010 Gilead launched Ledipasvir – a drug bearing the residues of two unnatural analogues of L
-Proline.
In this work, we have rationally designed, synthesized and applied a library of novel/previously scarcely
available analogues of L-Proline in medicinal chemistry. Details of the synthesis and application of the obtained
compounds will be discussed.1-9
References
1) V. Kubyshkin et al. Org.Biomol.Chem. 2015, in press (DOI: 10.1039/C5OB00034C).
2) A. Tymtsunik et al. Tetrahedron Lett. 2014, 53, 3847.
3) V. Kubyshkin et al. Org. Lett. 2012, 14, 5254.
4) I. Kondratov et al. Org.Biomol.Chem. 2012, 10, 8778.
5) P. Mykhailiuk et al. Tetrahedron 2011, 67, 3091.
6) V. Kubyshkin et al. Synthesis 2009, 3327.
7) P. Mykhailiuk et al. Angew.Chem.Int.Ed. 2008, 47, 5765.
8) V. Kubyshkin et al. Tetrahedron Lett. 2007, 48, 4061.
9) O. Grygorenko et al. Tetraheron: Asymm. 2006, 17, 252.
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OT053
DESIGN, SYNTHESIS AND APPLICATION OF NOVEL BUILDING

BLOCKS TO "ESCAPE THE FLATLAND" IN MEDICINAL
CHEMISTRY
D. Bandak, Y. Dmytriv, I. Komarov, S. Kokhan, O. Korolyov, A. Mitiuk, P. Mykhailiuk, S. Pavlenko, A.
Tolmachev, A Tymtsunik
Enamine Ltd., Chervonotkatska 78, Kyiv 01103 (Ukraine)
Given the modern trend in medicinal chemistry – “Escape the Flatland”1 – saturated 3D-shaped building blocks
do play an important role.2 Compared to their aromatic 2D-shaped counterparts, the saturated analogues usually
possess higher water solubility, higher activity and lower toxicity.
In this work, therefore, we have rationally designed and synthesized a library of novel saturated bioisosters of
benzene. Details of the synthesis and application of the obtained compounds will be discussed.3-5
References
1) F. Lovering et al. J. Med. Chem.2009, 6752.
2) A. F. Stepan et al. J. Med. Chem.2012, 3414.
3) D. Bandak et al. Org. Lett. 2015, 226.
4) P. Mykhailiuk et al. J. Fluorine Chem. 2010, 217.
5) P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2006, 5659.
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OT054
SYNTHESIS OF CONFORMATIONALLY RESTRICTED SCAFFOLDS

BY DOUBLE-MANNICH REACTION OF CYCLIC KETONES
O. Denisenko, T. Druzhenko, A. Mityuk, P. Garbuz, A. Tolmachev, P. Mykhailiuk
Enamine Ltd., Chervonotkatska 78, Kyiv 01103 (Ukraine)
Conformational restriction is an effective tool used in medicinal chemistry to improve/modify

pharmacological profiles of lead compounds. Due to a fixation of the functional groups in a biologically active
conformation, the sterically restricted compounds are often more efficient and selective ligands for various
targets, thus displaying pronounced biological activity.1
In this work, we synthesized a library of novel conformationally restricted bicyclic scaffolds by

Double-Mannich reaction of cyclic ketones. Details of the synthesis and application of the obtained compounds
will be discussed.
References
1) T. Druzhenko et al. Org. Lett. 2015, submitted.
2) A. Mityuk et al. Synthesis 2010, 493.
3) O. Denisenko et al. Tetrahedron Lett. 2010, 51, 1790.
4) O. Denisenko et al. Org. Lett. 2010, 12, 4372.
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OT055
DESIGN, SYNTHESIS OF NEW AMIDES DERIVED FROM

3,3-DISUBSTITUTED 2,5-DIOXO-PYRROLIDIN-1-YL-ACETIC ACID
AS POTENTIAL ANTICONVULSANT AGENTS
Jolanta Obniska (1), Sabina Rybka (1), Anna Rapacz (2), Krzysztof Kamiński (1), Małgorzata Góra (1)
1) Department of Medicinal Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
2) Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
The previous research from our laboratory have demonstrated diversified anticonvulsant activities among the
differently substituted pyrrolidine-2,5-diones, however the most promising were 3,3-disubstituted N-Mannich
bases derivatives of pyrrolidine-2,5-diones with 4-phenylpiperazine as basic moiety at the position-1. The most
active among these derivatives were compounds with electron-withdrawing chlorine and fluorine atoms or
trifluoromethyl group connected to the phenylpiperazine moieties at the position-2 or -3.1-3
Following these findings, in order to search for new, effective anticonvulsants as well as continue systematic
SAR studies, in current work we have synthesized a new series of amides of 3-ethyl-3-methyl- and
3,3-diphenyl-2,5-dioxo-pyrrolidine-1-yl-acetic. These compounds have been designed as analogues of
previously obtained N-Mannich bases with an amide bond between methylene group connected to imide
nitrogen atom and 4-arylpiperazine derivatives. The modifications proposed enable to assess the role of
supplementary amide function on anticonvulsant properties in this group of derivatives. In order to ensure
reliable SAR discussion variously substituted piperazines have been introduced as amine function.
All new synthesized amides have been evaluated for anticonvulsant activity and many of them showed
protection against seizures induced electrically (MES-test) and/or chemcally pentylenetetrazole (sc. PTZ).
This study was supported by the State Committee for Scientific Research, Poland (Grant No.
DEC-2013/11/B/NZ7/02081).
References
1) J. Obniska, I. Chlebek, K. Kamiński : Arch. Pharm. Chem. Life Sci. 345, (2012), 713-722
2) K. Kamiński, J. Obniska, I. Chlebek, P. Liana, E. Pękala: Eur, J. Med. Chem. 66, (2013), 12-21
3) J. Obniska, I. Chlebek, K. Kamiński, J. Karolak-Wojciechowska: Arch. Pharm. Chem. Life Sci. 346, (2013), 71-82
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OT056
NOVEL AMINOGLYCOSIDES FOR DRUG DEVELOPMENT

Julie Obszynski, Anne-Sophie Felten, Jean-Marc Weibel, Patrick Pale
Laboratoire de Synthèse et Réactivité Organiques et Catalyse (LASYROC), UMR7177, CNRS, Université de Strasbourg,
4 rue Blaise Pascal, 67070 Strasbourg, France.
The human immunodeficiency virus (HIV) remains one of the leading causes of mortality worldwide in spite of
the development of the multi-drugs therapies. The high mutation and recombination rates of HIV allow for the
emergence of drug-resistant viruses. There is therefore a crucial need for new drugs, especially drugs interacting
with novel targets within the HIV replication cycle.
The dimerization initiation site (DIS) of the HIV genomic RNA is a strongly conserved stem-loop located in the
5’ noncoding region of the viral genome that initiates the genome dimerization by forming a loop-loop complex
(kissing-loop complex).1 Since the DIS is essential for efficient viral replication at the RNA packaging and
reverse transcription stages, the dimerization step represents a new target for the development of future anti-HIV
drugs. Moreover, the kissing-loop complex revealed an unexpected and strong resemblance with the bacterial
16S ribosomal A site, which is the target of aminoglycoside antibiotics. It was also demonstrated that
4,5-disubstitued 2-deoxystreptamine (DOS) aminoglycosides could also specifically bind the DIS kissing-loop
complex.2 This binding could induce a strong stabilization of the DIS kissing loop, and could lead to the
inhibition of the replication of the viral particle.
In this work, we propose to design and synthesize new aminoglycosides analogs.3 We focused our work on the
development of novel sequences for the chemo-selective derivatization of neomycin (N-1 position of DOS ring
and O-5’’ position of ribose ring) and neamine (N-1 and O-5 positions of DOS ring). These approaches allowed
us to prepare small neomycin and neamine libraries. Evaluation of the affinity and the specificity of the latters,
allowed us to identify key structural modifications that are likely to increase the affinity and/or the specificity for
the DIS and/or the ribosomal A site.
References
1) a) Laughrea, M.; Jette, L. Biochemistry 1994, 33, 13464-13474; b) Skripkin, E.; Paillart, J.-C.; Marquet, R.; Ehresmann,
B.; Ehresmann, C. Proc. Natl. Acad. Sci. USA 1994, 91, 4945-4949.
2) a) Ennifar, E.; Paillart, J.-C.; Marquet, R.; Ehresmann, C.; Erhesmann, B.; Dumas, P., Walter, P. J Biol. Chem. 2003, 278,
2723-2730; b) Ennifar, E.; Paillart, J.-C.; Bodlenner, A.; Walter, P.; Weibel, J.-M.; Aubertin, A.-M.; Pale, P.; Dumas, P.;
Marquet, R. Nucleic Acids Res. 2006, 34, 2328-2339; c) Ennifar, E.; Paillart, J.-C.; Bernacchi, S.; Walter, P.; Pale, P.;
Decout, J.-L.; Marquet, R.; Dumas, P. Biochimie 2007, 89, 1195-1203; d) Freisz, S.; Lang, K.; Micura, R.; Dumas, P.;
Ennifar, E. Angew. Chem. Int. Ed. Engl. 2008, 47, 4110-4113.
3) Bodlenner, A.; Alix, A.; Weibel, J.-M.; Pale, P.; Ennifar, E.; Paillart J.-C.; Walter, P.; Marquet, R.; Dumas, P.; Org. Lett.
2007, 9, 4415-4418.
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OT057
THE FOCUS ON DRUG DISCOVERY: HOW?

Julie Osaretin Osayande
Antwerpen, Belgium
Science and drug discovery methods is as old as man, so is pathogen transmission and disease spread. It takes
little or no effort for diseases to break out but yet it takes the average Scientist decades to find lasting solutions
to combat disease.Pathogens need human beings (apart from other vectors like animals ) as vehicles to transport
them from place to place. Public enlightenment campaigns can help human beings to minimize disease spread.
Furthermore, reinventing available mechanical constructs, redirecting Scientific experiment towards knowing
what essential nutrient or compounds pathogenic organisms need to survive and get established to cause
infection in a host in addition to using avirulent bacteria strains as drug delivery tools and competitors may
probably go a long way in improving bacterial or pathogenic medicine development.
References
1) Banin et al., 2005. Iron and Pseudomonas aeruginosa biofilm formation. PNAS, 31 (102):11076-11081
2) Deasy et al., 2015. Nasal Inoculation of the Commensal Neisseria lactamica Inhibits Carriage of Neisseria meningitidis by
Young Adults: A Controlled Human Infection Study. Clinical Infectious Disease, cid.oxfordjournals.org.
3) Johnson et al., 2015. Increasing AIP macrocycle size reveals key features of agr activation in Staphylococcus aureus.
ChemBioChem.
4) Osayande J. O., 2015 . Pathogen traffickers : Disease causing pathogens do not have legs . Int. Res. J. Basic Clin. Stud.,
3(1)
5) Kaper J.B., Hacker J., eds. 1999. Pathogenicity Islands and Other Mobile Virulence Elements. Washington, DC: Am. Soc.
Microbiol.,1-11.
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OT058
IDENTIFICATION OF THERAPEUTIC COMPOUNDS FOR PROTEIN

AGGREGATION DISORDERS USING A WHOLE-ORGANISM-BASED
APPROACH
Joshua A. Benson, Linda P. O'Reilly, David H. Perlmutter, Gary A. Silverman, Stephen C. Pak
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Alpha-1-antitrypsin deficiency (ATD) is a genetic disorder characterized by the accumulation of misfolded

protein aggregates in the liver. To facilitate the identification of therapeutic compounds, we developed a
transgenic C. elegans model of ATD. In addition, we developed an automated, whole organism-based assay for
high-content screening of small molecules. Screens of pharmacologically active chemical libraries identified
drugs that significantly reduced the accumulation of misfolded protein aggregates in C. elegans. More
importantly, these compounds were also found to be efficacious in reducing protein aggregation and fibrosis in a
mouse model of ATD. These results suggest that our approach provides a rapid and economical means for
pre-clinical drug re-purposing for ATD and other protein aggregation disorders which can be easily modeled in
C. elegans.
References
1) Long OS, Luke CJ, Gosai SJ, Benson JA, Miedel MT, Kwak JH, O’Reilly LP, Vetica AC, King DE, Hidvégi T, Ewing M,
Perlmutter DH, Silverman GA, Pak SC. A C. elegans model of human α1-antitrypsin deficiency links RNAi to misfolded
protein turnover. Hum Mol Genet. 2014; 23:5109-22. PMID: 24838286.
2) O’Reilly LP, Long O, Cobanoglu MC, Luke CJ, Benson JA, Miedel MT, King DE, Bahar I, Perlmutter DH, Silverman
GA, Pak SC. A genome-wide, high-content RNAi screen identifies potential drug targets in a C. elegans model of
α1-antitrypsin deficiency. Hum Mol Genet. 2014; 23:5123-32. PMID: 24838285.
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OT059
A DRUG DELIVERY SYSTEM TARGETING THE

MICROENVIRONMENT OF SOLID TUMORS
Brigitte Renoux, Isabelle Opalinski, Jonathan Clarhaut, Thibaut Legigan, Sébastien Papot
IC2MP - UMR 7285 CNRS - Université de Poitiers

Equipe E5 - "Systèmes Moléculaires Programmés"
4, rue Michel Brunet, TSA 51106, 86073 Poitiers cedex, FRANCE
http://smp.labo.univ-poitiers.fr
Nowadays, chemotherapy is not entirely effective against many common solid tumor types. Most anticancer
drugs act by anti-proliferation mechanisms and lack any intrinsic antitumor selectivity. In turn, chemotherapy is
frequently associated with severe side effects due to the destruction of normal tissues. As a result, the amount of
drug that can be administered is usually insufficient to deliver a lethal concentration of anticancer agent at the
tumor site. Moreover, the lack of selectivity of cytotoxic drugs dramatically increases the risk of development of
cellular resistance by tumor cells. Thus, in view of non-specific toxicity of most anticancer drugs, the
development of more selective chemotherapeutic approaches has become a major goal of anticancer research.
Within this framework, we developed the first beta-glucuronidase-responsive albumin-binding prodrug1 of a
potent antimitotic agent. This compound includes a glucuronide trigger,2 the potent Monomethylauristatin E
(MMAE) and a self-immolative linker3 bearing a poly(ethylene glycol) side chain ended by a maleimide
functional group. After intravenous administration, the in situ binding of the prodrug to the thiol at the cysteine
34 position of plasmatic albumin via Michael addition produces the corresponding macromolecular drug carrier.
Therefore, the larger size of the latter prevents the rapid renal clearance observed with
beta-glucuronidase-responsive prodrugs developed so far. Once in targeted tumor tissues, the
beta-glucuronidase-catalysed cleavage of the glycosidic bond triggers the release of MMAE in a stringently
controlled fashion. The antitumor efficacy of this compound was evaluated on Mia-Paca orthotopic pancreatic
and MDA-MB-231 orthotopic breast models in mice. In these experiments, intravenous injections of 4 mg/kg of
the prodrug led to total and durable disappearance of the tumors, while treatment with MMAE induced only a
poor inhibition of tumor growth.
References
1) “Synthesis and Antitumor Efficacy of a -Glucuronidase-Responsive Albumin-Binding Prodrug of Doxorubicin” T.
Legigan, J. Clarhaut, B. Renoux, I. Tranoy-Opalinski, A. Monvoisin, J.-M. Berjeaud, F. Guilhot and S. Papot J. Med. Chem.
2012, 55, 4516-4520.
2) “-Glucuronidase-Responsive Prodrugs for Selective Cancer Chemotherapy: an Update.” I. Tranoy-Opalinski, T. Legigan,
R. Barat, J. Clarhaut, M. Thomas, B. Renoux and S. Papot, Eur. J. Med. Chem. 2014, 74, 302-313.
3) “Design of Self-Immolative Linkers for Tumour-Activated Prodrug Therapy” I. Tranoy-Opalinski, A. Fernandes, M.
Thomas, J.-P. Gesson and S. Papot Anti-Cancer Agents Med. Chem. 2008, 8, 618-637
- 215 -
OT060
VERSATILE SPECTROMETRIC PROBES: THE RELATION

BETWEEN MULTITARGET DNA / RNA SENSING AND
CYTOTOXICITY
Ivo Piantanida
Laboratory for Study of Interactions of Biomacromolecules, Division of Organic Chemistry and Biochemistry, Ruđer
Bošković Institute, P.O.B. 180, HR-10002 Zagreb, Croatia, pianta@irb.hr
Small molecules targeting DNA and RNA have attracted significant scientific interest not only because of their
biomedicinal applications, but also due to widespread use of spectrophotometric markers in the related scientific
research. For instance, fluorescent techniques significantly developed during the last two decades and now
represent about 60% of the detection enabling technologies used in molecular biology and medicine.
Scheme 1. Single small organic molecule interacting with various DNA/RNA structures and reporting the
structural specificity of each polynucleotide by sensitive and biologically applicable spectrometric method.
Our research is particularly focused on small organic molecules binding via non-covalent interactions (logKs > 5
M-1) non-selectively to the most of naturally occurring ds-DNA and ds-RNA secondary structures but yielding
different signals for each of the most common secondary structures (Scheme 1; A-DNA/RNA, B-DNA, subtypes
of DNA characterized by narrower minor groove, etc.) by sensitive and biologically applicable methods
(UV/Vis, CD/LD, fluorescence, SERS). The development of such single molecule multi-target sensors, able to
report simultaneously the presence of several different secondary structures of DNA / RNA varieties by different
spectroscopic signals could replace necessary application of several dyes, each one specific for one DNA or
RNA target. Additional benefit includes easier modulation of cytotoxicity for only one added molecule. Here
will be presented several most successful examples [1] and their structure – cytotoxicity relation.
Acknowledgements: Thanks to Croatian Science Foundation (grant No. 1477) support.
References
1) J. Gershberg et al, Chem., Eur. J., (2015), DOI: 10.1002/chem.201500184; M. Radić Stojković et al; Org. Biomol. Chem.,
13, (2015), 1629; T. H. Rehm et al, Chem. Sci., 3, (2012), 3393; L.-M. Tumir et al, Chem., Eur. J., 18 (2012), 3859; K.
Klemm et al; Chem., Eur. J., 18 (2012) 1352.
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OT061
NOVEL ANTILEISHMANIAL LEAD COMPOUND IN

3-NITROIMIDAZO[1,2-a]PYRIDINE SERIES
Cyril Fersing (1), Louise Basmaciyan (2), Anita Cohen (2), Caroline Castera-Ducros (1), Nicolas Primas
(1), Sébastien Hutter (2), Maxime D. Crozet (1), Michèle Laget (2), Pierre Verhaeghe (3), Pascal Rathelot
(1), Patrice Vanelle (1), Nadine Azas (2)
1) Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie,
27 Boulevard Jean Moulin, CS 30064, 13385 Marseille cedex 05, France
2) Aix-Marseille Université, UMR MD3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27
Boulevard Jean Moulin, CS 30064, 13385 Marseille cedex 05, France
3) Université Paul Sabatier, Faculté des Sciences Pharmaceutiques − CNRS UPR 8241, Laboratoire de Chimie de
Coordination, 205 Route de Narbonne, 31077 Toulouse cedex 04, France
Looking for original heterocyclic molecules presenting antiparasitic activity, our research team develops a new
program focusing on nitroaromatic compounds with antileishmanial activity.1-3 Thus, in 2013, we reported the
identification of a promising antileishmanial pharmacophore centered on the 3-nitroimidazo[1,2-a]pyridine
scaffold.4
We present herein the antileishmanial pharmacomodulation study that we conducted at positions 6 and 8 of the
imidazo[1,2-a]pyridine ring, by introducing new halogen atoms or by using nucleophilic aromatic substitution
reactions. A series of twenty five original derivatives was then synthesized and highlighted a lead compound,
bearing a p-chlorophenylsulfide substituent at position 8 and a chlorine atom at position 6. This lead compound
displays very good in vitro activity on both the promastigote and amastigote stages of the parasite (IC50 = 1-1.3
µM) in comparison with Amphotericin B (the most active antileishmanial drug on the market) and Miltefosine
(the only orally available antileishmanial drug on the market). Moreover, the lead compound did not show any
cytotoxicity on the human HepG2 cell line (CC50 > 62.5 µM).
The research for the mechanism of action of the lead molecule, the evaluation of its activity toward other
protozoa (to assess its selectivity) and the determination of its physicochemical properties and in vitro
pharmacokinetic parameters are under progress.
References
1) L. Paloque, P. Verhaeghe, M. Casanova, C. Castera-Ducros A. Dumètre, L. Mbatchi, S. Hutter, M. Kraiem-M'rabet, M.
Laget, V. Remusat, S. Rault, P. Rathelot, N. Azas, P. Vanelle, Eur. J. Med. Chem. 2012, 54, 75–86.
2) C. Kieffer, A. Cohen, P. Verhaeghe, S. Hutter, C. Castera-Ducros, M. Laget, V. Remusat, M. Kraiem M’Rabet, S. Rault, P.
Rathelot, N. Azas, P. Vanelle, Eur. J. Med. Chem. 2015, 92, 282-294.
3) C. Kieffer, A. Cohen, P. Verhaeghe, L. Paloque, S. Hutter, C. Castera-Ducros, M. Laget, S. Rault, A. Valentin, P.
Rathelot, N. Azas, P. Vanelle, Bioorg. Med. Chem. 2015, 23, 2377-2386.
4) C. Castera-Ducros, L. Paloque, P. Verhaeghe, M. Casanova, C. Cantelli, S. Hutter, F. Tanguy, M. Laget, V. Remusat, A.
Cohen, M. D. Crozet, P. Rathelot, N. Azas, P. Vanelle, Bioorg. Med. Chem. 2013, 21, 7155–7164.
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OT062
ANTIPLASMODIAL ACTIVITY OF NEW QUINAZOLINE SERIES

SYNTHESIZED BY A DMAP-CATALYZED AND
MICROWAVE-ASSISTED APPROACH
Armand Gellis (1), Nicolas Primas (1), Pierre Verhaeghe (2), Gilles Lanzada (1), Sébastien Hutter (3),
Nadine Azas (3), Patrice Vanelle (1)
2) Université Paul Sabatier, Faculté des Sciences Pharmaceutiques − CNRS UPR 8241, Laboratoire de Chimie de
Coordination, 205 Route de Narbonne, 31077 Toulouse cedex 04, France
3) Aix-Marseille Université, UMR MD3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27
Plasmodium falciparum is a protozoan parasite belonging to the Apicomplexa and is the causative agent of the
most severe type of malaria: cerebral malaria. Because of the emergence of multi-drug-resistant P. falciparum
strains, new antimalarial drug-compounds presenting original mechanisms of action are required in order to
contribute to solving such alarming public health problem.
Since more than 40 years, it is well known that the quinazoline ring can display antiplasmodial properties. Quite
recently, new molecules belonging to the quinazoline series, substituted at position 2, 4 or 6, were identified as
displaying promising antiplasmodial activities. Among them, three different series were issued from our research
team (Fig. 1) specialized on the design and the synthesis of original molecules with anti-infectious properties.1
Figure 1
In order to identify both more active and less toxic compounds, we studied the influence of the substitution at
position 4 of the quinazoline ring toward the in vitro antiplasmodial activity into a CQ-resistant strain (W2 P.
falciparum) and the cytotoxicity into HepG2 cell line in order to determine an selectivity index. Thus, we
prepared a new series of 2-trichloromethylquinazolines bearing an oxygenated substituent at position 4 by
reacting various alcohols into the 4-chloro-1-trichloromethylquinazoline in presence of DMAP as catalyst under
microwave assistance.
The chemical structures and the biological evaluation of this new series will be presented in the poster.
References
1) Y. Kabri, N. Azas, A. Dumètre, S. Hutter, M. Laget, P. Verhaeghe, A. Gellis, P. Vanelle, Eur. J. Med. Chem. 2010, 45,
616-622 ; Castera-Ducros, C.; Azas, N.; Verhaeghe, P.; Hutter, S.; Garrigue, P.; Dumetre, A.; Mbatchi, L.; Laget, M.;
Remusat, V.; Sifredi, F.; Rault, S.; Rathelot, P.; Vanelle, P. Eur. J. Med. Chem. 2011, 46, 4184-4191.
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OT063
NEW ANTILEISHMANIAL AGENTS: SYNTHESIS, EVALUATION

AND STRUCTURE-ACTIVITY RELATIONSHIPS STUDY OF
HYDROXYAMIDINE DERIVATIVES
Clémence Tabélé (1), Christophe Curti (1), Viviane dos Santos Faiões (2), Nicolas Primas (1), Youssef
Kabri (1), Eduardo Caio Torres-Santos (2), Patrice Vanelle (1)
2) Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ,
Brazil.
The preparation of hydroxyamidines as antileishmanial agents is described (1-2) by cyclization of alkenes with β
-ketosulfones using an oxidative free-radical mechanism mediated by manganese(III) acetate (Figure 1). The
biological assessment of hydroxyamidines series highlighted a hit. Further pharmacomodulations on amidoximes
showed that R1 moiety must contain a -CH2- group in α-position of the dihydrofurane to provide antileishmanial
activity (3). In order to synthesize such new derivatives, we developed an original cross-coupling reaction
between 2-methyl-2-propen-1-ol and various boronic acids (Figure 2) to obtain methylallyl derivatives (4,5). Then
corresponding hydroxyamidines were obtained and evaluated on L. amazonensis promastigote and amastigote
(Figure 3): antileishmanial activity is enhanced by ortho- or meta- substitution of the benzyl, -NO2 or –CF3
groups and ortho- or meta- polysubstitution of benzyl group.
References
1) L. Paloque, A. Bouhlel, C. Curti, A. Dumètre, P. Verhaeghe, N. Azas, P. Vanelle. Eur. J. Med. Chem. 2011, 46,
2984–2991.
2) A. Bouhlel, C. Curti, A. Dumètre, M. Laget, M. Crozet, N. Azas, P. Vanelle. Bioorg. Med. Chem. 2010, 18, 7310–7320.
3) C. Tabélé, A. Cohen, C. Curti, A. Bouhlel, S. Hutter, V. Remusat, N. Primas, T. Terme, N. Azas, P. Vanelle. Eur. J. Med.
Chem. 2014, 87, 440-453.
4) Y. Kayaki, T. Koda, T. Ikariya. Eur. J. Org. Chem., 2004, 4989-4993.
5) H. Tsukamoto, T. Uchiyama, T. Suzuki, Y. Kondo. Org. Biomol. Chem., 2008, 6, 3005–3013
- 219 -
OT064
DELIVERY OF NATURAL ACTIVE COMPOUNDS BY

CYCLODEXTRIN / GOLD NANOPARTICLES COMPLEX
Shihong Qiu, Jean-Pierre Mbakidi, Robert Granet, Chritelle Pouget, David Leger, Bertrand Liagre,
Vincent Sol
Université de Limoges, Laboratoire de Chimie des Substances naturelles (LCSN), EA1069

123 avenue Albert THOMAS Limoges 87060 France
The objective of this work is to vectorize natural active compound by using nanocarriers between 20
and 30 nanometers in the goal to delivery selectively hydrophobic anticancer agent. Indeed, the great majority of
natural active compounds (NAC), such as tanshinone IIA1 and α-mangostine2, are not soluble in biological
media. First, these two compounds are extracted from dried plants (Salvia miltiorrhiza & Garcinia mangostana),
purified and their efficiency as anti-cancer drug were evaluated in our laboratory. Then, for the purpose of tumor
targeting by using EPR effect3, we propose to use gold nanoparticles which are equally able to be used in
PhotoThermal Therapy (PTT) by SPR effect (surface Plasmon Resonance effect)4.
The AuNPs are synthesized by using polyethyleneimine (10k Da), which plays both roles of reducer
and capping agent to avoid agglomeration. The size of AuNPs is controlled by the quantity of PEI. The anionic
cyclodextrin sulfate is fixed onto the surface of AuNPs by ionic bonding. Then, the NAC is inserted into the
cyclodextrin.
In order to evaluate the cytotoxicity of these nanocarriers, biological essays have been realized on PC3
and DU145 cancer cell lines.
References
1) L. Zhou, Q. Hu, H. Sui, S. Ci, Y. Wang, X. Liu, P. Yin, J. Qin, Q. Li, Asian Pacific J Cancer Prev, 2012, 13, 4453-4458
2) X. Fei, M. Jo, B. Lee, S.-B. Han, K. Lee, J.-K. Jung, S.-Y. Seo, Y.-S. Kwak, Bioorg. Med. Chem. Lett., 2014, 24, 2062
2065.
3) I. Fratoddi, I. Venditti, C. Cammetti, M. V. Russo, J. Mater. Chem. B , 2014, 2, 4204-4220
4) S. Jain, D. G. Hirst, J. M. O’sullivan, The british journal of Radiology, 2012, 85, 101-113
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OT065
STRUCTURE, CYTOTOXIC ACTIVITY AND DNA BINDING OF

NOVEL THIOCARBAMOYLPYRAZOLES Pd(II) COMPLEXES: THE
STRUCTURE ACTIVITY RELATIONSHIP BETWEEN PYRAZOLES
COMPOUNDS
Thales R. Moura (1), Fillipe V. Rocha (1), Carolina V. Barra (1), Adelino V. G. Netto (1), Antonio E.
Mauro (1), Regina C. G. Frem (1), Francine A. Manente (2), Iracilda Z. Carlos (2)
1) Department of General and Inorganic Chemistry, Institute of Chemistry – Unesp, CEP 14081-970, Araraquara, SP, Brazil
2) Department of Clinical Analysis, College of Pharmaceutical Science - UNESP, CEP 14801-902, Araraquara, SP, Brazil
Success of cisplatin on chemotherapy to treat distinct types of cancer has encouraged the development of new
metal-based compounds for therapeutic purposes. The Pt(II) and Pd(II) coordination stereochemistry are similar.
However, palladium complexes can exhibit a distinct activity behavior in comparison with cisplatin [1]. The
using of N,S-donor on Pd(II) complexes gives higher kinetic stability and impels the cis-coordination to the
more labile ligand, we described in this research the antitumor evaluation and DNA studies of novel compounds
of the type [PdX2(tedmPz)] {X = Cl (1), I (2), SCN (3); tedmPz = N-ethyl-3,5-dimethyl-1-thiocarbamoyl
pyrazole}. The ligand tedmPz was synthesized according to the method described by Barra et al. [2]. Compound
1 was prepared by the displacement of CH3CN ligands from the precursor [PdCl2(CH3CN)2] by the tedmPz.
Compounds 2 and 3 were readily obtained by metathetical reactions of the [PdCl2(tedmPz)] (1) with potassium
salts of the appropriate anions. The formation of the organic compound and N,S-chelated products was strongly
supported by IR, NMR spectroscopic and elemental analysis. In order to evaluate the structure-activity
relationship we compared the cytotoxic activity of our previous thiocarbamoylpyrazole complexes[2] and these
new compounds (Figure 1).
Figure 1. a) IC50 Values for palladium complexes 1-3 in comparison with other thiocarbamoylpyrazoles
complexes and cisplatin b) 1H NMR from guanosine and complexes formed with nucleoside in 1:2 ratio.
The cytotoxic activity of the complexes was evaluated in LM3 (murine mammary adenocarcinoma) after 24h
using the MTT assay. Complexes 1-3 showed excellent cytotoxic activity towards murine mammary
adenocarcinoma LM3, with slight variation on IC50 values (3.85-3.06 µM). These values are approximately 10
times smaller than cisplatin. The cytotoxic effects in vitro are greater with the replacement of hydrogen at the N
atom of the thioamide moiety by a methyl group [2]. However, N-methyl complexes are more potent
cytotoxicity than N-ethyl complexes, demonstrating that the N-methyl group have an important role on the
activity. The three free ligands are considered inactive, since no drug response was observed at drug
concentrations (140 µM). The interaction of the Pd(II) complexes with a purine base has also been studied.
Compounds 1-3 were reacted in methanol with guanosine, and their 1H NMR spectra agreed with the
coordination of the nucleoside to metal through N7-guanine (Figure 2). Strengthening the idea of a possible
interaction between the complexes and DNA, studies were performed to determine the ability of the compounds
to modify the electrophoretic mobility of the circular plasmid in a gel electrophoresis assay.
References
1) Rijt, S. H. V.; Sadler, P. J., Drug Discovery Today 2009, 14, 1089.
2) Barra, C. V.; Rocha, F. V.; Gautier, A.;Morel, L.; Quilles, M. B.; Carlos, I. Z.; Treu-filho, O.; Frem, R. C. G.; Mauro, A.
E.; Netto, A. V. G., Polyhedron 2013, 65, 214–220.
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OT066
REPOSITIONING OF AMINOBENZOSUBERONE AS POTENTIAL

ANTIMALARIAL AGENT TARGETING PfA-M1 AMINOPEPTIDASE
Germain Revelant (1), Sébastien Albrecht (1), Marjorie Schmitt (1), Lotfi Bounaadja (2), Isabelle Florent
(2), Céline Tarnus (1)
1) Laboratoire de Chimie Organique et Bioorganique, EA4566, Université de Haute Alsace ENSCMu, F-68093, Mulhouse
Cedex, France.
2) Molécules de Communication et Adaptation des Micro-organismes, CNRS/MNHN UMR7245, F-75231, Paris, France.
Malaria is an infectious disease caused by Plasmodium parasites, mainly P. falciparum, and widely-observed in
the inter-tropical areas of America, Asia and Africa. Various ways to fight this disease already exist, but the high
cost of therapies for the most affected deprived populations and the appearance of parasite resistance to current
drugs foster the discovery of novel therapeutic targets and the development of new compounds to expand the
antimalarial drug arsenal.
PfA-M1, a metalloaminopeptidase involved in the hemoglobin degradation by Plasmodium, has recently

emerged as a potential new therapeutic target.(a) Actually, the parasite growth and load can be reduced by its
enzymatic inhibition with metal-chelating peptide derivatives or tetrahedral intermediate mimics.(b) Although
those inhibitors have shown low nanomolar PfA-M1 binding affinities, their activity in the cell-based parasite
growth assay was only in the micromolar range. This discrepancy might be due to a poor bioavailability, hence
the development of new PfA-M1 inhibitors, with a better pharmacological profile, is an attractive therapeutic
approach.
Previous work at the laboratory paved the way to several series of aminobenzosuberone derivatives (Compound
I) able to selectively inhibit the one zinc aminopeptidase family.(c) Starting from these observations, we decided
to repurpose this scaffold on PfA-M1 and performed various modifications on the core to better fit into the active
site and improve the pharmacological properties of our compounds.
The biological results obtained so far suggest that these structures are promising hits for the development of
novel potential antimalarial agents targeting the PfA-M1 aminopeptidase.
Correspondence : germain.revelant@uha.fr, sebastien.albrecht@uha.fr
References
a) T.S. Skinner-Adams et al. Trends Biochem. Sci. 2010, 35, 53.
b) For Example : S. McGowan et al. PNAS 2009, 106, 2537
c) For Example : S. Albrecht et al. Bioorg. Med. Chem. 2012, 20, 4942.
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OT067
DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF

PEPTIDOMIMETICS TARGETING NRP-1 RECEPTOR
Mylène Richard (1), Cédric Boura (2), Bernard Maigret (3), Yves Chapleur (1), Nadia Pellegrini-Moïse (1)
1) SRSMC – équipe MoBAT, UMR 7565 CNRS, Université de Lorraine, 54506 Vandœuvre-Lès-Nancy, France
2) CRAN – département SBS, UMR 7039 CNRS, Université de Lorraine, 54506 Vandœuvre-Lès-Nancy, France
3) Loria – équipe Orpailleur, UMR7503 CNRS – Université de Lorraine, 54506 Vandoeuvre-Lès-Nancy, France
Neuropilin-1, (NRP1) a transmembrane receptor expressed by endothelial cells, acts as a co-receptor along with
VEGR-2 and binds VEGF165 (an isoform of VEGFs).1 NRP-1 also binds smaller peptides (ATWLPPR,2 TKPR3)
resembling the C-terminus sequence DKPRR of VEGF165. Recently, we and others demonstrated that
peptidomimetics and non-peptidic compounds can effectively bind to NRP-1.4 The aim of this work is to
develop stable and more efficient small ligands which can serve as addressing molecules to target cancer cells
overexpressing NRP-1, opening the way to new applications in cancer diagnosis and treatment.
Chiral carbohydrate-based scaffolds are well suited for introducing multifunctionnality and stereodiversity in
biologically active compounds. On the basis of our previous results obtained in NRP-1 binding,4a the active
ligand AN241 needs to be improved to reach more significant affinity. Thus, with molecular modelling docking
studies, new sugar-based peptidomimetic compounds were prepared. The biological properties (binding to
NRP-1, adhesion and proliferation of HUVEC) of these new derivatives were evaluated and a new hit has been
identified (MR563).
References
1) Bagnard D., Neuropilin: From Nervous System to Vascular and Tumour Biology, Adv. Exp. Med. Biol., 2002, 515.
2) a) Binetruy-Tournaire, R. et al. / EMBO J. , 2000, 19, 1525. b) Starzec A. et al. / Peptides, 2007, 28, 2397.
3) Vander Kooi C. W. et al. / Proc. Natl. Aca. Sci. U. S. A., 2007, 104, 6152.
4) a) Novoa A. et al. / Bioorg. Med. Chem., 2010, 18, 3285. b) Jarvis A. et al. / J. Med. Chem., 2010, 53, 2215. c) Borriello
L. et al. / Cancer Letters, 2014, 349, 120–127
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OT068
DESIGN, SYNTHESIS AND EVALUATION OF ANTICONVULSANT

PROPERTIES OF NEW N-MANNICH BASES DERIVED FROM
3-BENZHYDRYL-PYRROLIDINE-2,5-DIONE.
Sabina Rybka (1), Jolanta Obniska (1), Anna Rapacz (2), Beata Wiklik-Poudel (1), Agnieszka Chudzińska
(1)
1) Department of Medicinal Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
2) Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Kraków, Poland
Over the past decades many attempts have been made to identify the structural features essential for
anticonvulsant activity. As a result, it is well established that one of the important core fragments is defined by a
nitrogen heteroatomic system, usually cyclic imide, with at least one carbonyl group and phenyl or alkyl groups
attached to the heterocyclic system. Therefore we decided to obtain compounds, which structure contains these
features.1,2
The previous research from our laboratory have demonstrated diversified anticonvulsant activities among the
differently substituted pyrrolidine-2,5-diones. The most promising were N-Mannich bases with aromatic
substituent at the position-3 and the phenylpiperazine moiety at the position-1 of imide ring. Some of the most
active molecules were derivatives, which consisted at the position-3 of succinimide two aromatic ring.3,4
Consequently, as a continuation of studies among variously substituted succinimides, we have synthesized new
N-Mannich bases, which contained methine bridge between two phenyl rings and the imide core.
The obtained compounds were evaluated for their anticonvulsant activity in the maximum electroshock (MES)
and subcutaneous pentylenetetrazole seizure tests (scPTZ). The results revealed that the majority of
3-bezhydryl-succinimide derivatives exhibited anticonvulsant activity, especially in the scPTZ test. Moreover,
several of them revealed activity in the MES test. The quantitative studies in mice after i.p. administration
showed that several compounds were more potent than ethosuximide in the scPTZ test and also several of them
revealed activity in the MES test higher than valproic acid. It is important that all of the active compounds
demonstrated low neurotoxicity. Moreover, for the most effective compounds, attempts of determination of the
possible mechanism of action in vitro have been established.
This work was supported by the State Committee for Scientific Research, Poland (Grant No.
DEC-2013/11/N/NZ7/00426)
References
1) K. Kaminski, S. Rzepka, J. Obniska: Bioorg. and Med. Chemistry Letters 21 (2011) 5800–5803
2) S. Rybka, J. Obniska, A. Rapacz, B. Filipek, K. Kaminski: Arch. Pharm. Chem. Life Sci. 347 (2014) 1–9
3) J. Obniska, S. Rzepka, K. Kaminski: Bioorg. and Med. Chemistry 20 (2012) 4872–4880
4) J. Obniska, I. Chlebek, K. Kaminski, J. Karolak-Wojciechowska: Arch. Pharm. Chem. Life Sci. 346, (2013) 71–82
- 224 -
OT069
SYNTHESIS AND BIOLOGICAL ACTIVITY OF

1,2,4-TRIAZOLE-3-CARBOXAMIDES OF AMINOADAMANTANES
Boyka Stoykova (1), Maya Chochkova (1), Tsenka Milkova (1), Martin Štícha (2)
1) Faculty of Mathematics and Natural Sciences, South-West University ‘‘Neofit Rilski’’, 2700 - Blagoevgrad, Bulgaria
2) Department of Chemistry, Charles University, Prague, Czech Republic
Triazole derivatives have attracted considerable attention amongst the medicinal chemistry community, due to a
wide range of pharmacological activities such as antimicrobial, anti-inflammatory, antineoplastic,
antiproliferative, anticancer, anti-tyrosinase and other activities.
Since it has known that the substitutions on triazole ring have played a major role in the high binding affinity to
tyrosinase [1], there is a great demand to discover new, effective and safer tyrosinase inhibitors. In the present
work, we have synthesized triazole carboxamides of aminoadamantanes (rimantadine, amantadine). The
estimation of their mushroom tyrosinase inhibitory activity in vitro is in progress.
We are grateful to the South-West University ”Neofit Rilski”, Bulgaria (Contract SRP A19/15).
References
1) U. Ghani, N. Ullah, Bioorganic & Medicinal Chemistry 18 (2010) 4042–4048.
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OT070
INTERPRETATION AND COMPARISON OF QSAR/QSPR MODELS

USING MATCHED MOLECULAR PAIRS
Igor V. Tetko
Institute of Structural Biology, Helmholtz Zentrum Muenchen

German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, b. 60w, D-85764 Neuherberg, Germany
The Matched Molecular Pairs (MMP) uses pairs of molecules, which differ with only one structural group to
analyze chemical data and derive rules hidden in them. This approach is very useful to identify “activity cliffs”,
i.e., small changes in the chemical structure leading to large changes in the activity of molecules. The MMP are
extensively used in scientific literature to analyze experimental measurements. In this work the MPPs are
extended to analysis of Quantitative Structure-Activity/Property Relationship (QSAR/QSPR) models. The
statistically significant MMPs derived from predictions of a model (prediction-driven MMP) allows to
understand rules that were learn by the model as well as to identify dependencies, which were not correctly
captured by it. Such analysis does not depend on the used machine learning algorithms and descriptors and can
be used for any model. The prediction-driven MMPs are also useful approach to compare different QSAR/QSPR
models and to provide a mechanistic interpretation of individual predictions. Moreover, they can be also used to
drive optimization of molecules. All these features of prediction-driven MMPs make them an important tool for
drug discovery studies. The developed approach is publicly available at http://ochem.eu and it has been also
recently published1.
References
1) Sushko, Y.; Novotarskyi, S.; Korner, R.; Vogt, J.; Abdelaziz, A.; Tetko, I.V. Prediction-driven matched molecular pairs to
interpret QSARs and aid the molecular optimization process. J. Cheminform. 2014, 6, 48.
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OT071
PREDICTION OF OCTANOL/WATER PARTITION COEFFICIENT OF

Pt(II)/Pt(IV) COMPLEXES
Igor V. Tetko (1), Hristo P. Varbanov (2)
1) Institute of Structural Biology, Helmholtz Zentrum Muenchen

German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, b. 60w, D-85764 Neuherberg, Germany
2) Laboratory of Organometallic and Medicinal Chemistry, EPFL SB ISIC LCOM, BCH 2409 (Batochime UNIL), Av. F.-A.
Forel 2, CH-1015 Lausanne, Switzerland
Prediction of the lipophilicity (i.e. log Po/w) of Pt complexes is important for the design of new metal-based
anti-cancer agents. This property is essential for the bioavailability of drugs and drug candidates and correlates
with their efficacy. While there is a publicly available model for prediction of log P of Pt(II) complexes1
(http://www.vcclab.org/web/pt/) the prediction of log P of their Pt(IV) analogues has been a challenging task. In
this study we report the development of models to predict logP of both Pt(II) and Pt(IV) complexes based on the
largest published set with about 200 molecules. We report the prediction ability of the developed models and
compare their performance across 13 different sets of descriptors. The challenges with representation of
coordination (metal-organic) bonds in metal complexes are discussed. The best models have been calculated
using the functional group counts provided as a part of ToxAlert framework.2 The developed publicly available
models are available at http://ochem.eu site
Acknowledgements: Mrs T. Haque for her help with literature mining to collect logP data of Pt complexes.
References
1) Tetko, I.V.; Jaroszewicz, I.; Platts, J.; Kuduk-Jaworska, J. Calculation of lipophilicity for Pt(II) complexes: experimental
comparison of several methods, J. Inorg. Biochem. 2008, 102(7), 1424-1437.
2) Sushko I, Salmina E, Potemkin VA, Poda G, Tetko IV. ToxAlerts: A Web Server of Structural Alerts for Toxic Chemicals
and Compounds with Potential Adverse Reactions. J Chem Inf Model. 2012 Aug 27;52(8):2310-6
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OT072
TARGETING THE PRODUCTION OF ONCOGENIC MICRO-RNAS

USING SYNTHETIC SMALL MOLECULES.
Thi Phuong Anh Tran, Duc Duy Vo, Audrey Di Giorgio , Maria Duca
Institut de Chimie de Nice UMR7272, Université de Nice Sophia Antipolis, 06108 Nice Cedex, France
MicroRNAs (miRNAs or miRs) are a class of evolutionary conserved small non-coding RNAs that act as
post-transcriptional regulators of gene expression. Increasing evidence has indicated that the aberrant expression
of miRNAs is linked to initiation and development of human cancers. Most of these deregulated miRNAs are
overexpressed, thus being oncogenic. It is now clear that the inhibition of oncogenic miRNAs function or
production, would be a very promising approach for the development of new anticancer therapies. [1]
The purpose of this work is the discovery of small-molecule drugs targeting the precursors of specific oncogenic
miRNAs thus modulating their production. We have focused our attention on miRNA-372 and miRNA-373 that
are implicated in various cancers. For example, these two oncogenic miRNAs are overexpressed in gastric
cancer cells starting from their precusors (pre-miRNAs 372 and pre-miRNAs 373): two stem-loop structured
RNAs that lead to mature miRNAs after cleavage by the enzyme Dicer (Figure 1A). In the aim of inhibiting this
biogenesis step and based on our previous works [2], we synthesized and studied new small-molecule RNA
ligands able to bind to the pre-miRNAs thus inhibiting their cleavage by Dicer enzyme. The newly synthesized
compounds are composed of two RNA binding motives: aminosugars known to bind strongly to structured
RNAs and artificial nucleobase able to bind to double-stranded RNA specifically.
We demonstrated that some of the newly synthesized compounds are very strong RNA ligands and that they are
able to inhibit the production of the targeted oncogenic miRNAs and lead to the inhibition of cancer cells
proliferation. Based on these encouraging results, in vivo studies are currently in progress in order to evaluate the
anticancer activity of these original compounds.
Figure 1. A) Schematic representation of a cancer cell where the overexpression of miRNAs causes tumor
proliferation (left) and the strategy of inhibition of miRNA production proposed in this study (right); B)
Representation of the new family of ligands that have been synthesized and studied.
References
1) Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug
Discov. 2010, 9(10), 775-789.
2) Vo, D.D., Staedel, C., Zehnacker, L., Benhida, R., Darfeuille, F., Duca, M. Targeting the production of oncogenic
microRNAs with multimodal synthetic small molecules ACS Chem. Biol. 2014, 9, 711.
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OT073
DESIGN OF MORE SELECTIVE APICOMPLEXA HDAC INHIBITORS

Traoré Mohamed (1,3), Nurisso Alessandra (2), Jamet Hélène (3), Wong Yung-Sing (1)
1) Département de Pharmacochimie Moléculaire, Univ. Grenoble Alpes, UMR 5063 CNRS

470 rue de la chimie, BP 53, 38041 Grenoble Cedex 9, France
2) Pharmacochemistry and Phytochemistry & Bioactive Natural Products, School of
Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva 4,
Switzerland
3) Département de Chimie Moléculaire, Univ. Grenoble Alpes, UMR 5250 CNRS
301 rue de la chimie, BP 53, 38041 Grenoble Cedex 9, France
Histone deacetylase (HDAC) is involved in the epigenetic regulation of gene transcription by removing acetate
group from lysine residues on histone proteins. The goal of the project is to determine key structural elements in
order to design a species selective class I HDAC inhibitor, able to fight against apicomplexan parasites like
Toxoplasma gondii or Plasmodium falciparum.[1] The identification of a fluorescent HDACi targeting Tg
HDAC3 offers the opportunity to collect new data on the drug-enzyme interactions. Moreover, apicomplexa
parasite class I HDAC is different to human as they have two additional amino acids (alanine and threonine AT
(pink coloration), Figures a, b) located at the entrance of the catalytic pocket. [2]
This first and half year of work have mainly focused on the building of the chimeric TgHDAC3 from the crystal
structure of HSHDAC1 by multi-scale approach combining tools of bioinformatics, docking and molecular
mechanic simulations. A milestone has been reached by the validation of the chimeric TgHDAC3 model that
ensures a sufficient level of good matching results between simulation and bioassays. In this study, the class I
selectivity of the ketone hydroxyl zinc binding group has been confirmed, especially with the design and the
synthesis of new simplified HDACi. Rationalization of this class selectivity is in progress. We now turn to the
identification of fundamental structural differences between HsHDAC and TgHDAC, especially at the entrance
of the catalytic pocket.
References
1) M. Traoré, F. Mietton, D. Maubon, M. Peuchmar, Flaviane Francisco Hilario, Rossimiriam Pereira de Freitas, A.
Bougdour, A. Curt, A. Maynadier, H. Vial, H. Pelloux, M-A. Hakimi, Y -S. Wong, J. Org. Chem, 2013, 78, 3655-3675.
2) A. Bougdour, D. Maubon, P. Baldacci, P. Ortet, O. Bastien, A. Bouillon, J-C. Barale, H. Pelloux, R. Menard, M-A
Hakimi, J. Exp. Med, 2009, 206, 4, 953-966.
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OT074
SYNTHESIS OF SOME THIAZOLYL—PYRAZOLINE DERIVATIVES

AND EVALUATION OF ANTIMICROBIAL ACTIVITY,
CYTOTOXICITY AND GENOTOXICITY
Gulhan Turan-Zitouni (1), Awatef Tabbi (2), Leyla Yurttas (1), Zerrin Canturk (3), Sinem Ilgin (3),
Ozlem Atli (3), Zafer Asim Kaplancikli (1)
1) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey

2) Department of chemistry, Faculty of Sciences, University of Constantin, Algerie
3) Department of Microbiologie, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey
The synthesis of new thiazolyl-pyrazoline derivatives (1-14) and subsequent evaluation of their antimicrobial
activity and cytotoxicity and genotoxicity were aims of present work. The intermediate product
1-(4-methoxyphenyl)-3-(5,6,7,8,-tetrahydronaphthalen-2-yl)-2-propen-1-one was synthesized via the
base-catalyzed Claisen-Schmidt condensation of 4-methoxy acetophenone with appropriate aromatic aldehydes.
Secondly, 3-(4-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-y)-1-thiocarbamoyl-2-pyrazoline was
obtained by the cyclization of chalcone with thiosemicarbazide in the presence of sodium hydroxide (1,2).
Finally, the ring closure reaction of the last compound with phenacylbromide gave
2-[3-(4-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-1H–pyrazol-1-yl]-4-phenylthiazoles
(1-14). The structures of the compounds were elucidated by IR, 1H NMR, 13C NMR and MS spectral data. The
prepared compounds were investigated for their potential antimicrobial activity (3,4), cytotoxicity (5) and
genotoxicity (6).
References
1) Turan-Zitouni G., Chevallet P., Kiliç F. S., Erol K., Synthesis of some thiazolyl-pyrazoline derivatives and preliminary
investigation of their hypotensive activity, Eur.J.Med.Chem., 35,635-641 (2000)
2) Özdemir A., Turan-Zitouni G., Kaplancikli Z.A., Revial G., Güven K., Synthesis and antimicrobial activity of
1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives, Eur. J Med. Chem., 42, 403-409 (2007)
3) CLSI . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard,
CLSI Document M7-A7 . 7 th Ed. ISBN 1-56238 . 587 – 589 (2006)
4) Yurttaş L. , Özkay Y., Karaca H., Tunali, Y., Kaplancikli Z.A., Synthesis and antimicrobial Evaluation of some
2,5-disubstituted benzimidazole derivatives, Lett Drug Des Discov. 10, 486 – 491 (2013)
5) Berridge M.V., Herst P.M., A.S.Tan A.S., Tetrazolium dyes as tools in cell biology: New insights into their cellular
reduction, Biotechnol. Annu. Rev., 11, 127-152 (2005)
6) Flückiger-Isler S., Kamber M., Direct comparison of the Ames microplate format (MPF) test in liquid medium with the
standard Ames pre-incubation assay on agar plates by use of equivocal to weakly positive test compounds Mutat Res.,
747(1), 36-45 (2012)
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OT075
DECONSTRUCTION OF PDZ INHIBITORS

Gary Vallon (1), Isabelle Ripoche (1), Liam Dorr (2), Lu-Yun Lian (2), Philippe Marin (3), Christine
Courteix (4), Sylvie Ducki (1)
1) Clermont Université, UBP, ENSCCF, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000

CLERMONT-FERRAND; CNRS, UMR 6296, ICCF, F-63171 AUBIERE
2) University of Liverpool, NMR Center for Structural Biology, UK-L69 3BX Liverpool
3) IGF, CNRS UMR5203 – INSERM U661, Universités Montpellier 1 & 2, F-34094 Montpellier
4) Clermont Université, Université d'Auvergne, Institut NEURO-DOL, BP 10448, F-63000 CLERMONT-FERRAND,
INSERM, UMR 1107, F-63001 Clermont-Ferrand
PDZ domains are involved in protein–protein interactions (PPI); they are often associated with the cell
membrane where they play an essential role in the clustering of proteins and signal transduction. Disrupting the
interaction between the PDZ- containing protein PSD-95, and the 5-HT2A receptor, was found to reduce
hyperalgesia in a rodent model of neuropathic pain.1,2 Thus, inhibiting the PPI between PSD-95 and the 5-HT2A
receptor with a small organic molecules could lead to a novel class of analgesic agents. A structure activity
relationship (SAR) study on indole derivatives permitted us to show a promising reduction of hyperalgesia on
neuropathic rats with indoles 1-2.3 The fragment based drug design approach is a screening of fragments
susceptible to interact with a given protein and then lead to potential ligand by linking these fragments. To
validate the relevance of this approach on PDZ proteins, we chose to deconstruct indoles 1-2 into 7 fragments
3a-3g (Figure 1).
These fragments were synthesized and NMR studies have been performed (HSQC 1H-15N of the protein ±
fragment) with each fragment, then with two fragments together in order to determine if there are some additive
or antagonist effects. We will present the results of the screening and the synthesis of novels ligands able to
interact with PSD-95 an inhibit PPI.
References
1) Becamel, C., et al. The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J Biol Chem,
2004, 279, 20257-20266.
2) Pichon, X., et al. Disrupting 5-HT2A Receptor/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI
Efficacy in Neuropathic Pain. Molecular Therapy, 2010, 18, 1462-1470.
3) Vogrig, A., et al. Structure-Based Design of PDZ Ligands as Inhibitors of 5-HT2A Receptor/PSD-95 PDZ1 Domain
Interaction Possessing Anti-hyperalgesic Activity. ACS Chemical Biology, 2013, 18, 2209-2216.
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OT076
4,5-DIMETHOXYBENZENE DERIVATIVES: SYNTHESIS,

ANTI-RHINOVIRAL EVALUATION, IN SILICO OPTIMIZATION
Laurène Da Costa (1), Manon Roche (1), Johan Neyts (2), Pieter Leyssen (2), Thierry Terme (1), Romano
Silvestri (3), Patrice Vanelle (1)
2) Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medicinal Research, KU Leuven, Belgium.
3) Department of drug Chemistry and Technologies, Sapienza University, Rome, Italy.
Once considered a cause of relatively benign upper respiratory illnesses, human rhinovirus (hRV) are also now
linked to severe respiratory tract infections. This observation has led to a renewed interest in anti-rhinoviral
molecules.
Our research team has recently identified a novel chemical scaffold of inhibitors of rhinovirus replication in a
virus-cell-based cytopathic effect (CPE) reduction assay [1,2]. In this context, we explored their
structure–activity relationships using an original synthesis method, i.e. through one organic agent
Tetrakis(DimethylAmino)Ethylene (TDAE). Among the 1,2-diarylethanols developed,
4-[2-(4,5-dimethoxy-2-nitrophenyl)-1-hydroxyethyl]benzonitrile has shown an interesting biological profile on
HeLa cells (EC50 of 2.2 ± 0.4 µM) with the same action mechanism as the capsid-binder Pleconaril (EC50 of 0.3
± 0.1 µM).
According these preliminary results, we oriented our study to a hit-to-lead process optimization based on
Quantitative Structure Activity Relationship (QSAR) and computational approach.
We report herein chemical synthesis and first biological results of this optimization strategy.
References
1) M. Roche, C. Lacroix, O. Khoumeri, D. Franco, J. Neyts, T. Terme, P. Leyssen, P. Vanelle, Eur. J. Med. Chem., 2014, 76,
445-459.
2) C. Lacroix, J. Querol-Audí, M. Roche, D. Franco, M. Froeyen, P. Guerra, T. Terme, P. Vanelle, N. Verdaguer, J. Neyts, P.
Leyssen, J. Antimicrob. Chem., 2014, 69, 2723-2732.
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OT077
GREEN AND EFFICIENT SYNTHESIS OF 2,6,8-TRISUBSTITUTED

4-AMINOQUINAZOLINES
Youssef Kabri, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27
The palladium catalyzed Suzuki-Miyaura reaction is one of the most highly regarded processes in synthetic
chemistry and a widely studied cross-coupling reaction for carbon-carbon bond formation.[1] On the other hand,
organic reactions using water[2] as a cheap, non-toxic, non-volatile solvent, together with multistep sequences
carried out in a single flask, such as tandem, cascade or sequential reactions, have received considerable
attention in organic chemistry.[3] In this context and in connection with our research program on the design and
synthesis of original molecules with pharmacological properties,[4] the SNAr reaction was combined with the
Suzuki-Miyaura cross-coupling reaction to perform one-pot sequential polyfunctionalization of the quinazoline
ring.
This approach affords rapid and efficient access to 2,6,8-trisubstituted 4-aminoquinazoline derivatives in high
yields using an one-pot chemoselective methodology via consecutive tri-Suzuki-Miyaura or SN
Ar/bis-Suzuki-Miyaura cross-coupling reactions in water under microwave irradiation. In addition, this
environmentally friendly procedure tolerates a wide range of boronic acids and represents a promising green
route for the synthesis of these important pharmaceutical heterocyclic compounds.
References
1) N. Miyaura, A. Suzuki, J. Chem. Soc., Chem. Commun. 1979, 866-867. b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,
2457-2483.
2) a) A. Gellis, N. Boufatah, P. Vanelle, Green Chem. 2006, 8, 483-487. b) Y. Kabri, A. Gellis, P. Vanelle, Green Chem.
2009, 11, 201-208. c) A. Cohen, M. D. Crozet, P. Vanelle, Green Chem. 2009, 11, 1736-1742.
3) a) K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun. 2003, 551-564. b) A. Padwa, Pure Appl. Chem. 2004,
76, 1933-1983. c) G. Wu, W. Yin, H. C. Shen, Y. Huang, Green Chem. 2012, 41, 580-585. d) V. Gembus, J.-F. Bonfanti, O.
Querolle, P. Jubault, V. Levacher, C. Hoarau, Org. Lett. 2012, 14, 6012-6015.
4) a) M. P. Crozet, G. Archaimbault, P. Vanelle, R. Nouguier, Tetrahedron Lett. 1985, 26, 5133-5134. b) C. Roubaud, P.
Vanelle, J. Maldonado, M. P. Crozet, Tetrahedron 1995, 51, 9643-9656. c) M. D. Crozet, C. Botta, M. Gasquet, C. Curti, V.
Rémusat, S. Hutter, O. Chapelle, N. Azas, M. De Méo, P. Vanelle, Eur. J. Med. Chem. 2009, 44, 653-659. d) N. Primas, P.
Suzanne, P. Verhaeghe, S. Hutter, C. Kieffer, M. Laget, A. Cohen, J. Broggi, J.-C. Lancelot, A. Lesnard, P. Dallemagne, P.
Rathelot, S. Rault, P. Vanelle, N. Azas, Eur. J. Med. Chem. 2014, 83, 26-35.
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OT078
RAPID AND EFFICIENT SYNTHESIS OF SUBSTITUTED-

PYRIDO[4,3-b]QUINOXALIN-1(2H)-ONE DERIVATIVES
Majdi Hajri, Omar Khoumeri, Gonzalo Gonzalez, Thierry Terme, Patrice Vanelle
Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27
The quinoxaline derivatives show very interesting biological properties,1 such as antibacterial,2 antiviral,3
anticancer,4 antifungal, antihelmintic, antileishmanial,5 anti-HIV,5 insecticidal, anti–inflammatory activities6 and
their interest in medicinal chemistry is far from coming to an end. Many drug candidates bearing quinoxaline
core structures are in clinical trials in antiviral, anticancer, antibacterial,2 and CNS (central nervous system)
therapeutic areas. Among them, the XK469 ((±)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid) was
known as antineoplastic quinoxaline topoisomerase II inhibitor and possesses antitumor activity especially
against murine and human solid tumors.7
On the other hand, the pyridin-2(1H)-one derivatives exhibited interesting biological activity as anticancer
agents.8 In spite of the great interest that could represent combined structures presenting the quinoxaline and the
pyridin-2(1H)-one nucleus, few synthesis of pyrido[4,3-b]quinoxalin-1(2H)-one derivatives have been reported.
We report herein an original and efficient synthesis of new substituted pyrido[4,3-b]quinoxalin-1(2H)-one

derivatives by the Sonogashira reaction in the first step followed by cyclization reaction with different anilines.
References
1) Arthur, G.; Elor, K. B.; Robert, G. S.; Guo, Z. Z.; Richard, J. P.; Stanley, D.; John, R. K.; Sean, T. J. Med. Chem. 2005,
48, 744-752.
2) Naylor, M. A.; Stephen, M. A.; Nolan, J.; Sutton, B.; Tocher, J. H.; Fielden, E. M.; Adams, J. E.; Strafford, I. Anticancer
Drug Des. 1993, 8, 439-461.
3) Loriga, M.; Piras, S.; Sanna, P.; Paglietti, G. Farmaco 1997, 52, 157-166.
4) Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.; Defeo Jones, D.; Jones, R. E.; Hartman, G. D.;
Huff, J. R.; Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem. Lett. 2005, 15, 761-764.
5) Fournet, A.; Mahieux, R.; Fakhfakh, M. A.; Franck, X.; Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. Lett. 2003,
13, 891-894.
6) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 541-544.
7) (a) Hazeldine, S.; Polin, L.; Kushner, J.; White, K.; Corbett, T. H.; Horwitz, J. P. Bioorg. Med. Chem. 2006, 14,
2462–2467. (b) Nguyen, H.T.L.; Gulevskaya, A.V.; Pozharskii, A.F.; Nelina-Nemtseva, J. I. Tetrahedron 2014, 70,
4617-4625. (c) Tyaglivy, A.S.; Gulevskaya, A.V.; Pozharskii, A.F.; Askalepova, O. I. Tetrahedron 2013, 69, 9804-9812.
8) Doonya-udtayan, S.; Yotapan, N.; Woo, C.; J.Bruns, C.; Ruchirwat, S.; Thassana, N. Chem. Asian. J. 2010, 5, 2113-2123.
- 234 -
OT079
PCBIS: CHEMICAL LIBRARIES, BIOLOGICAL MODELS,

TECHNOLOGICAL TOOLS AND EARLY ADMETOX FOR
LABORATORIES
Pascal Villa (1), Sophie Gioria (1), Christel Valencia (1), Adeline Obrecht (1), Bruno Didier (1,2), Claire
Marsol (1,2), Pascale Buisine (1,2), Romain Hany (1), Patrick Gizzi (1,3), François Daubeuf (1,2)
1) UMS 3286 CNRS Plate-forme de Chimie Biologique Intégrative de Strasbourg & Labex Medalis
CNRS et Université de Strasbourg
Bld S Brant 67412 ILLKIRCH
2) UMR 7200 Laboratoire d'Innovation Thérapeutique
Route du Rhin
67400 ILLKIRCH
3) UMR 7242 Laboratoire de Biotechnologie et signalisation cellulaire
Bld S Brant 67412 ILLKIRCH
High Throughput Screening (HTS) is the technology which best facilitates the search of new molecules with the
potential of becoming the drugs of tomorrow.
Starting 16 years ago, the "Plate-forme de Chimie Biologique Integrative de Strasbourg" (PCBIS) developed the
expertise in this field in order to be able to offer this technology in an academic context. One of our main goals is
to offer our expertise to laboratories aiming to find new drugs to cure rare and/or neglected diseases. Our
commitment to quality drove us to set up a quality management system granted by ISO 9001 and NF X50-900
certifications.
The PCBIS's expertise and equipment necessary for new drug discovery is now proposed to academic
laboratories, start-ups and industries interested in a fast paced approach to screening. In order to help the
optimization of active molecules we also developed tests for early ADME-Tox determination.
We also propose to train people and give an access to our technologies to interested laboratories.
We will show some of the tools that PCBIS can propose to the scientific community.
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OT080
PRACTICAL PREPARATION OF CHALLENGING AMIDES FROM

NON-NUCLEOPHILIC AMINES AND ESTERS UNDER FLOW
CONDITIONS
Johannes Vrijdag (1), Francisca Delgado (2), Nerea Alonso (2), Jesus Alcazar (2), Wim De Borggraeve (1)
1) KU Leuven, Department of chemistry: division of molecular design & synthesis, Celestijnenlaan 200F, B2404, 3001
Heverlee, Belgium
2) Janssen Research and Development: Department of Medicinal Chemistry Janssen-Cilag, S.A., C/Jarama 75, 45007,
Toledo, Spain
The amide is a most important functional group present in numerous types of high impact drug molecules
(antibiotics, antiarrhythmics, sedatives, etc). It is also the key linking moiety in proteins and related peptide drug
products. Hence, a lot of research has been conducted on the synthesis of the amide moiety, leading to
multitudinous synthetic protocols as we speak. Most known approaches however are suffering from severe
drawbacks, such as: expensive coupling reagents, tedious workups and the unability to deal with unreactive
substrates.
In line with the general interest of our groups in flow chemistry,1,2,3 we present the development of a novel
preparation of synthetically challenging amides under continuous flow conditions mediated by LiHMDS. A
broad variety of amides was synthesized from commercially available esters and classical unreactive amines,
yielding the desired compounds in up to quantitative yield. With both sustainability and scalability in mind,
several tailored and simple workup procedures were developed, usually avoiding the need for chromatography.
References
1) J. L. Vrijdag, A. M. Van den Bogaert, W. M. De Borggraeve, Org. Lett. 2013, 15, 1052
2) B. Egle, J. M. Muñoz, N. Alonso, W. M. De Borggraeve, A. Hoz, A. Díaz-Ortiz, J. Alcázar, J. Flow. Chem. 2013, 4, 22
3) J. L. Vrijdag, F. Delgado, N. Alonso, W. M. De Borggraeve, N. Pérez-Macias, J. Alcázar, Chem. Commun., 2014, 50,
15094
- 236 -
OT081
THE USE OF ARYL BORONIC ESTER PRECURSORS IN PROVIDING

FACILE ACCESS TOWARDS 123I AND 18F RADIOLABELLED
TARGETS FOR SPECT AND PET IMAGING
Thomas Wilson (1), Greg McSweeney (1), Dr. Matthew Tredwell (1), Stephan Verhoog (1), Dr. Graham
Smith (2), Dr. Thomas Cailly (3), Prof. Veronique Gouverneur (1)
1) University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK
2) The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK
3) Normandie Université, Université de Caen Basse-Normandie CERMN (EA 4258 - FR CNRS 3038 INC3M - SF 4206
ICORE) UFR des Sciences Pharmaceutiques Bd Becquerel, CS 14032 Caen cedex 5, France.
Both single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide
scientists with powerful non-invasive tools towards; the understanding of biological pathways, the diagnosis of a
wide variety of diseases as well as potentially providing an alternative method towards drug development
[1]. Coupled with recent technological advances within high-resolution molecular imaging, this field has the
potential to revolutionise both approaches in health care and clinical practice [2].
Both radioisotopes Fluorine-18 and Iodine-123 have been employed within a wide range of radiotracers [3] for
which when in conjunction with SPECT and/or PET, provide their own unique advantage [2]. Therefore, access
to both of these radiolabelled functional groups from a robust, biologically non-toxic precursor and synthetic
protocol are highly desirable. While a variety of other precursors have been employed [4], no one precursor has
been shown to allow facile access to both of these radiolabelled functional groups whilst maintaining high RCY
and SA.
In the Gouverneur group, we have developed protocols to allow access to both aryl fluoro [5] and iodo
radiolabelled functional groups in both high RCY and SA via the boronic ester precursor. Both protocols show
tolerance towards a range of functional groups as well as a variety of known radiotracers. This robust precursor
in conjunction with each respective protocol provides a platform through which other research groups will be
able to access a broad range of imaging agents employed within both SPECT and PET.
References
1) P. M. Matthews, E. A. Tabiner, J. Passchier, R. N. Gunn, Br. J. Clin. Pharmacol., 2011, 73, 175.
2) A. Rahmima, H. Zaidib, Nuc. Med. Comm., 2008, 29, 193.
3) H. Zhang, R. Huang, N. Pillarsetty, D. L. J. Thorek, G. Vaidyanathan, I. Serganova, R. G. Blasberg, S. J. Lewis, Eur. J.
Med. Mol. Imaging., 2014, 41, 322.
4) M. Tredwell, V. Gouverneur, Angew. Chem. Int. Ed., 2012, 51, 11426.
5) M.Tredwell, S.M.Preshlock, N.J. Taylor, S.Gruber, M. Huiban, J. Passchier, J.Mercier, C.Génicot, V.Gouverneur, Angew.
Chem., Int. Ed., 2014, 53, 7751.
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OT082
SYNTHESIS OF NOVEL CUBANE AMINO ACIDS

Joanna Wlochal (1), Rob Davies (1), Jonathan Burton (2)
1) Oncology, Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
2) Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Cubane is a highly strained molecule where the carbon atoms are arranged in the shape of a cube. Despite being
discovered in the 1960s it has largely been neglected by the pharmaceutical industry. We have already explored
the synthesis of cubane building blocks for use in medicinal chemistry (1). This poster describes our recent
efforts towards the synthesis of, hitherto inaccessible, cubane containing alpha- and beta-amino acids.
Modified amino acids incorporating rigid cyclic and caged structures have gained much attention in recent years,
a key example being Bristol-Myers Squibb DPPIV inhibitor Saxagliptin, which contains an adamantane glycine
residue. This is due to the improved selectivity and metabolic stability these unnatural amino acids can confer on
parent molecules. To date, the only example of cubane amino acid reported in literature is cubane carboxy
glycine and its two derivatives, accessed via Strecker methodology in very poor yields. The other existing
literature precedent described the failed synthesis of cubane glycine using an Ellman reaction. Our innovative
work details the first successful synthetic entry into a range of enantiopure cubane containing simple amino acids
(i) cubane glycine; (ii) cubane alanine; (iii) cubane β-amino propanoic acid and (iv) cubane N-protected
B-alanine, which have the potential of being incorporated into medicinal chemistry programmes.
References
1) Wlochal, J.; Davies, R. D.; Burton J. (2014) Cubanes in Medicinal Chemistry: Synthesis of functionalized building blocks.
Organic Letters 16, 4094-4097
2) Wlochal, J.; Davies, R. D.; Burton J. (2015) Synthesis of Novel Amino Acids Containing Cubane. Chemical
Communications, manuscript in preparation.
- 238 -
OT083
DESIGN OF POTENTIAL COVALENT INHIBITORS LIBRARIES

Svetlana Kovalenko, Anna Zaitseva, Tetiana Matviiuk
Life Chemicals Inc.

1A Dixie Avenue
Niagara-on-the-Lake ON L0S 1J0
Canada
In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical
trials or being approved by FDA has increased significantly; around 30% of the marketed drugs are covalent
inhibitors. Covalent interaction with the target protein has benefit of prolonged duration of the biological effect
and potential for improved selectivity. Examples of proteins that have been targeted by covalent drugs include
serine penicillin-binding proteins, cysteine proteases, hepatitis C virus (HCV) protease and kinases. The strategy
of covalent bindings could be also applied for development of new potent protein-protein interaction inhibitors
for the proteins that carried nucleophilic residues on PPI zone. Furthermore, covalent inhibitors are often used to
investigate and evaluate features of amino acid residues in protein binding site. The design of selective covalent
inhibitors is conceptually very attractive but in practice hard to achieve. That is because it is difficult to strike the
right balance between reactivity and selectivity. We have designed our covalent inhibitors libraries based on
combination of presence reactive electrophilic groups with drug-like core in the molecules. The General
Covalent Inhibitors Library was created by selecting compounds from Life Chemicals Stock Compounds
Collection with specific structural fragments (functional groups) that are known to form covalent bonds with
amino acid residues in binding sites of target proteins: Lys, Cys, Ser, Asp, Glu His and Tyr. Following structural
fragments filters were used for selection: β-lactams, epoxides, aziridines, Michael acceptors (such as
α,β-unsaturated ketones, -nitriles, -esters, maleimide-like compounds, activated vinyl derivatives),
cyanoacrylamides, sulfonate esters, thioles, rhodanines, thiourea and thioketone, quinones, ketales, acetales,
terminal acetylenes, sulfoalkenes. Compound set passed these filters were narrowed down according to “Rule of
five” and “Veber rule”. The final Covalent Inhibitors Library was formed by removing of non-drug like structure
cores and selected PAINS filters (11,000 compounds). The same algorithm was used to create Cysteine Focused
Covalent Library (3,700 compounds) within selection of Michael acceptors as well as fragments capable for
nucleophilic displacement or addition with Cys residue. Compounds with strong electrophilic reactivity were
removed from the Library to avoid non-specific protein reactivity.
According to growing interest and widespread use of fragment-based drug discovery (FBDD) we have also
created the Library of Covalent Fragments (2,200 compounds). Moreover, such compounds could be used to
insight the mechanism of inhibition of some proteins. For this purpose, Life Chemicals Stock Collection was
initially filtered according to “Rule of three” criteria. Subsequently compounds with functional groups that are
known to form covalent bonds with residues in protein binding sites were selected. The final drug-like set of
Covalent Fragments was formed by removing of molecules with high reactivity, undesired core structures and
selected PAINS moieties.
References
1) Mah R., Thomas J. R., Shafer C. M. Bioorg. Med. Chem. Lett., Vol. 24, 2014, pp. 33–39.
2) Johnson D. S., Weerapana E., Cravatt B. F. Future Med. Chem., Vol. 2 (6), 2010, pp. 949–964.
3) Weerapana E., Simon G., Cravatt B. F. Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
4) Liu Q., Sabnis Y., Zhao Z., Zhang T., Buhrlage S. J., Jones L. H., Gray N. S. Cell Press: Chem. Biol., Vol. 20 (2), 2013,
pp. 146–159.
5) Kathman S., Ziyang X., Statsyk A. V. J. Med. Chem., 2014, 57 (11), pp. 4969–4974.
6) Warshaviak D. T., Golan GBorrelli., K. W., Zhu K., Kalid O. J. Chem. Inf. Model., 2014, 54 (7), pp 1941–1950.
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OT084
PHYSICAL AND BIOCHEMICAL PROPERTIES OF BACTERICIDAL

LIPOPHOSPHONOXINS
Eva Zbornikova (1), Natalya Panova (1), Eva Tloustova (1), Milan Kolar (2,3), Katerina Bogdanova (2),
Renata Vecerova (2), Libor Krasny (4), Dominik Rejman (1)
1) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2,
166 10 Prague 6, Czech Republic
2) Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 3, 775 15
Olomouc, Czech Republic
3) TRIOS, Ltd., Zakouřilova 142, Prague 4, 149 00, Prague, Czech Republic
4) Institute of Microbiology, Academy of Sciences of the Czech Republic v.v.i., Vídeňská 1083, 142 20 Prague 4, Czech
Republic
There is an urgent need for novel efficient antibacterial compounds in the modern society. Recently a novel class
of antimicrobial compounds termed lipophosphonoxins (LPPO) were discovered in our laboratory.1
Characterization of these compounds and understanding the mechanism of their action is the key step for their
further development.
(I) Stability of LPPOs: All tested compounds were stable enough at very low or high pH or elevated
temperature for more than 1 day.
(II) LogP of LPPOs: The amphiphilic character of these compounds cause failure in reproducible
experimental determination of partition coefficient. Calculated data are in agreement with our expectations and
lies in wide region according to the length of lipophilic chain and modification of nucleobase.
(III) Localization of LPPO in cells: All added LPPO´s were captured by the prokaryotic cells (B.subtilis)
and it was determined they were localized mainly in the cell membrane. Smaller amount of the tested compound
was also detected in the cytoplasm fraction. On the other hand, eukaryotic human cells (cell line K526) did not
show an affinity for LPPO at the same concentration.
(IV) Caco permeability assay to investigate intestinal permeability of LPPOS: Eight compounds were
picked up and tested in caco permeability assay. Results show that none of the tested LPPOs is able to pass
through a caco cell monolayer.
(V) Use of LPPOs in biofilm formation prophylaxis: LPPO´s didn´t sorb on vessels (glass or plastic) at
significant level even during sterilization process. Experiments using LPPOs as an additive to the synthetic resin
for bone surgery have shown promising results in preventing formation of biofilm by Staphylococcus
epidermidis 7221.
Acknowledgement: The work was supported by grant no. TA02010035 (Technological Agency of the Czech
Republic)
References
1) Rejman D, Rabatinova A, Pombinho AR, Kovackova S, Pohl R, Zbornikova E, et al. Lipophosphonoxins: new modular
molecular structures with significant antibacterial properties. J. Med. Chem. 2011;54(22):7884-98. doi: 10.1021/jm2009343.
PubMed PMID: 22007704
- 240 -
OT085
SYNTHESIS AND EVALUATION OF NAD KINASE INHIBITORS

Julie PAOLETTI (1), Liliane ASSAIRI (2), Muriel GELIN (3), Valérie HUTEAU (1), Marie-Anne
NAHORI (4), Gilles LABESSE (3), Olivier DUSSURGET (4), Sylvie POCHET (1)
1) Unité de Chimie et Biocatalyse, Institut Pasteur, CNRS, UMR3523, 28, rue du Dr Roux, 75015 Paris, France
2) Institut Curie, INSERM, U759, Orsay, France
3) Atelier de Bio- et Chimie Informatique Structurale, CBS, CNRS, UMR5048, Université Montpellier 1 et 2, 29 rue de
Navacelles, 34090 Montpellier, France
4) Unité des Interactions Bactéries-Cellules, Institut Pasteur, INSERM U604, INRA, USC2020, 28, rue du Dr Roux, 75015
Paris, France
The increase in antimicrobial resistance has become one of the most important and pressing public health
problems. In this context, there is a clear and urgent need to develop new classes of therapeutics having a novel
mechanism of action or acting through a novel target.
Recently, the NAD(P) biosynthesis pathways have attracted interest as a source of enzyme targets for the
development of antimicrobial agents. The nicotinamide adenine dinucleotides, NAD(H)/NADP(H), are
coenzymes found in all living cells. Both forms are critical cofactors for a large number of enzymes involved in
redox and non-redox reactions. NAD kinases (EC 2.7.1.23) are ubiquitous enzymes involved in the last step of
the biosynthesis of NADP. They catalyse the phosphorylation of NAD to NADP using ATP, other nucleoside
triphosphate or inorganic polyphosphate as phosphoryl donor. NADK has been found to be essential for survival
in various bacteria as M. tuberculosis, S. aureus, P. aeruginosa.
We focused on the enzyme from a human pathogen, the NAD kinase from the Gram-positive Listeria
monocytogenes (named LmNADK1). The crystal structure of the apo-enzyme NADK1 from L. monocytogenes
(LmNADK1) as well as in complex with its natural ligands, NAD and NADP, were solved.[1] Based on these
structural data, we initiated the screening of a focused library of adenosine derivatives using X-ray
crystallography. An unexpected and biocompatible chemical reactivity allowed the in situ linking of two
adenosine derivatives that fully occupy the active NAD site. This guided the design of a first analogue showing
micromolar inhibition of two human pathogenic NAD kinases (L. monocytogenes and Staphylococcus aureus)
and potent bactericidal activity against Staphylococcus aureus in vitro.[2] This first molecule was next developed
into more potent inhibitors.
Here, we describe a synthetic access to this new class of NAD mimics, their in vitro inhibitory activity against
two bacterial NAD kinases and in vivo bactericidal activity against S. aureus in a mouse model of infection.
References
1) G. Poncet-Montange, L. Assairi, S. Arold, S. Pochet, G. Labesse, J Biol Chem., 2007, 282, 33925-33934.
2) M. Gelin, G. Poncet-Montange, L.Assairi, L.Morelatto, V. Huteau V, L. Dugué, O. Dussurget, S. Pochet, G. Labesse,
Structure, 2012, 20, 1107-1117.
- 241 -
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EXHIBITORS
COMPANY DESCRIPTIONS
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PREMIUM EXHIBITORS
Radarweg 29 - Amsterdam 1043 NX

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www.elsevier.com
Elsevier is a world-leading provider of information solutions that enhance the
performance of science, health, and technology professionals, empowering them to
make better decisions, and deliver better care.
78 Chervonotkatska Street - 02094 Kyiv

ENAMINE Ukraine
m.bossert@enamine.net - www.enamine.net - www.enaminestore.com
The chemistry-driven company active in design and synthesis of novel building
blocks and compound libraries. Enamine offers the world’s largest collection of
building blocks (>118,000) and screening compounds (2,000,000) including 40,000
fragments. Comprehensive services in lead discovery and optimization are available
including integrated biomolecular and ADME/Tox screening, all on-site.
Unit 14, Graphite Way, Hadfield, Derbyshire, SK13 1QH

FLUORCHEM United Kingdom
kates@fluorochem.co.uk - www.fluorochem.co.uk
Fluorochem is so much more than just a fluorochemical supplier; we stock a
diverse range of products, from fluorinated chemicals, heterocyclics, boronic
acids, organometallics, silanes, siloxanes and biochemicals to NMR solvents and
tubes, even silicagel and tlc plates. We have been supplying products for research
and development to pharmaceutical companies, universities, and biotechnology
companies for nearly 50 years, for more details of our special offers visit our web site
www.fluorochem.co.uk, or come and visit our stand for some freebies.
EXHIBITORS
Am Mitterweg 12, D-83209 Prien

ACTIVATE SCIENTIFIC Germany
info@activate-scientific.com - www.activate-scientific.com
Activate Scientific is a European Catalogue supplier of multifunctional building blocks
and complex scaffolds specialised in the field of medicinal chemistry drug discovery.
Our catalogue offers 24.000 novel heterocyclic Synthons, which are readily available
from stock through our offices in the UK and Germany. We are monitoring the latest
trends in publications in medicinal chemistry research. In 2013 a total of ~ 4000
highly innovative building blocks were accepted as new products for applications in
various therapeutic areas of research for the new catalogue. Our compounds are
small, multifunctional molecules for constructing complex and highly functionalised
entities. They are extremely versatile and powerful synthetic tools to provide chemical
diversity for early hit-discovery, focused library production and hit-to-lead exploration.
For your review of our products and data please refer to www.activate-scientific.com
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EXHIBITORS
A Johnson Matthey Company, Postfach 11 07 65 , 76057 Karlsruhe

ALFA AESAR Germany
EuroSales@alfa.com - www.alfa.com
Alfa Aesar is a leading international manufacturer and supplier of research chemicals,
metals and materials. With over 46,000 products listed it is the single source for
customers’ needs for chemicals and materials in sizes for research and scale up.
The catalogue carries materials for biological research, organic compounds, high
purity inorganics, pure elements, and more.
3 allée du titane, 45100 Orléans

AMBINTER France
contact@ambinter.com - www.ambinter.com
Ambinter is a global supplier of advanced chemicals for drug discovery applications.
Our database holds over 20 million compounds for screening and combinatorial
chemistry, including large selections of building blocks and natural products. With
associated proficient technical support, Ambinter also proposes advanced selection
& synthesis services.
Hermannswerder Haus 17, 14473 Potsdam

ANALYTICON DISCOVERY Germany
n.buonom@ac-discovery.com - www.ac-discovery.com
Natural product and medicinal chemistry - unique pure natural products libraries
from plants and microbes - semi-synthetic fragments, screening compounds and
macrocycles based on natural product building blocks - Modular MacroEvoLution
program with high scaffold diversity for macrocyclic R&D - Integrated discovery
programs for pharmaceutical, agrochemical, food and cosmetic industries.
12 avenue de la Scandinavie, 91959 Courtaboeuf

ANTON PAAR FRANCE France
Info.fr@anton-paar.com - www.anton-paar.com
Anton Paar develops, produces and distributes highly accurate laboratory instruments
and process measuring systems, and provides custom-tailored automation and
robotic solutions. It is the world leader in the measurement of density, concentration
and CO2 and in the field of rheometry. Anton Paar GmbH is owned by the charitable
Santner Foundation.
Whitefield Rd, Bredbury, Stockport, Cheshire, SK6 2QR

APOLLO SCIENTIFIC United Kingdom
www.apolloscientific.co.uk
Apollo Scientific now offers over 70,000 compounds, approximately a third of which
are fluorine containing, consisting largely of aromatic and heterocyclic building
blocks. We undertake custom synthesis in our UK lab on kg scale with further scale
up available within our parent company facilities. Pricing and availability can be found
on our website
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EXHIBITORS
Box 8 - SE-751 03 Uppsala

BIOTAGE Sweden
info@biotage.com - www.biotage.com
Biotage is a global leader in life science technology. With a broad scope of tools
for synthesis, work-up, purification, evaporation and analysis, the company provides
solutions, knowledge and expertise in the areas of analytical chemistry, medicinal
chemistry, and process-development. Our focus is on developing technology to
speed experimental procedures.
5 rue du Pont des Halles, 94656 Rungis

BUCHI France
france@buchi.com - www.buchi.fr
Worldwide leader in laboratory evaporation systems since the creation of the first
Rotavapor in 1957, BUCHI has developed a wide range of other technologies for
laboratories: industrial and parallel evaporation, flash chromatography, melting point,
spray drying, encapsulation, pressurized and classical extraction, Kjeldahl, NIR, …
As your local affiliate, BUCHI France is at your service to technically and commercially
support all your request and special needs.
Waldershofer Str. 49-51, D-95615 Marktredwitz

CFM OSKAR TROPITZSCH Germany
info@cfmot.de - www.cfmot.de
Cfm Oskar Tropitzsch assists the pharmaceutical and biotechnological industry in
sourcing and producing chemical specialties. We supply the product you are looking
for. To achieve these goals we use our excellent know how and worldwide network
of qualified experts.
Portfolio:
Contract manufacturing
Payloads (toxins) for ADCs
Phyto Reference Materials (>1000)
Small Molecules (>600)
Záhony u. 7., Budapest 1031

CHEMAXON Hungary
sales@chemaxon.com - www.chemaxon.com
ChemAxon is a leader in providing chemical software development platforms and
desktop applications for the biotechnology and pharmaceutical industries. By focusing
upon active interaction with users and core portability, ChemAxon creates leading
edge cross platform solutions to power modern cheminformatics and chemical
communication.
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EXHIBITORS
CHEMICAL COMPUTING St John’s Innovation Centre - Cowley Road, Cambridge CB4 0WS
United Kingdom
GROUP
info@chemcomp.com - www.chemcomp.com
CCG (Chemical Computing Group) is a leading supplier of software solutions for life
sciences. With a proven track record in scientific innovation, CCG provides state-of-
the-art applications in drug discovery to pharmaceutical, biotechnology and academic
researchers. CCG headquarters are in Montreal (Canada), with support offices in
North America, Europe and Asia.
The University of Queensland, Brisbane

CO-ADD Australia
info@co-add.org - www.co-add.org
CO-ADD is a not-for-profit initiative reaching out to chemists in academia who have
compounds ‘sitting on shelves’ that were not designed as antibiotics and would not
otherwise be screened for antimicrobial activity. These compounds are screened at
no cost against a key panel of drug-resistant bacterial strains
CRELUX Am Klopferspitz 19a, 82152 Martinsried

Germany
wenzkowski@crelux.com - www.crelux.com
CRELUX is a global leader in structure based drug discovery solutions. We provide
small molecule hit finding, validation and optimization services to our clients. Protein
production, a wide range of biophysical assay and screening methods, X-ray
crystallography, as well as cell based and ADME assays are part of our offering.
The Old Monastery, Windhill, Bishops Stortford, Herts CM23 2ND

DOTMATICS United Kingdom
info@dotmatics.com - www.dotmatics.com - 0044 1279 654 123
Dotmatics’ comprehensive informatics solutions include tools for knowledge
management, data storage, enterprise querying and reporting, and data analysis and
visualisation. Agile development guarantees a state-of-the-art high quality technology
platform that adapts to the ever changing needs of the scientific industry.
En Budron E9, CH-1052 Le Mont/Lausanne

FUJI SILYSIA Switzerland
thomas.kaiser@fuji-silysia.co.jp - http://www.Fuji-Silysia.co.jp
Fuji Silysia is a Japanese Silica Bulk Manufacturer, offering silica for usage in Liquid
Chromatography. Our portfolio covers spherical silica for analytical and preparative
LC in various Particle/Pore Size/Modification Combinations. Manufacturing all under
own control and out of running production, we offer highest value material for best
price possible.
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EXHIBITORS
s/n Cebreiro,15823 O Pino, A Coruña

GALCHIMIA Spain
Julie.masse@galchimia.com - www.galchimia.com
GalChimia is the leading Spanish company in the field of Organic Synthetic
Chemistry. We provide the pharmaceutical, biotechnology and chemical industries
with Custom Synthesis, Medicinal Chemistry and Process Development services,
through an expert, dedicated team of chemists, keeping close contact at all times and
guaranteeing absolute confidentiality at all levels.
The Russell Building No.1, Brunel Science Park, Uxbridge, Middlesex UB8 3PQ
HYPHA DISCOVERY United Kingdom
mail@hyphadiscovery.co.uk - www.hyphadiscovery.co.uk
Hypha solves drug metabolite synthesis issues using mammalian and microbial
biotransformation expertise, making mg-g amounts of human oxidative metabolites
and glucuronides. The technique also improves solubility at the lead optimization
stage by hydroxylating via C-H bond activation and highlights the production of active
metabolites for SAR investigation and IP protection.
Waldershofer Str. 49-51, D-95615 Marktredwitz

IRIS-BIOTECH Germany
info@iris-biotech.de - www.iris-biotech.de
Support during your projects from R&D to production as highly qualified supplier.
Iris-Biotech delivers lab quantities at very competitive prices and supply increasing
quantities with same quality and specifications during the evolution of your projects.
Portfolio:
Starting materials for Peptide Synthesis
Reagents for PEGylation
Reagents for Life Science Research
Biocatalysis
Contract manufacturing
1A Dixie Avenue, Niagara-on-the-Lake ON L0S 1J0

LIFE CHEMICALS Canada
Andrey.Tarnovskiy@lifechemicals.com - www.lifechemicals.com
Life Chemicals Inc. (est. in 2004) is an internationally reputed producer and supplier
of small organic compounds for R&D purposes to pharmaceutical, biotech and
agrochemical companies and academic institutions. Relying on long-term experience
and up-to-date equipment the Company offers high quality services in custom
synthesis of drug-like molecules, building blocks and compound libraries, process
optimization, early drug discovery and computational chemistry. Life Chemicals Inc.
operates worldwide with headquarters in Canada and sales offices in Germany,
Ukraine and USA.
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EXHIBITORS
Maybridge, Bishop Meadow Road, Loughborough, LE11 5RG

MAYBRIDGE United Kingdom
Maybridge.Sales@thermofisher.com - www.maybridge.com
From hit finding to lead optimization, Maybridge offers a comprehensive range of
chemistry products tailored to the drug discovery and biotechnology sector. For over
50 years, Maybridge products have been at the forefront of innovative heterocyclic
chemistry design, fuelled by the desire to access novel molecules of pharmaceutical
interest.
Kerkenbos 1013, 6546 BB Nijmegen

MERCACHEM The Netherlands
info@mercachem.com - www.mercachem.com
Mercachem is a chemistry CRO with 125 highly trained and dedicated chemists
supporting small molecule drug discovery and development projects of
biopharmaceutical companies. Services cover discovery, parallel and medicinal
chemistry, process research and GMP synthesis. A proven track record performing
complex projects underlines our problem solving capabilities and pro-active attitude.
NANOTEMPER Floessergasse 4 81369 Munich

TECHNOLOGIES Germany
francois.ogi@nanotemper.de - www.nanotemper.de
NanoTemper Technologies stands for strong commitment to quality and high precision
instrumentation made in Germany.The deeply experienced and globally operating
team of experts strongly focuses on the user’s benefits by ensuring maximum
efficiency for research in Pharmaceutical, Biotech industries and academic basic
research setting.
NanoTemper Technologies - the PLUS for your research!
Neuro-Sys, 410 Chemin Départemental 60,13120 Gardanne

NEURO-SYS France
yann.jaudouin@neuro-sys.fr - www.neuro-sys.fr
Neuro-Sys is a services and Drug Discovery company focusing on neurodegenerative
diseases (Alzheimer’s, Parkinson’s, ALS...). Our green-extraction and pharmacological
platforms used for our Drug Discovery programs on South-East Asian medicinal
plants are also made available to clients allowing the efficacy and mode of action
testing of compounds and natural products.w
Bioparc, boulevard Sebastien Brant, 67400 Illkirch

NOVALIX France
info@novalix-pharma.com - www.novalix-pharma.com
NovAliX is a client-centric organization providing expert-driven innovative outsourcing
and insourcing services. Core expertize includes synthetic organic chemistry
expertise, FBDD and SBDD. The comprehensive portfolio of biophysical and
analytical technologies include: chemical microarray SPR, native MS, NMR, Biacore,
ITC as well as strong structural biology expertise based on X-ray crystallography and
electronic microscopy.
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EXHIBITORS
7221 Cambridge Research Park, Beach Drive, Cambridge, CB25 9TL

OPTIBRIUM United Kingdom
info@optibrium.com - www.optibrium.com
Optibrium’s StarDrop™ software intuitively guides compound design and selection,
to quickly focus on high quality chemistry. Perform true multi-parameter optimization
and interactively design new compounds, guided by StarDrop’s Glowing Molecule™.
The latest release enables users to explore matched molecular series to identify
substitutions most likely to improve target activity.
940 Winter St, Waltham, MA 02451

PERKINELMER United States
informatics.customer_service@perkinelmer.com - www.perkinelmer.com/informatics
PerkinElmer Informatics delivers a comprehensive suite of scientific informatics and
software solutions from instrument generated data, to enterprise solutions to mobile
applications. Our products include the industry leading ChemDraw® application,
Electronic Lab Notebooks (cloud based Elements and enterprise E-Notebook, as
well as Tibco Spotfire® platform for scientific data analytics.
PROVENCE TECHNOLOGIES Head-Office: Provecube, 22 rue Marc Donadille, 13013 Marseille

AND PROVEPEP France
jhugon@provetech.com, jhugon@provepep.com - www.provetech.com - www.synprosis.com

Provence Technologies core competencies are to think, develop, optimize, make and
accompany the chemistry of small molecules from early stage to clinical. Provence
Technologies peptide business unit (ex Synprosis now Provepep) specializes in the
chemical synthesis (SPPS) of long peptides or little proteins for research or GMP
grade.
L’Isle D’abeau Chesnes BP 701, 38297 Saint Quentin Fallavier

SIGMA ALDRICH France
FRACS@sial.com - www.sigma-aldrich.com/chemistry
Aldrich® Chemistry is the market leader in organic & inorganic chemicals, providing
an innovative and comprehensive range of building blocks, reagents, advanced
materials and stable isotopes for chemical synthesis, medicinal chemistry and
materials science. Find out more at sigma-aldrich.com/chemistry
c/o ETH-Zürich, Vladimir-Prelog-Weg 1, HCI-D151.1, 8093 Zürich

SPIROCHEM AG Switzerland
contact@spirochem.com - nolwenn.daubin@spirochem.com - www.spirochem.com
SpiroChem AG is a Swiss fine chemicals company providing innovative building
blocks for the pharmaceutical and agrochemical industries. ur R&D team constantly
designs new series of small rings, spirocycles, SF5- and CF3-containing fragments.
We have developped a wide range of bicyclo[x.y.z]alkane derivatives and are offering
the most diverse set of bio-isosteric replacements. SpiroChem also provides custom
synthesis services (FTE/FFS).
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EXHIBITORS
288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131
WUXI APPTEC China
info@wuxiapptec.com - www.wuxiapptec.com
WuXi AppTec, a leading global life sciences R&D company, offers services from
discovery to marketplace. In discovery we provide a broad portfolio of services
from target ID through PCC selection including chemical design and synthesis, H2L
optimization, and candidate de-risking - offering fully integrated medchem programs
with local project management.
- 252 -
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LIST OF
ABSTRACTS
- 253 -
BookRICT.indd 103 15/06/2015 12:20:17

- 254 -
BookRICT.indd 102 3/06/2015 09:46:04

ADMAS Tizita Haimanot SYNTHESIS AND CHARACTERIZATION OF PHOTOACTIVATABLE OT001
PROBES FOR LABELING OF THE HUMAN CHEMOKINE RECEPTOR
CXCR3
ALEN Jo DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF SOFT ROCK OT002

INHIBITORS BASED ON THE ISOQUINOLINE SCAFFOLD
ALIBERT Sandrine EFFLUX PUMP: AN ATTRACTIVE TARGET TO TACKLE BACTERIAL MR003

RESISTANCE
ALIBERT Sandrine EFFLUX PUMP BLOCKERS IN GRAM-NEGATIVE BACTERIA: NEW MR002

HYDANTOIN BASED MODULATORS TO IMPROVE ANTIBIOTIC
ACTIVITY
ALVAREZ Karine ENZYMATIC SYNTHESIS OF ACYCLIC NUCLEOSIDE OT003

THIOPHOSPHONATE DIPHOSPHATES: EFFECT OF THE
α-PHOSPHORUS CONFIGURATION ON HIV-1 RT ACTIVITY
ALVES Isabel HOW DO A PROAPOPTOTIC AND A CELL PENETRATING PEPTIDE SC01
WORK TOGETHER TO KILL A CANCER CELL?
AMIABLE Claire BIKINS, INNOVATIVE KINASE INHIBITOR LIBRARIES OT004
ARSENYAN Pavel THE STRUCTURE-ACTIVITY RELATIONSHIP IN A SERIES OF CS001

FUSED SELENOPHENO QUINOLINONES AND COUMARINS
ATTANA Fedaa EXPLORING THE MOLECULAR MECHANISM OF DNA RB001

METHYLATION INHIBITION BY ZEBULARINE USING
COMPUTATIONAL TOOLS
AZOULAY Michel COPPER-FREE CLICK CHEMISTRY IN TARGETED DELIVERY OF OT005

ANTICANCER DRUG USING B SUBUNIT OF SHIGA TOXIN
BARF Tjeerd COVALENT KINASE INHIBITORS: A PRACTICAL GUIDE TO L03

MOLECULAR TRAPPING
BARRÉ Anaïs DESIGN AND BIOLOGICAL EVALUATION OF CENTRAL SELECTIVE TA001

ACETYLCHOLINESTERASE INHIBITORS BY MEANS OF A “BIO-
OXIDIZABLE PRODRUG” STRATEGY
BARRÉ Anaïs NEW PALLADIUM-CATALYZED METHOD TO SYNTHESIZE N- OT006

HYDROXYSUCCINIMIDE ESTERS AND ITS APPLICATION THE
PREPARATION OF CENTRAL ACETYLCHOLINESTERASE
INHIBITORS
BELLON Steve INTERROGATING THE BROMODOMAIN FAMILY THROUGH RB002

CHEMICAL BIOLOGY
BERTRAND Romain FFAR1/GPR40 TARGETING FLUORESCENT PROBE FOR BETA OT007

CELL IMAGING
BIHEL Frédéric NOVEL ORALLY-ACTIVE NPFF RECEPTOR ANTAGONISTS SC04

PREVENTING OPIOID-INDUCED HYPERALGESIA
BILELLO John RESISTANCE PHENOTYPES AND SAR IN HCV DRUG L05

DEVELOPMENT
BONNET Dominique FLUORESCENT LIGANDS TO TRACK GPCRs RB003
BONNET Pascal SHEDDING LIGHT ON PROTEIN KINASE PLASTICITY L14
BORA Alina INNOVATIVE HUMAN KINOME INHIBITION MODEL UM001
BORDJIBA Ouahiba STUDY OF THE THERAPEUTIC POWER OF THE CRUDE EXCRACT OT008
OF LEAVES FROM MARRUBIUM VULGARE L. AGAINST
HEPATOTOXICITY INDUCED BY CCL4 AND AN INSECTICIDE IN
MOUSES
BOSC Nicolas THE USE OF VARIOUS SELECTIVITY SCORES IN KINASE OT009

RESEARCH
- 255 -
BOSMAT Levi Hevroni NUCLEOSIDE-2',3'/3',5'-BIS(THIO)PHOSPHATE ANALOGUES ARE OT010
PROMISING ANTIOXIDANTS AND AGENTS FOR DISASSEMBLY OF
AMYLOID BETA(1-42)-Zn(II)/Cu(II) AGGREGATES
BOSSERT Michael DESIGN, SYNTHESIS AND APPLICATION OF NOVEL MORPHOLINE OT011

SURROGATES
BOUKENNA LEILA AZO DYES AS POTENTIAL DRUGS: SYNTHESIS AND IN VITRO OT012
ANTIMICROBIAL EVALUATION OF A SERIES OF 5-ARYL AZO-4, 6-
DIHYDROXYPYRIMIDINE DERIVATIVES
BOUQUET Jaufret SYNTHESIS OF SELECTIVE INHIBITORS OF NAGZ, AN ENZYME OT013

INVOLVED IN THE ANTIBIOTIC RESISTANCE OF THE PATHOGEN
PSEUDOMONAS AERUGINOSA
BOURG Stéphane IN SILICO KINASE PLATFORM (ISKP): A TOOL FOR THE OT014
IDENTIFICATION OF SELECTIVE KINASE INHIBITORS
BOURIN Arnaud DISCOVERY OF NEW INDAZOLE DERIVATIVES AS SOFT ROCK OT015

INHIBITORS: DESIGN, SYNTHESIS AND IN-VITRO EVALUATION
BRENNAN Paul CHEMICAL PROBES FOR EPIGENETIC PROTEINS L10
BUGLIONI Laura SULFOXIMINE ANALOGS OF S-ADENOSYL-L-METHIONINE OT016
BURON Frederic DESING AND SYNTHESIS OF DUAL PI3K/mTOR IN THE OT017

TREATMENT OF BREAST CANCER
CAMERINO Michelle PRMT5 INHIBITORS AS NOVEL TREATMENT FOR CANCERS CS002
CAMI-KOBECI Gerta IMPROVED ANALGESIC: BU08028 A NOVEL, BIFUNCTIONAL TA002

NOP/MOP LIGAND
CAMÓ MARÍN Cristina SYNTHETIC PEPTIDES AS ELICITORS OF PLANT DEFENSE OT018

RESPONSES
CARLSSON Jens TWO STEPS FORWARD, ONE STEP BACK: SUCCESSES AND L17
FAILURES IN STRUCTURE-BASED DISCOVERY OF GPCR
LIGANDS
CATENI Francesca SYNTHESIS OF ALFA-ALKYLIDEN-GAMMA-LACTONES AS FAS OT019

INHIBITORS
CENAS Narimantas MURINE HEPATOMA MH22A CELLS RESISTANT TO AZIRIDINYL- MR007

BENZOQUINONE RH1: ENZYME ACTIVITIES AND PROTEOMIC
ANALYSIS
CHAILLOU Bérénice DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF P. OT020

FALCIPARUM AMINOPEPTIDASE M17 INHIBITORS
CHAMPNESS Edmund PREDICTING REGIOSELECTIVITY AND LABILITY OF RB004

CYTOCHROME P450 METABOLISM USING QUANTUM
MECHANICAL SIMULATIONS
CHARRIER Jean- DISCOVERY AND CHARACTERISATION OF ATR INHIBITORS FOR L02

Damien THE TREATMENT OF CANCER
CHATRON Nolan PISTON-DRIVEN ACTIVATION MECHANISM OF VKORC1, THE RB005

HUMAN VITAMIN K EPOXIDE REDUCTASE
CHAUHAN Ritesh RAPID TECHNIQUE FOR NEW SCAFFOLD GENERATION II: WHAT UM002
IS THE BEST SOURCE OF INSPIRATION?
CHAYROV Radoslav RIMANTADINE ANALOGUES - SYNTHESIS, CHEMICAL STABILITY OT021

AND INFLUENZA VIRAL ACTIVITY
CHILLA N. MURTHY SYNTHESIS AND COMPLEXATION OF BIS-PHOSPHONIC ACID IA005

Satya DOTA LIKE CHELATOR AND ITS NMR RELAXATION PROPERTIES
CHOUCHOU Adrien SYNTHESIS OF IMIDAZOQUINOXALINE DERIVATIVES WITH OT022

ANTICANCER POTENTIAL ACTIVITIES
- 256 -
CHRISTOPHER John FRAGMENT AND STRUCTURE-BASED DRUG DISCOVERY FOR A L18
FAMILY C GPCR: DISCOVERY OF THE MGLU5 NAM PRE-CLINICAL
CANDIDATE HTL14242
CLARISSE Damien TUMOR-TARGETED ZWITTERIONIC POLYDIACETYLENE MICELLE OT023
CONTINO-PEPIN PHOTOTHERMIC ACTIVATED PHASE-SHIFTED TA003

Christine PERFLUOROCARBON DROPLETS FOR THERANOSTIC
APPLICATIONS IN CANCER
COURVALIN Patrice ANTIBIOTIC RESISTANCE: AN EMERGING DISEASE L04
CROIX Cécile SYNTHESIS AND BIOLOGICAL EVALUATION OF A NEW OT024

CATHEPSIN C INHIBITOR (XPZ-01)
DALLEMAGNE Patrick DISCOVERY OF DONECOPRIDE A NOVEL MULTI-TARGET CS003

DIRECTED LIGANDS FOR ALZHEIMER'S DISEASE
DENIAUD David NEW POLYAMINOQUINOLINE IRON CHELATOR FOR IA001

ANTINEOPLASIC AGENT VECTORIZATION
DENOYELLE Séverine SAR STUDY ON GHRELIN RECEPTOR TRISUBSTITUTED 1,2,4- OT025

TRIAZOLE ANTAGONISTS
DEPREZ-POULAIN FROM IN SITU CLICK TO IN VIVO PHARMACOLOGY: EFFECT OF L07

Rebecca CATALYTIC SITE INHIBITION OF INSULIN DEGRADING ENZYME
ON GLUCOSE INTOLERANCE
DERABLI Chamseddine SYNTHESIS AND DOCKING SIMULATION STUDY OF NEW OT026

TETRACYCLIC TACRINE ANALOGS CONTAINING PYRANO[2,3-
C]PYRAZOLE FOR THE TREATMENT OF ALZHEIMER’S DISEASE
DRIDI Delel SYNTHESIS OF NEW DERIVATIVES COMPOUNDS FROM OT027

SUBSTITUTED ACETYL-COUMARINES
DURAND Grégory DESIGN OF AMPHIPHILIC NITRONES WITH IMPROVED SPIN- OT028

TRAPPING AND ANTIOXIDANT PROPERTIES
FLIPO Marion FRAGMENT-BASED SCREENING USING TANDEM MASS TA004

SPECTROMETRY FOR THE DISCOVERY OF MYCOBACTERIUM
TUBERCULOSIS MABA INHIBITORS
GASTREICH Marcus REVERSIBLE MAO-B INHIBITORS WITH SUB-NANOMOLAR CS004

POTENCY: DISCOVERY OF PROMISING DRUG CANDIDATES FOR
THE TREATMENT OF PARKINSON'S DISEASE
GASTREICH Marcus VISUALIZING DESOLVATION IN THE FREE ENERGY OF BINDING UM003

AND TORSIONAL SIGNIFICANCES: SeeSAR, A NEW TOOL FOR
MEDICINAL CHEMISTRY AND CRYSTALLOGRAPHY
GLADYSZ Rafaela APPLICATION OF THE MSAS APPROACH IN THE DISCOVERY OF OT029

POTENT AND SELECTIVE INHIBITORS OF UROKINASE
GROZAV Adriana THIAZOLE-PHENOTHIAZINE DYADS WITH ANTITUMOR ACTIVITY OT030
GROZAV Adriana THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS WITH OT031

ANTIOXIDANT ACTION
GUICHOU Jean-François “DRY” CO-CRYSTALLIZATION AND IN SITU DIFFRACTION FOR IA007

AUTOMATIC LIGAND SCREENING BY X-RAY CRYSTALLOGRAPHY
GUILLON Jean NOVEL PYRROLO[1,2-a]QUINOXALINES AS ANTIPARASITIC MR001

AGENTS : DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION
HALLÉ François PALLADIUM-CATALYZED SYNTHESIS OF BRIDGED PHE-GLY UM004

DIPEPTIDES TO ACCESS NOVEL LIGANDS OF TRANSLOCATOR
PROTEIN 18kDa (TSPO)
HARARI Marine NEW METHOD OF MODULATION OF QUINAZOLIN-4(3H)-ONES: OT032

DIRECT C-H ARYLATION
- 257 -
HARRIS David J CERDELGA, AN ORAL THERAPY FOR GAUCHER DISEASE TYPE 1; L16
FROM DISCOVERY TO LAUNCH
HASHIMOTO Yuichi RETINOIDS/STEROIDS AS LIGANDS FOR PHARMACOLOGICAL L09

CHAPERONES AND PROTEIN KNOCKDOWN APPROACH
HEINRICH Timo MERIOLIN DERIVED HIGHLY POTENT PDK1 INHIBITORS UM005
HENDRIKS Christine PENTAFLUOROSULFANYL-SUBSTITUTED MOLECULES OT033
HENRY Axelle NEW APPROACH FOR THE DEVELOPMENT OF A REDOX OT034

CHEMICAL DELIVERY SYSTEM TO TARGET META-
IODOBENZYLGUANIDINE INTO THE BRAIN
HIENZSCH Antje MOLECULAR MECHANISM OF SALINOMYCIN-INDUCED CANCER RB006

STEM CELL DEATH
HO Soo Yei THE DISCOVERY AND OPTIMIZATION OF A ORALLY OT035

BIOAVAILABLE PORCUPINE INHIBITOR
HONG Sunhye FLEXIBLE DOCKING STUDY AND STRUCTURE-ACTIVITY OT036

RELATIONSHIPS OF TRPV1 ANTAGONISTS FOR NEUROPATHIC
PAIN DRUG DISCOVERY
HUVELLE Steve SYNTHESIS AND KINETIC STUDIES OF CYCLISATION-BASED OT037

SELF-IMMOLATIVE SPACERS
IVANCICH Anabella A SPECTROSCOPY-BASED NEW PARADIGM TO EXPLAIN AND RB007

OVERCOME RESISTANCE OF MYCOBACTERIUM TUBERCULOSIS
TO THE PRO-DRUGS ISONIAZID AND ETHIONAMIDE
IVANOV Vladimir DESIGN AND SYNTHESIS OF NOVEL FLUORINATED AMINES: OT038

IVANOV Vladimir SYNTHESIS OF NOVEL UNIQUE PYRROLIDINES BY [3+2]- OT039

CYCLOADDITION OF AZOMETHINE YLIDES WITH ELECTRON-
DEFICIENT ALKENES
IVANOV Vladimir FLUORINATED DIAZOALKANES IN THE SYNTHESIS OF BUILDING OT040

BLOCKS FOR MEDICINAL CHEMISTRY
JEANMART Stephane NOVEL ANTIFUNGAL ACETYL COENZYME-A CARBOXYLASE OT041

INHIBITORS
JIRICEK Jan LESSONS LEARNED IN TB DRUG DISCOVERY L15
JUNG Marie-Louise THE PRESTWICK CHEMICAL LIBRARY, A VALUABLE TOOL FOR RB008
SCREENING
KAPLAN Elise IN SILICO SCREENING AND ANTIBACTERIAL EVALUATION OF MR005

AMINOGLYCOSIDE PHOSPHOTRANSFERASE INHIBITORS
KONDA Shyam REVERSIBLE AND COVALENT DNA BINDING OF AN RB009

ANTHRACYCLINE DERIVATIVE: JEM-150
KONDRATOV Ivan NEW SYNTHETIC APPROACH TO DIVERSE HETEROCYCLIC OT042

SULFONYL CHLORIDES
KONDRATOV Ivan PHENOXYMETHYL 1,3-OXAZOLES AND 1,2,4-OXADIAZOLES AS CS005

POTENT AND SELECTIVE AGONISTS OF FREE FATTY ACID
RECEPTOR 1 (GPR40)
KORNICKA Anita SEARCH FOR NEW DRUGS STRUCTURALLY RELATED TO OT043

MARSANIDINE, A HIGHLY SELECTIVE ALPHA2-ADRENOCEPTOR
AGONIST WITH HYPOTENSIVE ACTIVITY
LABRUERE Raphaël N-ACYLATED POLYAMINE DERIVATIVES AS ANTIKINETOPLASTID OT044

AGENTS
- 258 -
LAMANDÉ-LANGLE DEVELOPMENT OF [18F]FLUORO-GLYCORGD FOR PET IMAGING TA005
Sandrine
LETALLEC jean philippe DISCOVERY OF SAR623, A NOVEL, POTENT AND SELECTIVE OT045
INHIBITOR OF VPS34 FOR CANCER TREATMENT
LIPINSKI Piotr NOVEL ASPECTS OF CHIRAL QSPR ANALYSIS OT046
LUNVEN Laurent EVALUATION OF AURONES WITH TAU AGGREGATES IN OT047

ALZHEIMER'S DISEASE
MAI Trang SELECTIVE TARGETING LYSOSOME WITH SMALL MOLECULES RB010
MALECKI Maciej GENE THERAPY FOR MELANOMA: THE EVALUATION OF rAAV TA006
TRANSDUCTION EFFICIENCY OF B16-F10 CANCER CELLS
MARCHAND Pascal DISCOVERY OF (IMIDAZO[1,2-a]PYRAZIN-6-YL)UREAS AS OT048

ANTIPROLIFERATIVE AGENTS TARGETING HEF1 GENE IN NON-
SMALL CELL LUNG CANCER CELL LINES
MARIANI Angelica DIFFERENTIAL TARGETING OF TOPOISOMERASE II ISOFORMS OT049

WITH SMALL MOLECULES
MASURIER Nicolas IMIDAZOPYRIDINE-FUSED [1,3]-DIAZEPINONES : SYNTHESIS AND IA004

ANTIPROLIFERATIVE ACTIVITY
MEIBOM Daniel BAY 1067197 - DISCOVERY AND OPTIMIZATION OF A PARTIAL L12

ADENOSINE A1 AGONIST FOR THE TREATMENT OF HEART
FAILURE
MENET Christel NOVEL TRIAZOLOPYRIDINE COMPOUNDS AS SELECTIVE JAK1 L22

INHIBITORS: FROM TARGET DISCOVERY TO FILGOTINIB
(GLPG0634)
MESSINIS Dimitris SIGNALLING PATHWAY-BASED SCREENING FOR DRUG CS006

DISCOVERY: AN APPLICATION IN MULTIPLE SCLEROSIS
MESSOUSSI INSIGHT INTO BINDING MODE AND SELECTIVITY OF CS007

ABDELLAH HETEROCYCLIC INHIBITORS OF JNK KINASES USING
STRUCTURE BASED DRUG DESIGN APPROACH
MILANOLE Gaelle DESIGN OF A CRYPTOPHANE-BASED BIOSENSOR FOR THE OT050

DETECTION OF NON-SMALL CELL LUNG CANCER USING
HYPERPOLARIZED 129Xe MAGNETIC RESONANCE IMAGERY
MOGEMARK Mickael DEVELOPMENT OF HIGHLY POTENT AND SELECTIVE RB011

PREVENTION OF ACTIVATION (POA) MK2 INHIBITORS
MONTOIR David SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-METHYL-1,6- OT051

NAPHTHYRIDIN-2(1H)-ONE DERIVATIVES AS POTENT Hsp90 C-
TERMINAL INHIBITORS
MORICE Christophe COMPARISON OF HIT DISCOVERY APPROACHES TA007

CASE STUDY: NIK INHIBITORS
MULLER Sylviane THE SYNTHETIC PEPTIDE P140, A SKILLED STRATEGIST AND L01
MANIPULATOR OF THE IMMUNE SYSTEM
MUNOZ Lenka ALLOSTERIC INHIBITORS OF p38 MAPK-MK2 PATHWAY FOR SC02

SELECTIVE CANCER CELL KILLING
MYKHAILIUK Pavel SYNTHESIS AND APPLICATION OF PROLINE ANALOGUES: OT052

MYKHAILIUK Pavel DESIGN, SYNTHESIS AND APPLICATION OF NOVEL BUILDING OT053

BLOCKS TO ESCAPE THE FLATLAND" IN MEDICINAL CHEMISTRY"
MYKHAILIUK Pavel SYNTHESIS OF CONFORMATIONALLY RESTRICTED SCAFFOLDS OT054

BY DOUBLE-MANNICH REACTION OF CYCLIC KETONES
- 259 -
NAM GHILSOO SYNTHESIS AND BIOLOGICAL EVALUATION OF TA008
PYRAZOLYLMETHYLBENZENSULFONAMIDES AS T-TYPE
CALCIUM CHANNEL BOLCKERS
NOMURA Sumihiro REVOLUTIONARY IDEA YIELDED SGLT2 INHIBITOR L08

CANAGLIFLOZIN FOR TREATMENT OF TYPE 2 DIABETES
NURISSO Alessandra HYDANTOINS AS A NOVEL SCAFFOLD FOR SIRT INHIBITION: CS008

FROM VIRTUAL SCREENING TO ACTIVITY ASSAYS
OBNISKA Jolanta DESIGN, SYNTHESIS OF NEW AMIDES DERIVED FROM 3,3- OT055
DISUBSTITUTED 2,5-DIOXO-PYRROLIDIN-1-YL-ACETIC ACID AS
POTENTIAL ANTICONVULSANT AGENTS
OBSZYNSKI Julie NOVEL AMINOGLYCOSIDES FOR DRUG DEVELOPMENT OT056
OPREA Tudor I. DRUGS, TARGETS, DISEASES AND THE DRUGGABLE PROTEOME L13
OSAYANDE Julie THE FOCUS ON DRUG DISCOVERY: HOW? OT057
PAILLASSE Michael IN SILICO IDENTIFICATION, SYNTHESIS AND EVALUATION OF TA009

TPH-3: AN ORIGINAL TIAM-1 INHIBITOR TARGETING PH-DOMAIN
TO PREVENT CANCER CELL INVASION
PAK Stephen IDENTIFICATION OF THERAPEUTIC COMPOUNDS FOR PROTEIN OT058

AGGREGATION DISORDERS USING A WHOLE-ORGANISM-BASED
APPROACH
PAPOT Sebastien A DRUG DELIVERY SYSTEM TARGETING THE OT059

MICROENVIRONMENT OF SOLID TUMORS
PARVATHANENI Nanda A NEW CONCEPT OF DUAL TARGETING DRUGS: DTP 348 A RB012
Kumar CARBONIC ANHYDRASE IX INHIBITOR SPECIFIC FOR HYPOXIC
TUMORS
PIANTANIDA Ivo VERSATILE SPECTROMETRIC PROBES: THE RELATION OT060

BETWEEN MULTITARGET DNA / RNA SENSING AND
CYTOTOXICITY
PLOWRIGHT Alleyn T. PHENOTYPIC SCREENING TO IDENTIFY COMPOUNDS L11

ENHANCING PROLIFERATION AND DIFFERENTIATION OF HUMAN
CARDIAC PROGENITOR CELLS AND EPICARDIUM-DERIVED
CELLS
POCHET Sylvie SYNTHESIS AND EVALUATION OF NAD KINASE INHIBITORS OT085
PRIMAS Nicolas NOVEL ANTILEISHMANIAL LEAD COMPOUND IN 3- OT061

NITROIMIDAZO[1,2-a]PYRIDINE SERIES
PRIMAS Nicolas ANTIPLASMODIAL ACTIVITY OF NEW QUINAZOLINE SERIES OT062

SYNTHESIZED BY A DMAP-CATALYZED AND MICROWAVE-
ASSISTED APPROACH
PRIMAS Nicolas NEW ANTILEISHMANIAL AGENTS: SYNTHESIS, EVALUATION AND OT063

STRUCTURE-ACTIVITY RELATIONSHIPS STUDY OF
HYDROXYAMIDINE DERIVATIVES
PUGLIESE Luisa SAFAN-ISP: A NEW SMALL MOLECULE FRAGMENT INFORMATICS UM006

APPROACH FOR IN-SILICO PROFILING
QIU Shihong DELIVERY OF NATURAL ACTIVE COMPOUNDS BY OT064

CYCLODEXTRIN / GOLD NANOPARTICLES COMPLEX
RAGEOT Denise A DELICATE BALANCE - TARGETING PI3K AND/OR MICROTUBULE RB013

DE-POLYMERIZATION
RAHIMOVA Rahila FRAGMENT-BASED DRUG DESIGN OF ECTO-5’NUCLEOTIDASE MR008

INHIBITORS: APPLICATION TO CANCER TREATMENT
RESISTANCE
- 260 -
REGGIANI DE MOURA STRUCTURE, CYTOTOXIC ACTIVITY AND DNA BINDING OF OT065
Thales NOVEL THIOCARBAMOYLPYRAZOLES PD(II) COMPLEXES: THE
STRUCTURE ACTIVITY RELATIONSHIP BETWEEN PYRAZOLES
COMPOUNDS
REJMAN Dominik INSIGHTS INTO THE MECHANISM OF ACTION OF BACTERICIDAL RB014

LIPOPHOSPHONOXINS
REVELANT Germain REPOSITIONING OF AMINOBENZOSUBERONE AS POTENTIAL OT066

ANTIMALARIAL AGENT TARGETING PfA-M1 AMINOPEPTIDASE
REZAEIZADEH Golnaz A SYSTEMATIC REVIEW OF THE UTERINE RELAXANT EFFECT OF RB015

HERBAL SOURCES
RICHARD Mylène DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF OT067

PEPTIDOMIMETICS TARGETING NRP-1 RECEPTOR
RIOUX Benjamin COLON CANCER CHEMOTHERAPY: DESIGN AND MULTI-STEP IA003

SYNTHESIS OF VECTORIZED CHALCONES BY POLYAMINE TAILS
ROCHAIS Christophe DEVELOPMENT OF NOVEL MULTI-TARGET DIRECTED LIGANDS SC03

FOR ALZHEIMER'S DISEASE: IDENTIFICATION OF DONECOPRIDE
RODRIGUEZ Raphaël SMALL MOLECULES, BIG PLAYERS L21
RYBKA Sabina DESIGN, SYNTHESIS AND EVALUATION OF ANTICONVULSANT OT068

PROPERTIES OF NEW N-MANNICH BASES DERIVED FROM 3-
BENZHYDRYL-PYRROLIDINE-2,5-DIONE
RYCKEWAERT Lucie IDENTIFICATION OF NOVEL DRUG-LIKE SIRT INHIBITORS WITH RB016

ANTI-ANGIOGENIC ACTIVITY
SANTORO DE RUTHENIUM(II) BASED COMPOUNDS AS DUAL TOPOISOMERASE RB017

CAMARGO Mariana I AND II INHIBITORS
SEMAAN Josiane 3-HYDROXY-3',4,4',5'-TETRA-METHOXY-CHALCONE INDUCES RB018

G2/M ARREST AND TRIGGERS APOPTOSIS IN HUMAN HT-29 AND
HCT-116 COLORECTAL CANCER CELLS
SGARIGLIA Melina ASSESSMENT OF BIOACTIVE COMPONENTS FROM CAESALPINIA IA006

Araceli PARAGUARIENSIS AS ROS SCAVENGERS AND COLLAGENASE
INHIBITORS IN HUMAN SKIN FIBROBLASTS
SOFIA Michael SOFOSBUVIR: A CURE FOR HCV L19
SOLMAJER Tomaz STRUCTURE-BASED DESIGN OF NOVEL HUMAN DNA CS009

TOPOISOMERASE IIα INHIBITORS
STOYKOVA Boyka SYNTHESIS AND BIOLOGICAL ACTIVITY OF 1,2,4-TRIAZOLE-3- OT069

CARBOXAMIDES OF AMINOADAMANTANES
STUTZMANN Aurélien PROPERTIES OF PHENOTHIAZINE DERIVATIVES ON THE MR004

BACTERIAL EFFLUX PUMP SYSTEM
TETKO Igor INTERPRETATION AND COMPARISON OF QSAR/QSPR MODELS OT070

USING MATCHED MOLECULAR PAIRS
TETKO Igor PREDICTION OF OCTANOL/WATER PARTITION COEFFICIENT OF OT071

Pt(II)/Pt(IV) COMPLEXES
TETKO Igor HOW ACCURATELY CAN WE PREDICT THE MELTING POINTS OF UM007
DRUG-LIKE COMPOUNDS?
TRAN Thi Phuong Anh TARGETING THE PRODUCTION OF ONCOGENIC MICRO-RNAS OT072
USING SYNTHETIC SMALL MOLECULES
TRAORE Mohamed Dit DESIGN OF MORE SELECTIVE APICOMPLEXA HDAC INHIBITORS OT073
Mady
- 261 -
TURAN-ZITOUNI SYNTHESIS OF SOME THIAZOLYL—PYRAZOLINE DERIVATIVES OT074
GULHAN AND EVALUATION OF ANTIMICROBIAL ACTIVITY, CYTOTOXICITY
AND GENOTOXICITY
UESUGI Motonari SYNTHETIC MOLECULES FOR CELL BIOLOGY AND CELL L06
THERAPY
VALLON Gary DECONSTRUCTION OF PDZ INHIBITORS OT075
VAN LINDEN Oscar USING BIOPHYSICS TO TARGET METHYL TRANSFERASES UM008

(HKMTS) WITH SMALL MOLECULES
VANELLE Patrice GREEN AND EFFICIENT SYNTHESIS OF 2,6,8-TRISUBSTITUTED 4- OT077

AMINOQUINAZOLINES
VANELLE Patrice 4,5-DIMETHOXYBENZENE DERIVATIVES: SYNTHESIS, ANTI- OT076

RHINOVIRAL EVALUATION, IN SILICO OPTIMIZATION
VANELLE Patrice RAPID AND EFFICIENT SYNTHESIS OF SUBSTITUTED- OT078

PYRIDO[4,3-b]QUINOXALIN-1(2H)-ONE DERIVATIVES
VILLA Pascal PCBIS: CHEMICAL LIBRARIES, BIOLOGICAL MODELS, OT079

TECHNOLOGICAL TOOLS AND EARLY ADMETOX FOR
LABORATORIES
VON NUSSBAUM Franz FREEZE THE BIOACTIVE CONFORMATION! DISCOVERY OF THE L23
HIGHLY POTENT AND SELECTIVE ELASTASE INHIBITOR BAY 85-
8501 FOR THE TREATMENT OF PULMONARY DISEASES
VRIJDAG Johannes PRACTICAL PREPARATION OF CHALLENGING AMIDES FROM OT080

NON-NUCLEOPHILIC AMINES AND ESTERS UNDER FLOW
CONDITIONS
WAI John DISCOVERY OF HIV INTEGRASE INHIBITORS L20
WILSON Thomas THE USE OF ARYL BORONIC ESTER PRECURSORS IN OT081

PROVIDING FACILE ACCESS TOWARDS 123I AND 18F
RADIOLABELLED TARGETS FOR SPECT AND PET IMAGING

WLOCHAL Joanna SYNTHESIS OF NOVEL CUBANE AMINO ACIDS OT082
YELEKCI Kemal IN SILICO MODELING OF HUMAN DOPAMINE TRANSPORTER AND UM009

DESIGN OF NOVEL INHIBITORS
ZAITSEVA Anna DESIGN OF POTENTIAL COVALENT INHIBITORS LIBRARIES OT083
ZANELLATO Ilaria POOR CELL DETOXIFICATION ENABLES LIPOPHILIC PT(IV) MR006

PRODRUGS TO BYPASS CISPLATIN RESISTANCE
ZBORNIKOVA Eva PHYSICAL AND BIOCHEMICAL PROPERTIES OF BACTERICIDAL OT084

LIPOPHOSPHONOXINS
ZGHAIB Zahraa TRANSCRIPTOMIC ANALYSES: NEW INSIGHTS ON EAPB0503 RB019

ANTICANCER AGENT
ZUEGG Johannes NEW APPROACH TO THE DISCOVERY OF NOVEL IA002

ANTIMICROBIALS
- 262 -
INDEX OF AUTHORS
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BookRICT.indd 115 15/06/2015 12:21:28

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BookRICT.indd 114 3/06/2015 09:46:04

Lastname and firstname Initial Pres. ID AVES S. L18
ABDELWAHAB A. B. OT026 AVRAM S. UM001
ABDOLLAHI M. RB015 AVRAM S. UM001
ABECASSIS P.-Y. OT045 AZAS N. MR001, OT061,
OT062
ACI-SÈCHE S. OT014
AZOULAY M. OT005
ADMAS T. H. OT001
BADOSA E. OT018
AHER A. B. RB013
BAFFOU G. TA003
AKHMANOVA A. RB013
BALLANDONNE C. CS003
ALBRECHT S. OT066, OT020
BANACZKOWSKA- E. TA006
ALCAZAR J. OT080 DUDA
ALEN J. OT002, OT015 BANDAK D. OT053
ALEXOPOULOS L. G. CS006 BANÈRES J.-L. OT025
ALIBERT S. MR002, MR003, BARF T. L03

MR004 BÄRFACKER L. L23
ALIX F. OT006 BARGESTEN K. RB013
AL-KARADAGHI S. TA007 BARILLÉ-NION S. OT051
AL-KATTAN A. TA003 BARRA C.V. OT065
ALLAN E. CS002 BARRÉ L. OT034
ALLEMAND F. IA007 BARRÉ A. TA001, OT006
ALLERHEILIGEN S. L23 BARRIÈRE C. OT045
ALONSO N. OT080 BARTOLI A. OT049
ALOUANE A. OT037 BARVÍK I. RB014
ALTIERI T. OT019 BASMACIYAN L. OT061
ALVAREZ K. OT003 BATISTA A. A. RB017
ALVES I. SC01 BAULARD A. TA004
AMIABLE C. OT004 BAUVAIS C. OT004
ANDRUSHKO O. OT011 BAZIN M.-A. OT051, OT048
ANG S. H. OT035 BEAUFILS F. RB013
ANLAUF S. L23 BECHEM M. L23
ARAMA D. IA004 BEGU S. OT022
ARANDA J. RB001 BELLIS M. RB019
ARIGON J. OT045 BELLON S. RB002
ARORA R. OT014 BENARD T. OT045
ARSENYAN P. CS001 BÉNÉDETTI H. OT017
ARTAMONOV A. OT040 BENKHERARA S. OT008
ARTAMONOV O. OT038 BENMOHAMED S. OT012
ARTEMENKO A. OT011 BENNETT K. L18
ASIRI A.M. UM007 BENOIT E. RB005
ASSAIRI L. OT085 BENSON J. A. OT058
ATLI O. OT074 BERGMAN Y. E. CS002
ATTANA F. RB001 BERNARDES- V. RB007
ATWAL M. OT049 GENISSON
BERNDT S. RB016
AUBERT-POUESSEL A. OT022
BERTHAULT P. OT050
AUGUSTYNS K. OT029
BERTHIER P. OT017
AUSTIN C. A. OT049
BERTRAND T. OT045
- 265 -
BERTRAND R. OT007 BROLEN G. L11
BESSON T. OT032 BRÖNSTRUP M. OT007
BIHEL F. UM004, SC04 BROTIN T. OT050
BILELLO J. L05 BRVAR M. CS009
BILENKO V. OT052 BUCHSTALLER H.-P. UM005
BIOT F. MR004 BUGLIONI L. OT016
BLASKOVICH M. A. IA002 BUISINE P. OT079
BLÉRIOT Y. OT013 BURKE J. E. RB013
BLONSKI C. OT044 BURON F. OT017
BLUMBERG P. M. OT036 BURTON J. OT082
BOBLEWSKI K. OT043 CACLARD A. MR004
BOGDANOVA K. OT084, RB014 CAILLY T. OT081
BOHN P. TA001 CAIO TORRES- E. OT063
SANTOS
BOHNACKER T. RB013
CAMARGO M. S. RB017
BOLAND S. OT002, OT015
CAMERINO M. A. CS002
BOLD P. RB011
CAMI-KOBECI G. TA002
BOLLA J.-M. MR002, MR003,
CAMÓ C. OT018
MR004
BOLLOT G. OT004 CANARD B. OT003
BOLM C. OT033, OT016 CANAULT B. OT014
BONARRIGO I. MR006 CANEQUE T. RB010
BONNET D. RB003 CANTURK Z. OT074
BONNET P.-A. RB019, OT022 CARLOS I.Z. OT065
BONNET P. OT009, OT017, CARLSSON J. L17

OT014, L14 CARON A. OT045
BORA A. UM001 CARON N. TA009
BORDJIBA O. OT008 CARPENTIER G. RB016
BOSC N. OT009, OT014 CARRÉ M. SC01
BOSSERT M. OT011 CARRUPT P.-A. RB016, CS008
BOTTA M. UM006 CASTELLI S. RB017
BOUET V. CS003 CASTERA-DUCROS C. OT061
BOUGRIN K. CS007 CATENI F. OT019
BOUKENNA L. OT012 ČĖNAS N. MR007
BOULCINA R. OT026 CHAILLOU B. OT020
BOULOUARD M. CS003 CHALOIN L. MR005, MR008
BOUMENDJEL A. OT047 CHAPLEUR Y. OT067, TA005
BOUNAADJA L. OT066 CHARMAN S. A. CS002
BOUQUET J. OT013 CHAROCHKINA L. UM007
BOURA C. OT067 CHARRIER J.-D. L02
BOURG S. OT017, OT014 CHATRON N. RB005
BOURGUET W. IA007 CHAUHAN R. UM002
BOURIN A. OT002, OT015 CHAYROV R. OT021
BOYER G. MR002, MR003, CHEESERIGHT T. UM002
MR004 CHEN L. TA009
BRAGUER D. SC01, TA003
CHEONG V. W. OT035
BRENNAN P. L10 W.
- 266 -
CHEVALIER J. MR002 CZAJKA M. TA006
CHEVE G. CS007 CZODROWSKI P. UM005
CHEW Y. S. OT035 DA COSTA L. OT076
CHIERICI S. OT047 DALLEMAGNE P. CS003
CHILLA S. IA005 DALLET CHOISY S. OT024
CHOCHKOVA M. OT069 DAMAZ Y. IA007
CHODKOWSKA- A. TA006 DAMIAN M. OT025
GORA
DATCENKO O. OT011
CHOI K. I. TA008
DAUBEUF F. OT079
CHOI S. OT036
DAUMANTAS M. CS008
CHOO H. TA008
DAVIES R. OT082
CHOUCHOU A. OT022
DAVIS A. RB011
CHRISTOPHER J. L18
DE BORGGRAEVE W. OT080
CHUDZIŃSKA A. OT068
DE SILVA M. CS002
CHUNG M. CS002
DE SIMONE G. RB012
CIUCANU I. UM001
DE TAUZIA M.-L. OT017
CLAEYSEN S. CS003
DE WINTER H. OT029
CLARHAUT J. OT059
DEBACHE A. OT026
CLARISSE D. OT023
DEFERT O. OT002, OT015
CMILJANOVIC N. RB013
DELBECK M. L23
CMILJANOVIC V. RB013
DELEUZE- C. OT022
COCHRAN A. RB002
MASQUEFA
COHEN A. MR001, OT061 DELFOSSE V. IA007
COLLET C. TA005 DELGADO F. OT080
COLLIANDRE L. OT017 DENIAUD D. IA001
COLLINS J. G. RB009 DENISENKO O. OT054, OT011
CONGREVE M. L18 DENOYELLE S. OT025
CONTINO-PÉPIN C. TA003 DEPREZ B. TA004
CONTRERAS J.-M. TA007, RB008 DEPREZ-POULAIN R. L07
COOPER M. A. IA002 DERABLI C. OT026
CORCÉ V. IA001 DERDAU V. OT007
CORLU A. OT017 DESGRANGES S. TA003
CORRÉARD F. TA003 DESIDERI A. RB017
COURTEIX C. OT075 DÉSIRÉ J. OT013
COURVALIN P. L04 DEVLIN M. CS002
CRISTEA C. OT030 DI GIORGIO A. OT072
CROIX C. OT024 DIAB ASSAF M. RB018, RB019
CROZET M. D. OT061, OT077 DÍAZ J. F. RB013
CUENDET M. RB016 DIDIER B. RB008, OT079
CUI M. OT036 DING L. OT035
CUQ P. RB019, OT022 DJAHRA A. B. OT008
CURTI C. OT063 DMYTRIV Y. OT053
CURTIS D. J. CS002 DOEBELIN C. UM004
CUTILLAS V. TA009 DOERFLINGER A. OT023
CUTTS S. M. RB009 DOLOVANYUK V. OT052
- 267 -
DOMRACHEVA I. CS001 FERRON F. OT003
DORÉ A. L18 FERSING C. OT061
DORIS E. OT023 FILOCHE-ROMMÉ B. OT045
DORR L. OT075 FIRTH M. L11
DORSCH D. UM005 FISCHER B. OT010
DOS SANTOS V. OT063 FISCHER-FODOR E. OT030
FAIÕES
FIŠER R. RB014
DOS SANTOS C. CS008
PASSOS FITZGERALD M. F. L23
DRANSART E. OT005 FLIPO M. TA004
DRIDI D. OT027 FLORENT I. OT066, OT020
DROWLEY L. L11 FLORIO C. OT019
DRUZHENKO T. OT054 FOITZIK R. C. CS002
DUBOIS L. RB012 FOSTER N. RB004
DUCA M. OT072 FREM R.C.G. OT065
DUCHER M. TA006 FRERET T. CS003
DUCKI S. OT075 FRUIT C. OT032
DUCONGÉ F. OT023 FUSCO L. RB013
DUFLOS M. OT051 GABANO E. MR006
DUGAVE C. OT050 GABORIAU F. IA001
DUMAS F. OT012 GAGNE D. OT025
DUMONT E. MR003 GALABOV A. OT021
DUPUIS E. RB003 GALLUD A. IA004
DURAISWAMY A. J. OT035 GALLY J.-M. OT014
DURAND G. OT028 GAMOND A. IA003
DUREUIL C. OT045 GANAME D. CS002
DUROUX J.-L. IA003 GAO B. OT050
DURROUX T. RB003 GARBUZ P. OT054
DUSSURGET O. OT085 GARCIA M. IA004
ECKERT A. UM004 GARCIA- C. OT045
EL-AHMAD Y. OT045 ECHEVERRIA
GARNIER C. OT051
ELLIOTT A. G. IA002
GASTREICH M. CS004, UM003
ENGKVIST O. L11
GAUTHIER F. OT024
ESDAR C. UM005
GAVEN F. CS003
ESTEVE M.-A. TA003
GAWRYCHOWSKI K. TA006
EVERTSSON E. RB011
GELIN M. OT085, IA007
FABBRO D. RB013
GELLIS A. OT062
FAGNÈRE C. IA003, RB018
GEMBUS V. TA001, OT006
FALK H. CS002
GER M. MR007
FARGE M. TA009
GERAETS J. OT002, OT015
FASSY F. OT045
GERISCH M. L23
FEHRENTZ J.-A. OT025
GHIASI S. RB015
FELIU L. OT018
GIANNONI P. CS003
FELTEN A.-S. OT056
GIELEN-HAERTWIG H. L23
FERDOUSI M. OT043
GIORIA S. OT079
FERRER J.-L. IA007
- 268 -
GIZZI P. OT079 HENRY A. OT034
GLADYSZ R. OT029 HERMANS S. J. CS002
GODEAU J. OT032 HERNANDEZ J. MR003
GOLIB F. OT014 HIBERT M. RB003
GONZALEZ G. OT078 HIENZSCH A. RB006, RB010
GÓRA M. OT055 HINZ S. CS004
GORULIA O. OT011 HO S. Y. OT035
GOTTHARDT M. OT007 HOH F. IA007
GOUIN S. IA001 HOLMES I. P. CS002
GOUMANS M. J. L11 HONG J. R. TA008
GOURAND F. OT034 HONG S. OT036
GOUVERNEUR V. OT081 HOUNSOU C. RB003
GRAEDLER U. UM005 HUDSON A. L. OT043
GRAILLE E. MR005 HUNT P. RB004
GRANET R. OT064 HUSBANDS S. M. TA002
GRAVEL E. OT023 HUTEAU V. OT085
GREINER H. UM005 HUTTER S. MR001, OT061,
OT062
GRELLIER P. MR001
HUVELLE S. OT037
GROZAV(IGNAT) A. OT030, OT031
ILGIN S. OT074
GRUSOVIN J. CS002
IMINOV R. OT038
GRYGORENKO O. OT052
INGLIS A. RB013
GUICHOU J.-F. IA007, MR005
ISABELLE C. IA001
GUILLON J. MR001
IVANCICH A. RB007
GUILLOUZO C. OT017
IVANOV I. OT039
HADJ-KADDOUR K. RB019
IVANOV V. OT038, OT040
HADRAVOVÁ R. RB014
IVASHCHENKO Y. OT007
HAJRI M. OT078
IVON Y. OT052
HALLÉ F. UM004
JAGU E. OT044
HAMAÏ A. RB006
JAMET H. OT073
HAMON Y. OT024
JANE S. M. CS002
HANDZLIK J. MR002
JANEZIC M. CS009
HANGANU D. OT031
JEANMART S. OT041
HANING H. L23
JIRICEK J. L15
HANTOUSHZADEH S. RB015
JOHANNES L. OT005
HANY R. OT079
JONEBRING A. L11
HARARI M. OT032
JOOSSENS J. OT029
HARRENGA A. L23
JOURDAN M.-L. OT017
HARRIS D. J. L16
JUHASZ M. OT016
HASHIMOTO Y. L09
JULLIEN L. OT037
HASSAN L. RB018
JUNG M.-L. RB008
HEDSTROM U. RB011
KABASHIN A. TA003
HEINRICH B. L05
KABRI Y. OT063, OT077
HEINRICH T. UM005
KAMIŃSKI K. OT055
HEMLEY C. F. CS002
KANNUNA A. RB016
HENDRIKS C.M.M. OT033
- 269 -
KAPLAN E. MR005 LAGET M. OT061
KAPLANCIKLI Z. A. OT074 LAGIAKOS H. R. CS002
KARCHER G. TA005 LALIES M. OT043
KARPENKO I. RB003 LAMANDE-LANGLE S. TA005
KARTHAUS D. L23 LAMBEIR A.-M. OT029
KASSAB I. RB019 LAMBIN P. RB012
KE Z. OT035 LANG D. L23
KELLER T. H. OT035 LANGENFELD F. RB005
KEMAL Y. UM009 LANGER T. TA007, RB008
KERSTEN W. J. CS002 LANZADA G. OT062
KEUM G. TA008 LÁTAL T. RB014
KHEYLIK Y. CS005 LATTARD V. RB005
KHOUMERI O. OT078 LAURENT A. IA003
KIEC-KONONOWICZ K. MR002 LAURENT S. IA005
KIM J. H. TA008 LAURILA J. M. OT043
KIRSCH G. OT027, OT026 LAVIELLE S. SC01
KLEIN C. UM004 LE PAPE P. MR001
KLYMCHENKO A. RB003 LEBAN N. MR005
KO M.-C. TA002 LECOUTEY C. CS003
KOKHAN S. OT053 LEE J. OT036
KOLAR M. OT084, RB014 LEE K. C. OT049
KOMAROV I. OT052, OT053, LEE M. A. OT035
OT039, OT040
LEGER D. OT064
KONDA S. K. RB009
LEGIGAN T. OT013, OT059
KONDRATOV I. OT042, OT038,
OT052, OT011, LEHMANN A. OT043
UM007, CS005
LEJRI I. UM004
KONG W. TA009
LELANDAIS B. OT023
KORKMAZ B. OT024
LEPVRIER E. OT051
KORNICKA A. OT043
LESSENE R. CS002
KOROLYOV O. OT053
LETALLEC J.-P. OT045
KOSTOVA V. OT005
LEVACHER V. OT034, TA001,
KOTEK J. IA005 OT032, OT006
KOVALENKO S. OT083 LEVER S. RB011
KRASAVIN M. CS005 LEVI HEVRONI B. OT010
KRASNY L. OT084, RB014 LEYCHENKO E. OT052
KUBBUTAT M. H. TA007 LEYSEN D. OT002, OT015
KUBRAK I. TA006 LEYSSEN P. OT076
KUBYSHKIN V. OT052, OT038 LI V.-J. L23
KÜPPERS P. CS004 LIAGRE B. OT064, IA003,
RB018
KVIST A. L11
LIAN L.-Y. OT075
LABESSE G. OT085, IA007
LIM E. J. TA008
LABROSSE J.-R. OT045
LIONNE C. MR005, MR008
LABRUERE R. OT044
LIPINSKI P. F. J. OT046
LACLEF S. OT032
LISOWSKI V. IA004
LACOLLEY P. TA005
LOEWEN P. C. RB007
- 270 -
LÖHN M. OT007 MEGANEM F. OT027
LOISEAU P. OT044 MEHRPOUR M. RB006
LONN H. RB011 MEIBOM D. L23, L12
LOVECKÁ P. RB014 MELONE A. RB013
LUCIE L. CS008 MENET C. L22
RYCKEWAERT
MENSAH G. UM004
LUKES I. IA005
MENSAH S. TA003
LUNNISS G. E. CS002
MERABTENE S. OT012
LUNVEN L. OT047
MESSINIS D. E. CS006
LUSTIG K. L23
MESSOUSSI A. CS007
M’KADMI C. OT025
METWALLY K. TA003
MACKEY M. UM002
MEUILLET E. J. TA009
MADAN B. OT035
MICHURIN O. OT052
MAI T. T. RB006, RB010
MIKHALCHUK V. OT039
MAIGRET B. OT067
MILANOLE G. OT050
MAILLARD L. IA004
MILKOVA T. OT069
MAINGOT M. OT025
MITIUK A. OT053
MAITRE M. UM004
MITTENDORF J. L23
MALECKI M. TA006
MITYUK A. OT054
MANENTE F.A. OT065
MOARBESS G. RB019
MANOHARAN V. OT035
MOGEMARK M. RB011
MARCHAND P. OT048
MOHAMADI A. TA005
MARGINEDAS I. UM004
MONAHAN B. J. CS002
MARHADOUR S. OT048
MONTERO M.-P. SC01
MARIANI A. OT049
MONTESINOS E. OT018
MARIE J. OT025
MONTOIR D. OT051
MARIE P.-Y. TA005
MOREAU S. MR001
MARIN P. OT075
MORICE C. TA007, RB008
MARK B. L. OT013
MORROW B. J. CS002
MARKOVA V. OT021
MOUCHET E. L11
MARSAIS F. TA001
MOUNE M. TA004
MARSHALL F. L18
MOURA T.R. OT065
MARSOL C. OT079
MOURAY E. MR001
MARTINEZ J. OT025, IA004
MULLER R.N. IA005
MARTIROSOV R. OT011
MULLER S. L01
MARY S. OT025
MÜLLER C. E. CS004
MASKALI F. TA005
MULLIÉ C. MR001
MASQUÉFA C. RB019
MUNCK AF M. RB011
MASURIER N. IA004
ROSENSCHOLD
MATHIEU M. OT045 MUNOZ L. SC02
MATVIIUK T. OT083 MYKHAILIUK P. OT052, OT053,
OT054, OT038,
MAURO A.E. OT065
OT039, OT040,
MBAKIDI J.-P. OT064 OT011
MCCORT G. OT045 NAHORI M.-A. OT085
MCSWEENEY G. OT081 NAM G. TA008
- 271 -
NARJES F. RB011 PARKER M. W. CS002
NATOLI A. CS002 PARVATHANENI N. K. RB012
NAUMCHYK V. CS005 PASQUIER B. OT045
NEMEIKAITĖ- A. MR007 PATEL J. L18
ČĖNIENĖ
PATIN D. OT034
NETTO A.V.G. OT065
PATINOTE C. OT022
NEYTS J. OT076
PATINY L. UM007
N'GOMPAZA DIARRA J. MR003
PAVLENKO S. OT053
NIKAC M. CS002
PEAT T. S. CS002
NIKFAR S. RB015
PEDERSEN J. OT024
NITTI P. OT019
PEEL S. L11
NIVINSKAS H. MR007
PEETERS S. RB012
NOMME J. TA009
PELIN M. OT019
NOMURA S. L08
PELLEGRINI-MOÏSE N. OT067
NORBERG M. RB011
PENDHARKAR V. OT035
NORDQVIST A. L11
PERDIH A. CS009
NOVOTARSKYI S. UM007
PERLMUTTER D. H. OT058
NURISSO A. OT073
PERRUCCIO F. OT041
NURISSO A. RB016, CS008
PERTZ O. RB013
OBNISKA J. OT055, OT068
PETHE S. OT044
OBRECHT A. OT079
PETIT C. CS008
OBSZYNSKI J. OT056
PETRENKO A. E. UM007
OPALINSKI I. OT059
PEUCHMAUR M. OT047
OPREA T. L13
PEYROTTES S. MR008
O'REILLY L. P. OT058
PFLIMLIN E. RB003
OSARETIN J. OT057
OSAYANDE PHILLIPS D. R. RB009
OSELLA D. MR006 PIANTANIDA I. OT060
OSTUNI M. UM004 PIHAN E. OT014
OTREBSKA-MACHAJ E. MR002 PILLING P. CS002
OUKACHA D. OT012 PIN J.-P. RB003
PAE A. N. TA008 PINAUD N. MR001
PAGÈS J.-M. MR002, MR003, PINON A. IA003, RB018
MR004
PAGNIEZ F. MR001 PINSON J.-A. CS002
PAILLASSE M. R. TA009 PINTIALA C. TA004
PAK S. C. OT058 PIROCCHI M. IA007
PALE P. OT056 PLANAS M. OT018
PANOVA N. OT084, RB014 PLATONOV M. CS005
PAOLETTI J. OT085 PLETTENBURG O. OT007
PAPAMICAËL C. OT034, TA001, PLIAKA V. CS006

OT006 PLOWRIGHT A. L11
PAPOT S. OT059 POCHET S. OT085
PARAMBATH A. OT023 POGORELCNIK B. CS009
PARDALI K. RB011 POHL R. RB014
PARHOMENKO A. OT011 POMEL S. OT044
- 272 -
POUGET C. IA003, RB018, RYBKA S. OT055, OT068
OT064
RYCKEWAERT L. RB016
POULSEN A. OT035
SACCONNAY L. RB016, CS008
POUSSIER S. TA005
SĄCZEWSKI F. OT043
PRIET S. OT003
SĄCZEWSKI J. OT043
PRIMAS N. OT061, OT062,
OT063 SAEZ-AYALA M. OT003
SÁEZ-CALVO G. RB013
PROCIDA G. OT019
SAKELLAROPOULOS T. CS006
PROTA A. E. RB013
SAMPIETRO D. A. IA006
PUGLIESE L. UM006
ŠANDEROVÁ H. RB014
QIU S. OT064
SANGTHONGPITAG K. OT035
RACHEDI Y. OT012
SAURAT T. OT017
RAGEOT D. RB013
SAVCHUK T. OT052
RAHIMOVA R. MR008
SAVICH V. OT039
RAMIANDRASOA F. OT044
SAVRIMOUTOU S. MR001
RANDAZZO G. M. CS008
SCHABIKOWSKI J. MR002
RAPACZ A. OT055, OT068
SCHÄCHTELE C. TA007
RATHELOT P. OT061
SCHÄFER M. L23
RAVERA M. MR006
SCHÄFER S. L23
REGNAULT V. TA005
SCHAMBERGER J. L23
REJMAN D. RB014, OT084
SCHEININ M. OT043
RENOUX B. OT059
SCHIMDT F. OT037
REVELANT G. OT066
SCHIO L. OT045
REZAEIZADEH G. RB015
SCHMIDT F. OT005
RICHARD M. OT067
SCHMITT M. UM004
RIO P. OT017
SCHMITT M. OT066, OT020
RIOUX B. IA003, RB018
SCHNEIDER S. UM004
RIPOCHE I. OT075
SCHROEDERS P. OT002, OT015
RIVERA S. OT050
SEGALL M. RB004
RIVES A. TA009
SEMAAN J. IA003, RB018
ROCHA F.V. OT065
SEO S. H. TA008
ROCHAIS C. SC03, CS003
SEYDLOVÁ G. RB014
ROCHE M. OT076
SGARIGLIA M. A. IA006
RODRIGUES N. OT017
SHCHERBATIUK A. OT011, OT038
RODRIGUEZ R. L21, OT049,
RB006, RB010 SHYSHLYK O. OT011
RONAN B. OT045
SIEGAL G. UM008
RONGA L. MR001
ŠIKOVÁ M. RB014
ROSENTRETER U. L23
SILVA M. M. RB017
ROSSELIN M. OT028
SILVERMAN G. A. OT058
ROUSSAKIS C. OT048
SILVESTRI R. OT076
ROUSSEAU B. OT048
ŠIMÁK O. RB014
ROUSSEAU B. OT050
SIMOES-PIRES C. RB016, CS008
ROUTIER S. OT017
SIMON J.-M. RB008
ROUX L. OT003
SIMON A. IA003, RB018
RYBCZYŃSKA A. OT043
SKUBIS-ZEGADLO J. TA006
- 273 -
SLOBODYANUK E. OT040 TKACHENKO A. OT038
SMITH D. G. OT081 TKACHUK G. OT011
SOBERÓN J. R. IA006 TLOUSTOVA E. OT084
SOFIA M. L19 TOLL L. TA002
SOKOLIUK P. OT042 TOLMACHEV A. OT052, OT053,
OT054, OT038,
SOL V. OT064, IA003,
OT039, OT040,
RB018
OT011
SOLMAJER T. CS009
TOLMACHOV A. OT042
SOMAGLINO L. TA003
TOMASIO S. UM002
SONDEREGGER S. E. CS002
TOMASONI C. OT048
SONNET P. MR001
TOMULEASA C. I. OT030
SOUGAKOFF W. RB007
TONNERRE A. OT051
SOULIÉ M. TA003
TOSCO P. UM002
STAMATATOU S. CS006
TOTZKE F. TA007
STANKOVA I. OT021
TOULMIN E. CS002
STEINMETZ M. O. RB013
TRAN N. C. TA004
STÉPHANIE R. IA001
TRAN T. P. OT072
ŠTÍCHA M. OT069 A.
STOYKOVA B. OT069 TRAORE M. OT073
STREET I. P. CS002 TREDWELL M. OT081
STUPPLE A. E. CS002 TRINQUET E. RB003
STUPPLE P. A. CS002 TROFYMCHUK S. OT052, OT038
STUTZMANN A. MR004 TSCHAMMER N. OT001
SUPURAN C. T. RB012 TUCCIO B. OT028
SURLERAUX D. OT004 TUÑÓN I. RB001
SUSHKO Y. UM007 TURAN-ZITOUNI G. OT074
SVENSSON B. TA007 TYMTSUNIK A. OT052, OT053
SZYMAŃSKA E. MR002 TYZACK J. RB004
TABBI A. OT074 TZVETKOV N. T. CS004
TABÉLÉ C. OT063 UESUGI M. L06
TAN E. S. OT035 VADLAMANI G. OT013
W. VAILLAND O. IA004
TARNUS C. OT066, OT020
VALADE E. MR004
TAULIER N. TA003
VALENCIA C. OT079
TCHERTANOV L. RB005
VALIUS M. MR007
TEHAN B. L18
VALLON G. OT075
TELAN L. A. L23
VAN DER VEKEN P. OT029
TEODORE D. UM009
VAN KUIJK S. RB012
TERESHENKO O. OT052
VAN LINDEN O. UM008
TERME T. OT076, OT077,
OT078 VANDER ELST L. IA005
TERSTEEGEN A. L23 VANELLE P. OT061, OT062,
TETKO I. V. OT070, OT071, OT063, OT076,
UM007 OT077, OT078
VARBANOV H. P. OT071
THEODOROU I. OT023
VASILJEVA J. CS001
THISTLETHWAITE A. CS002
VATTUONE M. A. IA006
ŢÎNŢAŞ M.-L. OT006
- 274 -
VECEROVA R. OT084, RB014 ZBORNIKOVA E. OT084, RB014
VERHAEGHE P. OT061, OT062 ZEMEK O. IA005
VERHOOG S. OT081 ZGHAIB Z. RB019
VESELINOVA V. OT021 ZHANG S. TA009
VIAUD-MASSUARD M.-C. OT024 ZOZULYA S. CS005
VIEIRA S. D. RB017 ZUBRIEN A. CS008
VILCHINSKIY V. OT052 ZUEGG J. IA002
VILLA P. OT079 ZVELEBIL M. RB013
VILLAMENA F. A. OT028
VINCENDEAU P. MR001
VINCENT L.-A. RB019
VIRSHUP D. M. OT035
VO D. D. OT072
VON NUSSBAUM F. L23
VRIJDAG J. OT080
WAI J. L20
WALKER S. R. CS002
WALSE B. TA007
WANG Q.-D. L11
WASILEWSKA A. OT043
WEIBEL J.-M. OT056
WEINHOLD E. OT016
WHITE K. L. CS002
WIKLIK-POUDEL B. OT068
WILLAND N. TA004
WILLIAMS R. L. RB013
WILSON T. OT081
WINUM J.-Y. RB012
WLOCHAL J. OT082
WOLF A. OT007
WOZNIAK M. TA006
WUCHERER- M. UM005
PLIETKER
WYMANN M. P. RB013
YANG H. CS002
YARMOLCHUK V. OT038, OT039,
OT011
YAROMINA A. RB012
YASRI A. CS007
WONG Y-S OT073
YURTTAS L. OT074
ZACCHIGNA M. OT019
ZAHANICH I. CS005
ZAHARIA V. OT030
ZAITSEVA A. OT083
ZANELLATO I. MR006
- 275 -
NOTES
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- 276 -
BookRICT.indd 130 15/06/2015 12:23:00

THE EXPANDING TOOLBOX OF

MEDICINAL CHEMISTRY
From Chemical Biology to
EXECUTIVE COMMITTEE
Dr C. CONTINO-PEPIN (University of Avignon, France)
Clinical Applications
Prof. P. DALLEMAGNE (University of Caen, France)
Dr G. DURAND (University of Avignon, France) PARC DES EXPOSITIONS ET CONGRES
Prof. H. GALONS (SCT & Paris Descartes University, France) OCTOBER 16, 2015 - DIJON, FRANCE
Dr P. GEORGE (SCT & Independent Scientific Expert & Adviser, France)
Prof. J. SAPI (SCT & University of Reims-Champagne-Ardenne, France)
Dr L. VAN HIJFTE (SCT & NovAliX, France) This symposium, jointly organised by the Société de Chimie Thérapeutique (SCT) and the Division of Medicinal
Chemistry & Chemical Biology (DMCCB) of the Swiss Chemical Society, will discuss significant advances that
LOCAL ORGANISING COMMITTEE are part of the expanding scope of Medicinal Chemistry. A panel of experts will highlight these developments in
Mrs A. BARRIERE (Maison de la Recherche, University of Avignon, France)
Dr F. BONNETE (CNRS, Institut des Biomolécules Max Mousseron (IBMM)-University of Avignon, France)
the areas of chemical biology, metabolite pattern optimization, structural biology, analytics and clinical
Dr C. CONTINO-PEPIN (University of Avignon, France) imaging tracers with specific examples.
Dr G. DURAND (University of Avignon, France)
Dr P. GUILLET (University of Avignon, France)
Mr S. RAYNAL (University of Avignon, France) PROGRAMME
Mrs V. VIDAU (University of Avignon, France)
New Therapeutic Modalities to Unleash Pharma Drug Discovery
SCIENTIFIC ADVISORY BOARD
Dr J.-L. BANERES (Institut des Biomolécules Max Mousseron (IBMM), France)
Dr Carlos GARCIA-ECHEVERRIA (SANOFI, Vitry sur Seine, France)
Prof. R. BUREAU (University of Caen, France)
Dr K. BUSH (Indiana University, United States) Learning New Things About Old Drugs: Sulfa Drugs and Tetrahydrobiopterin Biosynthesis
Prof. E. M. CARREIRA (ETH Zürich / SpiroChem, Switzerland) Prof. Kai JOHNSSON (SWISS FEDERAL INSTITUTE OF TECHNOLOGY IN LAUSANNE (EPFL), Lausanne, Switzerland)
Dr P. CHENE (Novartis, Switzerland)
Dr R. COOKE (Heptares, United Kingdom)
Dr C. DOUSSON (Idenix Pharmaceuticals, France) Using Aged Drugs in New Ways, the Concept of Boosting Antibiotics
Prof. P. DUMY (Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), France) Prof. Nicolas WILLAND (UNIVERSITY OF LILLE, Lille, France)
Prof. E. GIRALT (Institute for Research in Biomedicine (IRB), Spain)
Dr J.-C. HARMANGE (Constellation Pharmaceuticals, United States)
Dr J.-M. JIMENEZ (Vertex Pharmaceuticals, United Kingdom) Uncovering and Mitigating Clearance in Early Discovery: New Technologies, New Opportunities, New Mindset
Prof. H. KAGECHIKA (Tokyo Medical and Dental University, Japan) Dr Alfred ZIMMERLIN (NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, Basel, Switzerland)
Prof. D. KIREEV (University of North Carolina, United States)
Dr U. LUCKING (Bayer HealthCare, Germany)
Dr B. MIROUX (University Paris Diderot - Institut de Biologie Physico-Chimique (IBPC), France) Discovery and Development of LC-MS/MS-Based Occupancy Tracers and Positron Emission Tomography
Prof. J. MITTENDORF (Bayer Pharma, Germany) Radioligands
Prof. N. MIYATA (Nagoya City University, Japan) Dr Vanessa Nicole BARTH (ELI LILLY, Indianapolis, United States)
Dr M. MOUREZ (Sanofi-Pasteur, France)
Dr M. NILGES (Pasteur Institute, France)
Dr M. OKANIWA (Takeda Pharmaceutical Company, Japan) Radiotracer Development in the Era of Personalized Medicine: When MedChem Meets Nuclear Medicine
Dr J.-M. PAGES (Aix Marseille University, France) Prof. Roger SCHIBLI (SWISS FEDERAL INSTITUTE OF TECHNOLOGY (ETH), Zürich, Switzerland)
Prof. E. PEBAY-PEYROULA (University Joseph Fourier, France)
Prof. J. ROBINSON (University of Zürich, Switzerland)
Dr H. SHEN (Roche, China)
Dr P. SJÖ (AstraZeneca, Sweden) www.sct-dmccb2015.org
Prof. H. SUGA (University of Tokyo, Japan)
Dr P. P. TAK (EFPIA, United Kingdom)
Dr H. VAN VLIJMEN (Janssen, Belgium) Organising Committee Symposium Secretariat
Dr R. VAZ (Sanofi-Genzyme, United States) Prof. K.-H. ALTMANN (SCS DMCCB & Swiss Federal Institute of Technology, Switzerland) LD Organisation sprl
Prof. S. WANG (University of Michigan, United States) Dr Y. P. AUBERSON (SCS DMCCB & Novartis, Switzerland) Scientific Conference Producers
Dr G. WECKBECKER (Novartis, Switzerland) Dr P. GEORGE (SCT & Independent Scientific Expert & Adviser, France) Rue Michel de Ghelderode 33/2
Dr J. Z. ZHU (UCB, United Kingdom) Prof. J.-L. REYMOND (SCS DMCCB & University of Bern, Switzerland) 1348 Louvain-la-Neuve, Belgium
Prof. J. SAPI (SCT & University of Reims-Champagne-Ardenne, France) Tel: +32 10 45 47 77 - Fax: +32 10 45 97 19
WWW.SCT-ASSO.FR WWW.RICT2015.ORG Prof. A. TARTAR (SCT & University Lille 2, France) secretariat@ldorganisation.com
RICT15-CoversBook-HD.indd 2 Depliant-SCT-DMCCB.indd 1 3/04/2015 10:28:00

11/06/15 13:14
PROGRAMME AT A GLANCE

WEDNESDAY JULY 01, 2015
10:00 Registration
Auditorium AT03
Elsevier Reaxys Workshop : Data-Driven Approaches to Medicinal
11:00
Chemistry : How Large-Scale Normalized Data Empowers Drug Discovery
Auditorium AT02
Opening Ceremony
SESSION 1 : Paul Ehrlich Award Lecture - Sponsored by Janssen-Cilag
13:30 L01 - S. Muller
SESSION 2 : Kinases & Oncology - Sponsored by Servier
14:30 L02 - J.D. Charrier
15:15 L03 - T. Barf
SESSION 3 : Resistance in Infectious Diseases
16:30 L04 - P. Courvalin
17:15 L05 - J. Bilello
18:00 Welcome Reception
THURSDAY JULY 02, 2015

Auditorium AT02
SESSION 4 : Tools for Cell Therapy
08:30 L06 - M. Uesugi
SESSION 5 : Short Communications - Targeting Apoptosis - Sponsored by SCT SESSION 6 : Short Communications - CNS Diseases - Sponsored by SCT
09:30 SC01 - I. Alves SC03 - C. Rochais
10:00 SC02 - L. Munoz SC04 - F. Bihel
SESSION 7 : Diabetes SESSION 8 : Tools for Target ID
11:15 L07 - R. Deprez-Poulain L09 - Y. Hashimoto
© Chiugoran
12:00 L08 - S. Nomura L10 - P. Brennan
13:30 Poster Session 1 (odd numbers)
13:45 Career Session (Room OE32)
SESSION 9 : Cardiac Diseases SESSION 10 : Structure Based Approaches
Sponsored by 'Fondation de la Maison de la Chimie'
14:45 L11 - A.T. Plowright L13 - T.I. Oprea
JULY 1-3, 2015 | AVIGNON, PROVENCE, FRANCE

15:30 L12 - D. Meibom L14 - P. Bonnet
SESSION 11 : Neglected/Rare Diseases SESSION 12 : GPCRs
16:45 L15 - J. Jiricek L17 - J. Carlsson
17:30 L16 - D.J. Harris L18 - J. Christopher
FRIDAY JULY 03, 2015

Auditorium AT02
SESSION 13 : Viral Diseases
08:30 L19 - M. Sofia ORGANISED BY
09:15 L20 - J. Wai

10:30 Poster Session 2 (even numbers)
SESSION 14 : Pierre Fabre Award Lecture - Sponsored by Pierre Fabre SOCIÉTÉ DE CHIMIE THÉRAPEUTIQUE (SCT)
11:45 L21 - R. Rodriguez
SESSION 15 : Immuno/Inflammatory Diseases - Sponsored by GSK
13:30 L22 - C. Menet
14:15 L23 - F. Von Nussbaum
SESSION 16 : Poster Prizes and Closing Remarks
WITH THE SUPPORT OF
SESSION 17 : Future Events and Closing
SECRETARIAT RICT 2015

LD ORGANISATION | Scientific Conference Producers | Tel: +32 10 45 47 77 | Fax: +32 10 45 97 19 | secretariat@LDOrganisation.com
WWW.SCT-ASSO.FR WWW.RICT2015.ORG
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PROGRAMME AT A GLANCE

51ST INTERNATIONAL CONFERENCE ON MEDICINAL CHEMISTRY

DRUG DISCOVERY AND SELECTION - UNDERSTANDING TARGETS AND MECHANISMS

THURSDAY JULY 02, 2015

JULY 1-3, 2015 | AVIGNON, PROVENCE, FRANCE

FRIDAY JULY 03, 2015

09:15 L20 - J. Wai

SECRETARIAT RICT 2015

RICT15-CoversBook-HD.indd 1 11/06/15 13:14

THE EXPANDING TOOLBOX OF

RICT15-CoversBook-HD.indd 2 Depliant-SCT-DMCCB.indd 1 11/06/15

Prof. Janos Sapi

Dr Luc Van Hijfte

BookRICT.indd 1 15/06/2015 12:02:37

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1: HyphaDiscovery 12: Biotage 23: Chemical Computing Group

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Sponsors and Supporters 3

Premium Exhibitors, Exhibitors and Media Partners 4

Plenary Lectures: Abstracts and Biographies 19

Short Communications: Abstract and Biographies 67

POSTERS: Integrative Approaches 77

POSTERS: Mechanisms of Resistance 87

POSTERS: Revealing Biological Mechanisms 97

POSTERS: Translational Approaches 119

POSTERS: Understanding of the Molecular Space 131

POSTERS: Case Studies 143

POSTERS: Others 155

Exhibitors: Company Descriptions 243

List of Abstracts 253

Index of Authors 263

List of Participants 277

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Further information will soon be available

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Wednesday July 1, 2015

11:00 Elsevier Reaxys Workshop: Data-Driven Approaches to Medicinal Chemistry: How

13:15 Welcome Address

Session 1: Paul Ehrlich Award Lecture

Session 2: Kinases & Oncology

15:15 L03 - Covalent Kinase Inhibitors: A Practical Guide to Molecular Trapping

16:00 Coffee Break & Exhibition

Session 3: Resistance in Infectious Diseases

16:30 L04 - Antibiotic Resistance is an Emerging Disease

17:15 L05 - Resistance Phenotypes and SAR in HCV Drug Development

18:00 Welcome Reception (until 19:30)

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Thursday July 2, 2015

Session 4: Tools for Cell Therapy

Session 5: Short Communications - Session 6: Short Communications -

Session 7: Diabetes Session 8 : Tools for Target ID

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12:45 Lunch & Exhibition

13:30 Poster Session 1 (Odd numbers)

Auditorium AT02 Auditorium AT03

Session 9: Cardiac Diseases Session 10: Structure Based