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We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt inhibitors. 5'-Substituents involving (methylsulfonyl)methyl, (Nmethylsulfamoyl) methyl, cyanomethyl, (1H-tetrazol-5-yl)methyl were... more
We report the synthesis of 5'-modified and 5,5'-modified thymidine analogues as TMPKmt inhibitors. 5'-Substituents involving (methylsulfonyl)methyl, (Nmethylsulfamoyl) methyl, cyanomethyl, (1H-tetrazol-5-yl)methyl were combined with a 5-methyl or a 5-hydroxymethyl group at the pyrimidine moiety. The successful synthesis of the bis-substituted analogues will be discussed as well as the capacity of the target analogues to inhibit TMPKmt.
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Research Interests: Chemistry, Organic Chemistry, Enzyme Inhibitors, Medicine, Glycoside hydrolase, and 11 moreIn Vitro, Amines, Stereochemistry, Molecular Conformation, Bioorganic and medicinal Chemistry, Biological activity, Structure activity Relationship, Chemical Synthesis, Amine, Substituent Effect, and Pharmacology and pharmaceutical sciences
Research Interests: Biochemistry, Microbiology, Chemistry, Organic Chemistry, Developmental Biology, and 15 moreBiology, Malaria, Pharmacokinetics, Medicine, Fr, Prodrugs, Escherichia coli, Inhibition, Fosmidomycin, Prodrug, Medicine and Health Sciences, Analogs, HUMAN MEDICINE, Pharmacology and pharmaceutical sciences, and antitubercular activity
Research Interests: Microbiology, Chemistry, Organic Chemistry, Biofilms, Pathogenesis, and 15 moreMRSA, Medicine, Biofilm, Discovery, Drug Design, Quorum Sensing, Antimicrobial, Gallic acid, Antibiotics, Microbial Sensitivity Tests, Antibiotic, Ligands, Quorum Sensing Inhibitor, Methicillin Resistant Staphylococcus Aureus, and Pharmacology and pharmaceutical sciences
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Research Interests: Chemistry, Forensic Science, Metabolism, Chromatography, Magnetic Resonance Spectroscopy, and 14 moreMedicine, Multidisciplinary, Identification, Humans, Methamphetamine, NPS, Ecstasy, High Performance Liquid Chromatography, Elucidation, Rat, Gas Chromatography/mass Spectrometry, Designer Drugs, Medicine and Health Sciences, and Molecular Structure
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For the last decades, antibacterial research and development has focused on drugs that kill bacteria or inhibit their growth by interfering with essential cellular processes. Conventional antibiotics inherently impose selective pressure... more
For the last decades, antibacterial research and development has focused on drugs that kill bacteria or inhibit their growth by interfering with essential cellular processes. Conventional antibiotics inherently impose selective pressure on bacteria and microbial drug resistance constitutes a complex global public health challenge. In this project we aim to design small molecules that potentiate the effect of existing antibiotics. More specifically, we want to synthesize compounds that target virulence factors and biofilm formation in Staphylococcus aureus and hence sensitize ‘golden staph’ towards antibiotic treatment. With careful consideration, we believe that these “antivirulence” drugs have a lower propensity to select for resistance.
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A library of 52 hamamelitannin analogues was synthesized and investigated for its ability to potentiate the effect of vancomycin toward Staphylococcus aureus biofilms. Several compounds were found to effectively increase the... more
A library of 52 hamamelitannin analogues was synthesized and investigated for its ability to potentiate the effect of vancomycin toward Staphylococcus aureus biofilms. Several compounds were found to effectively increase the susceptibility of staphylococcal biofilms toward this glycopeptide. The most active analogue identified in this study showed an EC50 value of 0.26 μM.
Research Interests: Biochemistry, Microbiology, Chemistry, Organic Chemistry, Biofilms, and 15 moreBiotechnology, Biology, Ecology, Medicine, Biofilm, Quorum Sensing, Ability, Antibiotics, Bacterial Biofilms, Analogues, Medicine and Health Sciences, Mix, Methicillin Resistant Staphylococcus Aureus, HUMAN MEDICINE, and Pharmacology and pharmaceutical sciences
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Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to its catalytic functions during mitosis and due to stabilisation of the key oncoprotein MYCN. We report a small structure-activity relationship (SAR) study... more
Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to its catalytic functions during mitosis and due to stabilisation of the key oncoprotein MYCN. We report a small structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and both the 4- and 5-position as thalidomide exit vectors. PROTAC SK2188 induces the most potent AURKA degradation (DC50, 24h < 10 nM, Dmax, 1h 98%, Dmax, 24h, 80%) and significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for f...
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The lack of selectivity and low solubility of many chemotherapeutics impels the development of different biocompatible nanosized drug carriers. Amphiphilic block copolymers, composed of a hydrophilic and hydrophobic domain, show great... more
The lack of selectivity and low solubility of many chemotherapeutics impels the development of different biocompatible nanosized drug carriers. Amphiphilic block copolymers, composed of a hydrophilic and hydrophobic domain, show great potential because of their small size, large solubilizing power and loading capacity. In this paper, we introduce a new class of degradable temperature-responsive block copolymers based on the modification of N-(2-hydroxypropyl)methacrylamide (HPMA) with an ethyl group via a hydrolytically sensitive carbonate ester, polymerized by radical polymerization using a PEG-based macroinitiatior. The micellization and temperature-responsive behavior of the PEG-poly(HPMA-EC) block copolymer were investigated by dynamic light scattering (DLS). We observed that the polymer exhibits lower critical solution temperature (LCST) behavior and that above the cloud point (cp) of 17 °C the block copolymer self-assembles in micelles with a diameter of 40 nm. Flow cytometry analysis and confocal microscopy show a dose-dependent cellular uptake of the micelles loaded with a hydrophobic dye. The block copolymer nanoparticles were capable of delivering the hydrophobic payload into cancer cells in both 2D and 3D in vitro cultures. The block copolymer has excellent cytocompatibility, whereas loading the particles with the hydrophobic anticancer drug paclitaxel results in a dose-dependent decrease in cell viability.
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ABSTRACT The design, synthesis and application of oxabicyclo[4.1.0]heptane amino acids as conformationally restricted sugar amino acid dipeptide isosteres are reported.
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... [23] and [24], Wang et al. 26, Barker et al. 24. Claridge et al. 27. Barker et al. 24. Johnson et al. 28. Johnson et al. [29] , [30] and [31], Johnson et al. 29, Sakya et al. 32. Johnson et al. [29] , [30] and [31]. Fleet et al. 33.... more
... [23] and [24], Wang et al. 26, Barker et al. 24. Claridge et al. 27. Barker et al. 24. Johnson et al. 28. Johnson et al. [29] , [30] and [31], Johnson et al. 29, Sakya et al. 32. Johnson et al. [29] , [30] and [31]. Fleet et al. 33. Johnson et al. [29] , [30] and [31]. Fleet et al. 33. Johnson et al. ...
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The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction-transimination-sodium borohydride reduction cascade of reactions on an enantiomerically... more
The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction-transimination-sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.
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In this study we report the synthesis of C5/C6-fused uridine phosphonates that are structurally related to earlier reported allosteric P2Y2 receptor ligands. A silyl-Hilbert-Johnson reaction of six quinazoline-2,4-(1H,3H)-dione-like base... more
In this study we report the synthesis of C5/C6-fused uridine phosphonates that are structurally related to earlier reported allosteric P2Y2 receptor ligands. A silyl-Hilbert-Johnson reaction of six quinazoline-2,4-(1H,3H)-dione-like base moieties with a suitable ribofuranosephosphonate afforded the desired analogues after full deprotection. In contrast to the parent 5-(4-fluoropheny)uridine phosphonate, the present extended-base uridine phosphonates essentially failed to modulate the P2Y2 receptor.
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ABSTRACT Four isomeric bicyclic sugar amino acids (SAAs) were prepared from α-acetylenic-C-glucoside 6 by employing a Petasis olefination and a ring-closing metathesis (RCM) as key steps. The applicability of the resulting SAAs in... more
ABSTRACT Four isomeric bicyclic sugar amino acids (SAAs) were prepared from α-acetylenic-C-glucoside 6 by employing a Petasis olefination and a ring-closing metathesis (RCM) as key steps. The applicability of the resulting SAAs in solid-phase peptide synthesis was demonstrated by the synthesis of tetrapeptide 36. (© Wiley-VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)
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Research Interests: Organic Chemistry, Medicinal Chemistry, Enzyme Inhibitors, Macromolecular X-Ray Crystallography, Mycobacterium tuberculosis, and 7 moreEscherichia coli, Plasmodium falciparum, Antimalarials, Microbial Sensitivity Tests, Protein Conformation, Structure activity Relationship, and Molecular Targeted Therapy
Two synthetic strategies for the generation of delta-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of the stereochemistry of the... more
Two synthetic strategies for the generation of delta-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of the stereochemistry of the applied sulfinamide, the product formed has a stereochemistry resembling that of a d amino acid at C7. Direct Grignard reaction on formyl-tetra-O-benzyl-beta-D-C-glucopyranoside in the second strategy and subsequent Mitsunobu inversion, yields the l,l-dipeptide isosters.