ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several... more
ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
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ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several... more
ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
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14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to... more
14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monother...
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The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the... more
The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RARgamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARgamma in the activity of RRMs: F9-wild type (WT); F9gamma-/-, lacking the RARgamma gene; F9gamma51, aF9gamma-/-derivative, complemented for the RARgamma deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G2/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RARgamma and the classic retinoid pathway are not relevant for the antiproliferative and apoptotic activities of RRMs in vitr...
Research Interests: Biochemistry, Biology, Calcium, Molecular Pharmacology, Medicine, and 15 moreMolecular, Mitosis, Cercopithecus aethiops, Cell Differentiation, Humans, Mice, Animals, Cell Death, Retinoic Acid, Retinoid, Adamantane, Antineoplastic Agents, Neurosciences, Gene expression profiling, and Pharmacology and pharmaceutical sciences
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... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ; (b) GE DuBois, GA Crosby and RA Stephenson, J. Med. ... Food Chem., 1986, 34, 339 Article CAS . 12, RM Horowitz and B. Gentili, Symposium:... more
... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ; (b) GE DuBois, GA Crosby and RA Stephenson, J. Med. ... Food Chem., 1986, 34, 339 Article CAS . 12, RM Horowitz and B. Gentili, Symposium: Sweeteners, ed. GE Inglett, Avi Publ. ...
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Systematic modification of the structure of the sweet natural compound phyllodulcin, containing the isovanillyl glucophoric group, led to the synthesis of about 120 compounds. Features of the heterocyclic ring conferring high sweetness... more
Systematic modification of the structure of the sweet natural compound phyllodulcin, containing the isovanillyl glucophoric group, led to the synthesis of about 120 compounds. Features of the heterocyclic ring conferring high sweetness potency were identified. A strong increase in sweetness was obtained by the introduction of sulfur atoms in the ring and by separation of the enantiomers. Results of the quantitative structureactivity relationship (QSAR) studies on this series are reported. Application of the pseudoreceptor modeling approach afforded a three-dimensional binding site model for isovanillyl sweeteners. Extension of this methodology to a large group of structurally diverse compounds, including the commonly used sweeteners, gave a general pseudoreceptor for the sweet compounds, consisting of 16 amino acids. This pseudoreceptor, which has the peculiarity of giving a semiquantitative evaluation of the sweetness intensity, could be used as a valid tool to model the ligandre...
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Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are... more
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (γ-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlyi...
Research Interests: Biology, DNA damage, DNA repair, Medicine, Humans, and 15 moreAnimals, Cell Death, Phosphorylation, Kinase, Comet Assay, Histones, Genetic Recombination, Cell Proliferation, Molecular Cancer Therapeutics, Adamantane, DNA double strand breaks, CHO cells, Cricetinae, Chromosome aberrations, and Pharmacology and pharmaceutical sciences
The chemical structures of sweet compounds are very different, ranging from sugars to amino acids and peptides or other compounds such as saccharin. The biological mechanism underlying the generation of sweet taste is still unknown,... more
The chemical structures of sweet compounds are very different, ranging from sugars to amino acids and peptides or other compounds such as saccharin. The biological mechanism underlying the generation of sweet taste is still unknown, although in the past few years much research has provided evidence for the existence of a true chemoreception process, mediated by receptor proteins on the taste buds. In particular, the initial step of the process involves the reversible binding of the sweet compounds to their receptor(s). In this work, we have investigated this binding via a pseudoreceptor model, which has been developed using a training set of 24 compounds belonging to different families including sugars, peptides, and other intensive sweeteners. This model provided a correlation coefficient (r(2)) of 0.985 between the calculated and the experimental free energies of binding, which are related to the molar relative sweetness, for the training set and is able to predict semiquantitatively free energies of ligand binding for an independent set of five test ligand molecules within 0.3-2.1 kcal mol(-1) of the experimental values.
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Modeling, Prediction, and 15 moreMedicine, Molecular Modelling, Free Energy, Molecular Model, Binding Energy, Molecular Conformation, Guanidines, Affinity, Molecule, Ligand, Ligands, Binding affinity, binding sites, Pharmacology and pharmaceutical sciences, and organoleptic properties
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Cytotoxicity, Medicine, and 15 moreDNA, In Vitro, Humans, Mice, Animals, Stereochemistry, Quantitative Structure Activity Relationship, In Vivo, Medicinal, Lipophilicity, Camptothecin, Antitumor Activity, Antineoplastic Agents, Immunoblotting, and Pharmacology and pharmaceutical sciences
... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-ing Conditions on the Mineral Content of Korean Red Gin-seng Extract. ... Lipophilicity-Antifungal Activity Relationships for Some... more
... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-ing Conditions on the Mineral Content of Korean Red Gin-seng Extract. ... Lipophilicity-Antifungal Activity Relationships for Some Isoflavonoid Phytoalexins Anna Arnoldi' and Lucio Merlini ...
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ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugenol or coniferyl alcohol is reported. A simple diagnostic method based on 13C nmr spectra is proposed to distinguish regioisomers of natural... more
ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugenol or coniferyl alcohol is reported. A simple diagnostic method based on 13C nmr spectra is proposed to distinguish regioisomers of natural benzodioxane lignoids
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The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R... more
The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, tastes intensely sweet. The conformations of the four compounds have been studied by means of molecular modelling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of the taste, acting as an important contraint in generating the active conformation. The most important glucophores have been identified in the terminal –NH3+ and –COO– groups and in the indole ring by comparison with known topological models of sweet compounds and through the synthesis of appropriate derivatives in which some of these groups are lacking or ...
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Research Interests: Chemistry, Organic Chemistry, Medicine, HSP, Humans, and 14 moreQSAR, Mice, Female, Animals, Naphthoquinones, Quantitative Structure Activity Relationship, Protein kinase B, In Vivo, Protein Conformation, Heat Shock Protein, Antineoplastic Agents, Minimum inhibitory concentration, Pharmacology and pharmaceutical sciences, and Minimum Inhibitory Concentration
Research Interests: Chemistry, Organic Chemistry, Kinetics, Enzyme Inhibitors, Medicine, and 13 moreSynthesis, Stereochemistry, Endocannabinoid System, Enzyme, Oximes, Bioorganic and medicinal Chemistry, Endocannabinoids, Structure activity Relationship, Carbamates, Selectivity, Amidase, kinetic analysis, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Organic Chemistry, Medicine, In Vitro, Prodrugs, and 15 moreHumans, Mice, Animals, Stereochemistry, RETINOIDS, Ether, Esterases, Bioorganic and medicinal Chemistry, Cell Proliferation, Retinoid, Antineoplastic Agents, Metabolite, Glucuronidation, Pharmacology and pharmaceutical sciences, and lung neoplasms
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... Anna Arnoldi, Eliseo Bettob, Gandolfina Farinab, Attilio Formigoni', Remo Galli and Lucio Merlini ... plants and pathogens and for inoculation have been reported previously.' Compounds were tested as aqueous suspensions;... more
... Anna Arnoldi, Eliseo Bettob, Gandolfina Farinab, Attilio Formigoni', Remo Galli and Lucio Merlini ... plants and pathogens and for inoculation have been reported previously.' Compounds were tested as aqueous suspensions; solids were suspended, with a Potter homogeniser, in ...
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ABSTRACT A short and efficient synthesis of the novel cytotoxic natural product berkeleyamide A, isolated from a deep-water Penicillium rubrum, has been accomplished. L-Leucinol was used as the only chiral starting material. A... more
ABSTRACT A short and efficient synthesis of the novel cytotoxic natural product berkeleyamide A, isolated from a deep-water Penicillium rubrum, has been accomplished. L-Leucinol was used as the only chiral starting material. A diastereoselective aldol condensation is the key step in the synthesis.
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ABSTRACT
ABSTRACT
... Alberto Arnonea, Lucio Merlinib, Gianluca Nasinia, Orso Vajna de Pava*a and Franco Zuninoc. a Centro di Studio del CNR sulle Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico di Milano, via Mancinelli 7, 20131 ...... more
... Alberto Arnonea, Lucio Merlinib, Gianluca Nasinia, Orso Vajna de Pava*a and Franco Zuninoc. a Centro di Studio del CNR sulle Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico di Milano, via Mancinelli 7, 20131 ... [Omphalotus olearius Singer (CBS 164.51 ...
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... Stefania Mazzini,a Lucio Merlini,a Rosanna Mondelli,*,a Gianluca Nasini,b Enzio Ragga andLeonardo Scaglionia a Dipartimento di Scienze Molecolari Agrolimentari, Sezione di Chimica, Università degli Studi di Milano, Via Celoria 2,... more
... Stefania Mazzini,a Lucio Merlini,a Rosanna Mondelli,*,a Gianluca Nasini,b Enzio Ragga andLeonardo Scaglionia a Dipartimento di Scienze Molecolari Agrolimentari, Sezione di Chimica, Università degli Studi di Milano, Via Celoria 2, 20133 Milano, Italy b Centro del CNR per ...
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... Stefania Mazzini, Lucio Merlini, Rosanna Mondelli* and Leonardo Scaglioni. Dipartimento di Scienze Molecolari ... Although Thomson has attempted in the last edition of his book on natural ... which is called hypocrellin B,... more
... Stefania Mazzini, Lucio Merlini, Rosanna Mondelli* and Leonardo Scaglioni. Dipartimento di Scienze Molecolari ... Although Thomson has attempted in the last edition of his book on natural ... which is called hypocrellin B, notwithstanding that other authors gave this name to another ...
Research Interests: Phytochemistry, Enzyme Inhibitors, Magnetic Resonance Spectroscopy, Biological Sciences, Cell line, and 10 moreProtein Tyrosine Kinase, Phosphorylation, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, CHEMICAL SCIENCES, Structure Elucidation, Quntitative Thin Layer Chromatography, Culture Media, Lactones, BASIDIOMYCOTA, and Tyrosine Kinase
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Relevant drawbacks of the molecular structure and mechanism of the action of camptothecins are the instability of the E ring lactone and the reversibility of drug-target interaction. Such features are expected to limit the clinical... more
Relevant drawbacks of the molecular structure and mechanism of the action of camptothecins are the instability of the E ring lactone and the reversibility of drug-target interaction. Such features are expected to limit the clinical efficacy of conventional camptothecins. In an attempt to overcome these limitations and to improve the pharmacological profile of camptothecins, a novel series of seven modified
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ABSTRACT Using pseudoreceptor modelling, we have derived a three-dimensional binding-site model for the structurally uncharacterised sweet-taste receptor. The receptor model was derived based on 17 sweet compounds of the isovanillyl class... more
ABSTRACT Using pseudoreceptor modelling, we have derived a three-dimensional binding-site model for the structurally uncharacterised sweet-taste receptor. The receptor model was derived based on 17 sweet compounds of the isovanillyl class (4-methoxy-3-hydroxybenzyl) as the training set and consists of nine key amino-acid residues embedded in a hydrophobic receptor cavity. The underlying technology (software PrGen) allows for a dynamical treatment of the ligand–receptor complex (ligand equilibration and Monte-Carlo scanning of receptor space) as well as for receptor-mediated ligand alignment. Free energies of ligand binding are estimated based on ligand–receptor interactions, ligand desolvation energy, change of ligand internal energy and change of ligand entropy upon receptor binding.
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The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large... more
The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC(50) values in the 0.05-1 microM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
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ABSTRACT
J. CHEM. SOC. PERKIN TRANS. I 1986 ... Secondary Mould Metabolites. Part 16.' Stemphyltoxins, New Reduced Perylenequinone Metabolites f rom Stemphylium botryosum var. Lactucum ... Albert0 Arnone and Gianluca Nasini * Dipartimento di... more
J. CHEM. SOC. PERKIN TRANS. I 1986 ... Secondary Mould Metabolites. Part 16.' Stemphyltoxins, New Reduced Perylenequinone Metabolites f rom Stemphylium botryosum var. Lactucum ... Albert0 Arnone and Gianluca Nasini * Dipartimento di Chimica del ...
... DOTHISTROMIN AND 2-EPIDOTHISTROMIN FROM CERCOSPORA SMILACIS* GEMMA ASSANTEf, LORENZO CAMARDA , LUCIO MERLINI:^ and GlANLUCA NASINI fistituto di ... TN, Gallacher, RT and Hodges, R (1970) Chem Commun 1705 5 Roffey,P and Sargent, MV... more
... DOTHISTROMIN AND 2-EPIDOTHISTROMIN FROM CERCOSPORA SMILACIS* GEMMA ASSANTEf, LORENZO CAMARDA , LUCIO MERLINI:^ and GlANLUCA NASINI fistituto di ... TN, Gallacher, RT and Hodges, R (1970) Chem Commun 1705 5 Roffey,P and Sargent, MV (1967 ...