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7 results on '"Hugues Lemoine"'

1. Mild and Chemoselective Lactone Ring-Opening with (TMS)ONa. Mechanistic Studies and Application to Sweroside Derivatives

Author

Brigitte Deguin, Hugues Lemoine, and Dean Marković

Subjects
chemistry.chemical_classification, Trimethylsilyl Compounds, Molecular Structure, Iridoid Glucosides, Sodium, Organic Chemistry, Kinetics, Lactones (TMS)ONa, Mechanistic Studies, Sweroside, Stereoisomerism, Ring (chemistry), Lactones, Nucleophile, chemistry, Solvents, Organic chemistry, Moiety, Molecule, Lactone
Abstract

Mild and chemoselective opening of lactones with sodium trimethylsilanolate in high yields and aprotic solvents is described. Kinetic studies demonstrate that the B(Ac)2 mechanistic pathway is followed. Nucleophilic attack of silanolate onto the carbonyl of the lactone moiety is the rate-determining step. NaOH present as an impurity accelerates the reaction. The method was further applied to the base-sensitive and stable lactones derived from highly functionalized iridoid derivatives.

Published
2014
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2. Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies

Author

Daniel Schwarz, Catherine Jorand-Lebrun, Didier M. Roche, Michael Blaesse, Theresa L. Johnson, Birgitta Leuthner, Hugues Lemoine, Ulrich Grädler, Andreas Marx, Gilardone Marine, Frederic Bernard, and Xuliang Jiang

Subjects
inorganic chemicals, Models, Molecular, Molar concentration, Inhibitor, Lactams, Stereochemistry, Fragment-based lead discovery, Clinical Biochemistry, Structure-based design, Pharmaceutical Science, Isomerase, Crystallography, X-Ray, 01 natural sciences, Biochemistry, Article, chemistry.chemical_compound, Cyclophilins, Structure-Activity Relationship, Amide, Surface plasmon resonance, Drug Discovery, Humans, Enzyme Inhibitors, Molecular Biology, ComputingMethodologies_COMPUTERGRAPHICS, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Ligand binding assay, Organic Chemistry, Fragment-screening, In vitro, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Molecular Medicine, X-ray structure, Protein crystallization, Cyclophilin D
Abstract

Graphical abstract, Highlights • 6 Cyclophilin D crystal structures with SPR binding confirmed fragment hits having millimolar potencies were discovered. • One fragment was merged with a potent reference Cyclophilin D inhibitor resulting in single-digit nanomolar potency. • A second fragment provided the basis for replacing the urea linker in the reference inhibitor scaffold by an oxalyl group. • Two fragment hits bound in the S1′ and S2 pockets were linked via an amide group resulting in submicromolar potencies., Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1′ and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

Published
2019

3. Multicomponent Reactions as a Powerful Tool for Generic Drug Synthesis

Author

Cedric Kalinski, Jurgen G. Schmidt, Hugues Lemoine, Jürgen Kolb, Michael Umkehrer, Günther Ross, and Christoph Burdack

Subjects
Steroidal antiandrogen, Chemistry, Drug discovery, Generic drug, Organic Chemistry, Organic chemistry, Catalysis
Abstract

Multicomponent reactions (MCRs) are not only a power- ful tool for drug discovery, they also represent an excellent method- ology for synthesis rationalization. Here we wish to illustrate the potential of MCRs in the production of generic drugs by synthesiz- ing, in racemic form, the antiplatelet agent clopidogrel and the non- steroidal antiandrogen bicalutamide, using Ugi, Petasis and Passe- rini reactions.

Published
2008
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4. ChemInform Abstract: Mild and Chemoselective Lactone Ring-Opening with (TMS)ONa. Mechanistic Studies and Application to Sweroside Derivatives

Author

Brigitte Deguin, Dean Marković, and Hugues Lemoine

Subjects
chemistry.chemical_classification, Chemistry, Stereochemistry, General Medicine, Ring (chemistry), Lactone
Abstract

The lactone ring opening allows a straightforward access to various hydroxy carboxylic acids including polyfunctionalized secoiridoid derivatives.

Published
2014
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5. Incorporation of a 3-(2,2,2-trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities

Author

Hugues Lemoine, Maurice Médebielle, Etsuji Okada, Florian Albrieux, Damien Cornut, Abdoul Habib Beavogui, Anne-Lise Bienvenu, Jean-Philippe Bouillon, Oleksandr S. Kanishchev, Stéphane Picot, Synthèse et structure de molécules d'interet pharmacologique ( SSMIP ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires ( ICBMS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon ( HCL ), Malaria Research Unit, Centre National de la Recherche Scientifique ( CNRS ), Sciences et Méthodes Séparatives ( SMS ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Synthèse et structure de molécules d'interet pharmacologique (SSMIP), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre National de la Recherche Scientifique (CNRS), Sciences et Méthodes Séparatives (SMS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Umbilical Veins, Lactams, Stereochemistry, Plasmodium falciparum, Drug Resistance, In Vitro Techniques, 010402 general chemistry, 01 natural sciences, Umbilical vein, chemistry.chemical_compound, Antimalarials, Structure-Activity Relationship, Parasitic Sensitivity Tests, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Drug Discovery, Side chain, Structure–activity relationship, Molecule, Humans, Aminoquinolines, ComputingMilieux_MISCELLANEOUS, biology, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Endothelial Cells, Chloroquine, biology.organism_classification, In vitro, 0104 chemical sciences, 3. Good health, Lactam, Molecular Medicine
Abstract

International audience; In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC₅₀ values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.

Published
2013
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