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2. A Calix[8]arene-Based Catalyst for Suzuki–Miyaura Couplings with Reduced Pd_Leaching

Author

Erika Adhel, Axel Labattut, Timothée Naret, Diana Dragoe, and Vincent Huc

Subjects
catalysis, palladium, calixarene, Physical and Theoretical Chemistry, Catalysis, General Environmental Science
Abstract

Pd-catalysed reactions are amongst the most important in current chemistry. Consequently, very reactive catalysts were developed during the last decades, allowing very high conversions at low catalytic rates. However, decreasing Pd leaching in final products without decreasing catalyst efficiency remains an unsolved issue, especially in the pharma industry. We recently showed that using calixarenes as platforms for Pd-based catalysts constitutes an efficient answer to this concern. In the present work, we show that using these calixarenic platforms in combination with suitably engineered ligands allows for an even more strongly decreased Pd leaching. It thus opens up interesting perspectives for the synthesis of new families of catalysts combining a very high reactivity and a very low Pd leaching in final products.

Published
2022
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3. Benzyloxycalix[8]arene supported Pd–NHC cinnamyl complexes for Buchwald–Hartwig C–N cross-couplings

Author

Cyril Martini, Julien Buendia, Timothée Naret, Emmanuelle Schulz, Vincent Huc, Sandra Abi Fayssal, Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
chemistry.chemical_classification, 010405 organic chemistry, Aryl, chemistry.chemical_element, [CHIM.CATA]Chemical Sciences/Catalysis, 010402 general chemistry, Heterogeneous catalysis, 01 natural sciences, Combinatorial chemistry, Catalysis, 0104 chemical sciences, Metal, chemistry.chemical_compound, chemistry, Homogeneous, visual_art, visual_art.visual_art_medium, Leaching (metallurgy), Alkyl, Palladium
Abstract

International audience; A scalable synthesis of Pd-NHC cinnamyl complexes supported on a benzyloxycalix[8]arene is reported. These catalysts are very active for Buchwald-Hartwig cross-coupling reactions, allowing the coupling of aryl chlorides and bromides with a wide variety of alkyl and aryl amines using low catalytic loadings. The supported complexes also successfully afforded attractive unsymmetrical triarylamines, and in one case promoted the synthesis of an unprecedented Pd-catalyzed C-H activation product. Thanks to the calixarenic support, the target products could be isolated with low levels of residual palladium, in some cases even below the restrictive toxic metal standards applied by pharmaceutical industry. Through an easy to implement procedure, these perfectly characterised catalysts thus combine the best of homogeneous and heterogeneous catalysis: high efficiency (similar or even better than the corresponding homogeneous complexes), and low Pd leaching levels expected from heterogeneous catalysts.

Published
2021
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4. Gemcitabine lipid prodrug nanoparticles: Switching the lipid moiety and changing the fate in the bloodstream

Author

Patrick Couvreur, Sophie Feuillastre, Simona Mura, Timothée Naret, Jean-Louis Paul, Jean-Philippe Michel, Magali Noiray, Grégory Pieters, Sébastien Garcia-Argote, Bastien Prost, Catherine Cailleau, Eleonore Coppens, Didier Desmaële, Audrey Solgadi, Institut Galien Paris-Saclay (IGPS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Lip(Sys)2 Athérosclérose: homéostasie et trafic du cholestérol des macrophages, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Desmaële, Didier, and ANR-17-CE11-0014,Carb2zyme,Carb2zyme: Nouvelle chimie pour la formation de liaisons carbone-carbone par une classe émergente de métallo-enzymes(2017)

Subjects
Male, [SDV]Life Sciences [q-bio], Lipoproteins, Pharmaceutical Science, 02 engineering and technology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Deoxycytidine, lipid prodrugs, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Drug Delivery Systems, In vivo, Animals, Humans, Distribution (pharmacology), Prodrugs, 030304 developmental biology, 0303 health sciences, Cholesterol, [CHIM.ORGA]Chemical Sciences/Organic chemistry, gemcitabine, Prodrug, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, [CHIM.ORGA] Chemical Sciences/Organic chemistry, Lipids, In vitro, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, Drug delivery, drug delivery, Biophysics, lipids (amino acids, peptides, and proteins), nanoparticles, 0210 nano-technology, Lipoprotein, Conjugate
Abstract

International audience; A simple approach to achieve a lipoprotein (LP)-mediated drug delivery is to trigger the spontaneous drug insertion into endogenous lipoproteins in the bloodstream, by means of its chemical modification. Nanoparticles (NPs) made of the squalene-gemcitabine (SQGem) conjugate were found to have a high affinity for plasma lipoproteins while free gemcitabine did not, suggesting a key role of the lipid moiety in this event. Whether the drug conjugation to cholesterol, one of the major lipoprotein-transported lipids, could also promote an analogous interaction was a matter of question. NPs made of the cholesterol-gemcitabine conjugate (CholGem) have been herein thoroughly investigated for their blood distribution profile both in vitro and in vivo. Unexpectedly, contrarily to SQGem, no trace of the CholGem prodrug could be found in the lipoprotein fractions, nor was it interacting with albumin. The investigation of isolated NPs and NPs/LPs physical mixtures provided a further insight into the lack of interaction of CholGem NPs with LPs. Although essential for allowing the self-assembly of the prodrug into nanoparticles, the lipid moiety may not be sufficient to elicit interaction of the conjugated drug with plasma lipoproteins but the whole NP physicochemical features must be carefully considered.

Published
2021
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5. Chemical Synthesis of [

Author

Timothée, Naret, Philippe, Lesot, Andrew R, Puente, Prasad L, Polavarapu, David-Alexandre, Buisson, Jeanne, Crassous, Grégory, Pieters, and Sophie, Feuillastre

Abstract

Small chiral molecules are excellent candidates to push the boundaries of enantiodiscrimination analytical techniques. Here is reported the synthesis of two new deuterated chiral probes, (

Published
2020

6. Tuning the Reactivity of a Heterogeneous Catalyst using N-Heterocyclic Carbene Ligands for C-H Activation Reactions

Author

Simon Tricard, Yannick Coppel, Philippe Lesot, Alberto Palazzolo, Marion Daniel-Bertrand, Sophie Feuillastre, David-Alexandre Buisson, Timothée Naret, Bruno Chaudret, Grégory Pieters, Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de physique et chimie des nano-objets (LPCNO), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE11-0014,Carb2zyme,Carb2zyme: Nouvelle chimie pour la formation de liaisons carbone-carbone par une classe émergente de métallo-enzymes(2017), Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
deuteration, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Context (language use), General Chemistry, General Medicine, Heterogeneous catalysis, 010402 general chemistry, Medicinal chemistry, 01 natural sciences, Catalysis, 0104 chemical sciences, Azine, chemistry.chemical_compound, heterogeneous catalysis, chemistry, Deuterium, isotopic exchange, Reactivity (chemistry), N-heterocyclic carbenes, Chemoselectivity, C-H activation, Carbene
Abstract

International audience; Heterogeneous CatalysisTuning the Reactivity of a Heterogeneous Catalyst usingN-Heterocyclic Carbene Ligands for CH Activation ReactionsAlberto Palazzolo, TimothØe Naret, Marion Daniel-Bertrand, David-Alexandre Buisson,Simon Tricard, Philippe Lesot, Yannick Coppel, Bruno Chaudret, Sophie Feuillastre, andGrØgory Pieters*Abstract:We report the dramatic impact of the addition of N-heterocyclic carbenes (NHCs) on the reactivity and selectivityof heterogeneous Ru catalysts in the context of CH activationreactions. Using a simple and robust method, we prepareda series of new air-stable catalysts starting from commerciallyavailable Ru on carbon (Ru/C) and differently substitutedNHCs. Associated with CH deuteration processes, dependingon Ru/C-NHC ratios, the chemical outcome can be controlledto a large extent. Indeed, tuning the reactivity of the Ru catalystwith NHC enabled: 1) increased chemoselectivity and theregioselectivity for the deuteration of alcohols in organicmedia; 2) the synthesis of fragile pharmaceutically relevantdeuterated heterocycles (azine, purine) that are otherwisecompletely reduced using unmodified commercial catalysts;3) the discovery of a novel reactivity for such heterogeneous Rucatalysts, namely the selective C-1 deuteration of aldehydes

Published
2020
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8. Metal-Catalyzed Synthesis of 1,1-Diarylethylene Scaffolds

Author

Mouad Alami, Abdallah Hamze, Olivier Provot, and Timothée Naret

Subjects
Metal, Polymerization, 010405 organic chemistry, Chemistry, visual_art, Organic Chemistry, visual_art.visual_art_medium, Organic chemistry, Homogeneous catalysis, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, Catalysis
Abstract

1,1-diarylethylene derivatives have a great interest in chemistry for its applications in polymerization chemistry and medicinal chemistry. This review present in a non-exhaustive manner for metal-catalyzed processes to synthesize 1,1-diarylethylene compounds.

Published
2017
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9. Chemical Synthesis of [ 2 H]-Ethyl Tosylate and Exploration of Its Crypto-optically Active Character Combining Complementary Spectroscopic Tools

Author

Timothée Naret, David-Alexandre Buisson, Philippe Lesot, Sophie Feuillastre, Prasad L. Polavarapu, Andrew R. Puente, Grégory Pieters, Jeanne Crassous, Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University [Nashville], Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Paris-Saclay, Centre National de la Recherche Scientifique, ANR-17-CE11-0014,Carb2zyme,Carb2zyme: Nouvelle chimie pour la formation de liaisons carbone-carbone par une classe émergente de métallo-enzymes(2017), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Deuterium NMR, 010402 general chemistry, 01 natural sciences, Biochemistry, Chemical synthesis, Crypto-chirality, Computational chemistry, QC calculations, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Absolute configuration, Physical and Theoretical Chemistry, Quantum chemical, Quantitative Biology::Biomolecules, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Optically active, Enantiopurity, 0104 chemical sciences, 2H-NMR, Deuterium, Chiral oriented media, VCD analysis, Vibrational circular dichroism, Enantiomer
Abstract

International audience; Small chiral molecules are excellent candidates to push the boundaries of enantiodiscrimination analytical techniques. Here is reported the synthesis of two new deuterated chiral probes, (R)- and (S)-[2H]-ethyl tosylate, obtained with high enantiomeric excesses. Due to their crypto-optically active properties, the discrimination of each enantiomer is challenging. Whereas their enantiopurity is determined by 2H NMR in chiral anisotropic media, their identification was performed by combining quantum chemical calculations and vibrational circular dichroism analysis.

Published
2020
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10. Palladium-Catalyzed One-Pot Synthesis of 5-(1-Arylvinyl)-1H -benzimidazoles: Overcoming the Limitation of Acetamide Partners

Author

Pascal Retailleau, Jérôme Bignon, Mouad Alami, Timothée Naret, Jean-Daniel Brion, and Abdallah Hamze

Subjects
010405 organic chemistry, Stereochemistry, One-pot synthesis, chemistry.chemical_element, General Chemistry, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, 0104 chemical sciences, Catalysis, Human lung, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, One pot reaction, Carcinoma Cell, medicine, Acetamide, Human colon, Palladium
Abstract

A new one-pot palladium-catalyzed process between N-tosylhydrazones, N-(dihalophenyl)-imidates, and amines was designed. This reaction involves Barluenga cross-coupling and N-arylation followed by cyclization to produce functionalized benzimidazoles. During this transformation, one CC bond and two CN bonds were created by a single palladium-catalyzed reaction. Depending on the starting materials, a library of 5-(1-arylvinyl)-1H-benzimidazoles was synthesized. Among several arylvinylbenzimidazole derivatives evaluated, one compound exhibits excellent antiproliferative activity in the nanomolar concentration range against human colon carcinoma cell lines (HCT-116) and human lung adenocarcinoma epithelial cell lines (A549).

Published
2016
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11. N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents

Author

Mouad Alami, Timothée Naret, Ilhem Khelifi, Jérôme Bignon, Abdallah Hamze, Maria Concepcion Garcia Alvarez, Olivier Provot, Hélène Levaique, Joëlle Dubois, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Mitosis, Antineoplastic Agents, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Methylamines, Structure-Activity Relationship, quinoline, carbazole, Drug Discovery, Quinazoline, Tumor Cells, Cultured, Humans, isoCA-4, Cytotoxicity, 030304 developmental biology, Cell Proliferation, Cancer, Pharmacology, Indole test, 0303 health sciences, Matrigel, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Carbazole, Cytotoxins, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Quinoline, General Medicine, Cell Cycle Checkpoints, tubulin 2, HCT116 Cells, 3. Good health, 0104 chemical sciences, Tubulin, chemistry, Biochemistry, indole, biology.protein, cytotoxicity, Drug Screening Assays, Antitumor, quinazoline
Abstract

International audience; The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are descriebed. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as Brings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50 = 70 pM against HCT116 cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5 nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116 cells. It was also showed that after few hours 1a at a concentration of 10 nM totally disrupted endothelial network formation on Matrigel.

Published
2019
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12. 1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

Author

Martin Souce, Mouad Alami, Timothée Naret, Olivier Provot, Paloma F. Varela, Athena Kasselouri, Hélène Levaique, Alain Deroussent, Ilhem Khelifi, Jérôme Bignon, Angelo Paci, Benoît Gigant, Joëlle Dubois, Abdallah Hamze, Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Groupe de Chimie Analytique de Paris-Sud, Université Paris-Sud - Paris 11 (UP11), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biochimie Structurale des Microtubules, des Kinésines et de leurs Cargos (MIKICA), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Carbazoles, Antineoplastic Agents, Plasma protein binding, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Quinaldines, 01 natural sciences, Polymerization, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, 0302 clinical medicine, Tubulin, Cell Line, Tumor, Drug Discovery, Human Umbilical Vein Endothelial Cells, Colchicine, Structure–activity relationship, [CHIM]Chemical Sciences, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, 010405 organic chemistry, Quinaldine, In vitro, Tubulin Modulators, 0104 chemical sciences, 3. Good health, Rats, G2 Phase Cell Cycle Checkpoints, chemistry, Biochemistry, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Microsome, Microsomes, Liver, Molecular Medicine, Drug Screening Assays, Antitumor, Protein Binding
Abstract

International audience; We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure-activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.

Published
2018
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13. A general synthesis of arylindoles and (1-arylvinyl)carbazoles via a one-pot reaction from N-tosylhydrazones and 2-nitro-haloarenes and their potential application to colon cancer

Author

Ali Hachem, Mouad Alami, Timothée Naret, Jérôme Bignon, Ali Khalaf, Tourin Bzeih, Abdallah Hamze, Nada Jaber, and Jean-Daniel Brion

Subjects
Indoles, Colorectal cancer, Carbazoles, Tumor cells, 010402 general chemistry, Hydrocarbons, Aromatic, 01 natural sciences, Catalysis, Tosyl Compounds, Tumor Cells, Cultured, Materials Chemistry, medicine, Humans, Molecule, Molecular Structure, 010405 organic chemistry, Chemistry, Hydrazones, Metals and Alloys, Colon cancer cell, General Chemistry, Nitro Compounds, medicine.disease, Combinatorial chemistry, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Cyclization, One pot reaction, Colonic Neoplasms, Ceramics and Composites, Nitro
Abstract

A convergent and effective synthesis of 3-aryl-indoles, 2,3-diaryl indoles, and (1-arylvinyl)carbazoles from a one-pot sequence involving the coupling of N-tosylhydrazones with ortho-nitro-haloarenes followed by a cyclization has been developed. Compound 5i exhibits excellent antiproliferative activity in the low nM range against colon cancer cell lines.

Published
2016
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14. A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation

Author

Mohamed Benchekroun, Mouad Alami, Timothée Naret, Delphine Borgel, Frédéric R. Leroux, Jean-Daniel Brion, Alain Pruvost, François Saller, Jérôme Bignon, Boris Manoury, Véronique Leblais, Guillaume Bernadat, Etienne Schmitt, Abdallah Hamze, Sébastien Apcher, Christine Lenoir, Joëlle Dubois, Romain Darrigrand, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, INSERM, UMR-S1176, INSERM, UMR-S1180, INSERM U1015, Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CNRS, Univ. Paris-Sud, La Ligue Nationale Contre le Cancer through an Equipe Labellisee grant, ANR [ANR-10-LABX-33], LABX LERMIT, Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Models, Molecular, Fluorinated analogs, Cytotoxic, Stereochemistry, chemistry.chemical_element, Antineoplastic Agents, 010402 general chemistry, 01 natural sciences, Polymerization, Structure-Activity Relationship, Microtubule, Tubulin, Cell Line, Tumor, Drug Discovery, Stilbenes, Humans, isoCA-4, Cytotoxicity, Cell Proliferation, Cancer, Pharmacology, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Aromaticity, Tubulin inhibitors, General Medicine, Fluorine, Cell cycle, 0104 chemical sciences, Drug Design, Cancer cell, biology.protein, Drug Screening Assays, Antitumor, Linker
Abstract

International audience; A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of isoCA-4 by introduction of difluoromethoxy group at the para-position (3i) and substitution of the two protons of the linker by two fluorine atoms (3m), produced the most active compounds in the series, with IC50 values of 0.15 -2.2 nM (3i) and 0.1-2 nM (3m) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or isoCA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G(2)/M phase arrest and, dramatically disrupted the microtubule network.

Published
2018
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15. Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors

Author

Jérôme Bignon, Ilhem Khelifi, Jean-Daniel Brion, Christine Lenoir, Dolor Renko, Mouad Alami, Olivier Provot, Timothée Naret, Guillaume Bernadat, Joëlle Dubois, Abdallah Hamze, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), and Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cell cycle checkpoint, binding, Stereochemistry, Antineoplastic Agents, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Chemistry Techniques, Synthetic, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Tubulin, quinoline, Cell Line, Tumor, Drug Discovery, Quinazoline, Cytotoxic T cell, isoCA-4, Humans, Cytotoxicity, Protein Structure, Quaternary, Cancer, Cell Proliferation, Pharmacology, biology, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Quinoline, General Medicine, Tubulin Modulators, 0104 chemical sciences, 3. Good health, G2 Phase Cell Cycle Checkpoints, Molecular Docking Simulation, 030104 developmental biology, Biochemistry, Docking (molecular), Cell culture, Drug Design, biology.protein, Quinazolines, cytotoxicity, M Phase Cell Cycle Checkpoints, Drug Screening Assays, Antitumor, Protein Multimerization
Abstract

International audience; (O.P.) and/or mouad.alami@u-psud.fr (M.A.) Abstract The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as Bring , led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.

Published
2016
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16. ChemInform Abstract: Palladium-Catalyzed One-Pot Synthesis of 5-(1-Arylvinyl)-1H-benzimidazoles: Overcoming the Limitation of Acetamide Partners

Author

Jérôme Bignon, Pascal Retailleau, Mouad Alami, Jean-Daniel Brion, Abdallah Hamze, and Timothée Naret

Subjects
One-pot synthesis, chemistry.chemical_element, General Medicine, Combinatorial chemistry, Human lung, Catalysis, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Carcinoma Cell, medicine, Acetamide, Human colon, Palladium
Abstract

A new one-pot palladium-catalyzed process between N-tosylhydrazones, N-(dihalophenyl)-imidates, and amines was designed. This reaction involves Barluenga cross-coupling and N-arylation followed by cyclization to produce functionalized benzimidazoles. During this transformation, one CC bond and two CN bonds were created by a single palladium-catalyzed reaction. Depending on the starting materials, a library of 5-(1-arylvinyl)-1H-benzimidazoles was synthesized. Among several arylvinylbenzimidazole derivatives evaluated, one compound exhibits excellent antiproliferative activity in the nanomolar concentration range against human colon carcinoma cell lines (HCT-116) and human lung adenocarcinoma epithelial cell lines (A549).

Published
2016
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18. Cover Picture: Palladium-Catalyzed One-Pot Synthesis of 5-(1-Arylvinyl)-1H -benzimidazoles: Overcoming the Limitation of Acetamide Partners (Adv. Synth. Catal. 11/2016)

Author

Pascal Retailleau, Timothée Naret, Abdallah Hamze, Jérôme Bignon, Mouad Alami, and Jean-Daniel Brion

Subjects
chemistry.chemical_compound, chemistry, One pot reaction, One-pot synthesis, chemistry.chemical_element, Organic chemistry, Cover (algebra), General Chemistry, Acetamide, Catalysis, Palladium
Published
2016
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