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1. Microwave-Assisted Synthesis of Potential Bioactive Benzo-, Pyrido- or Pyrazino-thieno[3,2-d]pyrimidin-4-amine Analogs of MPC-6827

Author

Yvonnick Loidreau, Marie-Renée Nourrisson, Corinne Fruit, Cécile Corbière, Pascal Marchand, and Thierry Besson

Subjects
microwave-assisted chemistry, thieno[3,2-d]pyrimidines, colorectal cancer, HT-29 cells, caco-2 cells, antiproliferative activity, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-d]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation.

Published
2020
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2. Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives

Author

Yvonnick Loidreau, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Nadège Loaëc, Laurent Meijer, Thierry Besson, and Pascal Marchand

Subjects
microwave-assisted chemistry, protein kinases, CK1, DYRK1A, CDK5, GSK-3, Medicine, Pharmacy and materia medica, RS1-441
Abstract

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.

Published
2020
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5. Microwave-Assisted Synthesis of Potential Bioactive Benzo-, Pyrido- or Pyrazino-thieno[3,2-d]pyrimidin-4-amine Analogs of MPC-6827

Author

Corinne Fruit, Cécile Corbière, Pascal Marchand, Marie-Renée Nourrisson, Yvonnick Loidreau, Thierry Besson, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), and Normandie Université (NU)-Normandie Université (NU)

Subjects
antiproliferative activity, thieno[3,2-d]pyrimidines, Colorectal cancer, lcsh:Medicine, lcsh:RS1-441, Pharmaceutical Science, colorectal cancer, 010402 general chemistry, 01 natural sciences, Microwave assisted, microwave-assisted chemistry, lcsh:Pharmacy and materia medica, HT-29 cells, Drug Discovery, medicine, [CHIM]Chemical Sciences, Inhibitory effect, ComputingMilieux_MISCELLANEOUS, caco-2 cells, 010405 organic chemistry, Cell growth, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, lcsh:R, medicine.disease, Combinatorial chemistry, 0104 chemical sciences, Caco-2, Cell culture, Molecular Medicine, Amine gas treating
Abstract

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-d]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation.

Published
2020
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6. Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives

Author

Laurent Meijer, Nadège Loaëc, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Yvonnick Loidreau, Thierry Besson, Pascal Marchand, 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), Université de Rouen Normandie (UNIROUEN), 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), Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), ManRos Therapeutics, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stereochemistry, CK1, CDK5, Pharmaceutical Science, lcsh:Medicine, lcsh:RS1-441, Microwave-assisted chemistry, 01 natural sciences, lcsh:Pharmacy and materia medica, 03 medical and health sciences, chemistry.chemical_compound, Harmine, Protein kinases, Furan, Drug Discovery, Thiophene, [CHIM]Chemical Sciences, 030304 developmental biology, Pyrrole, chemistry.chemical_classification, 0303 health sciences, GSK-3, 010405 organic chemistry, Kinase, Communication, Cyclin-dependent kinase 5, lcsh:R, DYRK1A, 0104 chemical sciences, chemistry, Molecular Medicine, Casein kinase 1, Tricyclic
Abstract

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.

Published
2020
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7. First synthesis of 4-aminopyrido[2′,3′:4,5]furo[3,2-d]pyrimidines

Author

Carole Dubouilh-Benard, Thierry Besson, Marie-Renée Nourrisson, Yvonnick Loidreau, Muriel Duflos, Pascal Marchand, 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), Université de Rouen Normandie (UNIROUEN), 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), Laboratoire d'Etudes et de Recherches Appliquées en Sciences Sociales (LERASS), Université Paul-Valéry - Montpellier 3 (UPVM)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Pyrimidine, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, 010402 general chemistry, Ring (chemistry), 01 natural sciences, Biochemistry, Dimroth rearrangement, 0104 chemical sciences, chemistry.chemical_compound, Drug Discovery, Microwave irradiation, ComputingMilieux_MISCELLANEOUS
Abstract

This Letter describes for the first time the synthesis of pyrido[2′,3′:4,5]furo[3,2-d]pyrimidines substituted by a primary or secondary amino group on position 4 of the pyrimidine ring. Application of microwave irradiation technology allowed fast and convenient procedures.

Published
2012
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9. A convenient route to functionalized 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides

Author

Pascal Marchand, Marie-Renée Nourrisson, Anne Breteche, Muriel Duflos, and Guillaume De Nanteuil

Subjects
chemistry.chemical_compound, Chemistry, Group (periodic table), Stereochemistry, Organic Chemistry, Drug Discovery, Pyridine, Surface modification, Biochemistry
Abstract

An efficient synthesis of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides is described via the formation of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile. Functionalization of the amino group at position 3 of the heterocycle will be discussed.

Published
2010
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10. Structural investigation and elucidation of new communesins from a marine-derived Penicillium expansum Link by liquid chromatography/electrospray ionization mass spectrometry

Author

Yves François Pouchus, Jean-François Biard, Fabrice Monteau, Olivier Grovel, Bruno Le Bizec, Marie-Renée Nourrisson, and Isabelle Kerzaon

Subjects
Indole test, Chromatography, biology, Electrospray ionization, Organic Chemistry, Epoxide, Carbon-13 NMR, Tandem mass spectrometry, biology.organism_classification, Analytical Chemistry, chemistry.chemical_compound, chemistry, Fragmentation (mass spectrometry), Bioassay, Penicillium expansum, Spectroscopy
Abstract

Penicillium expansum is a ubiquitous species for which there are only few reports for chemical investigation in marine environments. Among thenumerous secondary metabolites produced by this species, communesins represent a new class of cytotoxic and insecticidal indole alkaloids. In this study, we investigated a marine P. expansum strain exhibiting neuroactivity on a Diptera larvae bioassay. Bio-guided purification led to the isolation and the identification of communesin B as the main active compound by HRMS and 1 H and 13 C NMR. Liquid chromatography analyses with detection by electrospray ionization coupled with tandem mass spectrometry (LC/ESI-MS/MS) and high-resolution tandem mass spectrometry (LC/HRMS/MS) allowed the identification and characterization of four other known communesins (A, D, E and F) in the crude extract. A fragmentation modelfor dimethyl epoxide communesins was proposed after detailed interpretation oftheir MS/MS spectra. Further analyses of the extract using the modelled fragmentations led to the detection of seven new communesins found as minor compounds. Chemical structural elucidation of these new derivatives is discussed based on their fragmentation characteristics. Copyright #2009 John Wiley & Sons, Ltd.

Published
2009
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11. Indole carboxamides inhibit bovine testes hyaluronidase at pH 7.0 and indole acetamides activate the enzyme at pH 3.5 by different mechanisms

Author

Joachim Jose, Andre Kaessler, Muriel Duflos, and Marie-Renée Nourrisson

Subjects
Male, Indoles, medicine.drug_class, Stereochemistry, Hyaluronoglucosaminidase, Carboxamide, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Hyaluronidase, Acetamides, Testis, Drug Discovery, medicine, Animals, Structure–activity relationship, Bovine serum albumin, Pharmacology, chemistry.chemical_classification, Indole test, Molecular Structure, biology, Substrate (chemistry), General Medicine, Hydrogen-Ion Concentration, Enzyme, chemistry, Biochemistry, biology.protein, Cattle, Acetamide, medicine.drug
Abstract

Hyaluronidases are enzymes controlling many crucial physiological processes. Imbalanced enzymatic activity is connected with severe diseases. Because there is limited availability of drugs modulating hyaluronidase activity, the search for hyaluronidase interacting compounds is getting more and more important. A series of fifteen indole carboxamides and acetamides were synthesized and tested on inhibition of bovine testes hyaluronidase. In vitro assays were performed using stains-all at pH 7 and the Morgan-Elson reaction at pH 3.5. At neutral pH, the most active inhibitory compound was N-(Pyridin-4yl)-[5-bromo-1-(4-fluorobenzyl)indole-3-yl]carboxamide (20) with an IC(50) value of 46 microM. Surprisingly, inhibition of all compounds was completely abolished by a decrease in pH. At pH 3.5 the activity of the enzyme was increased up to 134% by compound N-(4,6-Dimethylpyridin-2yl)-(1-ethylindole-3-yl)acetamide (24) at a concentration of 100 microM. The known activating effect of bovine serum albumine (BSA) on hyaluronidase activity was verified in the assay and compared to the effect of compound 24. Structure-activity relationships are discussed and a model is proposed, which explains the increase in activity at pH 3.5 by bonding of the protonated form of N-(4,6-Dimethylpyridin-2yl)-(1-ethylindole-3-yl)acetamide (24) to hyaluronic acid. The bonding results in an elongated form of the substrate with easier enzymatic access.

Published
2008
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12. Synthesis, antileishmanial activity and cytotoxicity of 2,3-diaryl- and 2,3,8-trisubstituted imidazo[1,2-a]pyrazines

Author

Guillaume Riviere, Patrice Le Pape, Marc-Antoine Bazin, Pascal Marchand, Blandine Baratte, Carine Picot, Denis Castillo Pareja, Sophie Marhadour, Stéphane Bach, Michel Sauvain, Lizeth Bodero, Sandrine Ruchaud, Marie-Renée Nourrisson, Abraham Vaisberg, Fabrice Pagniez, Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN), Sorbonne Universités (COMUE), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-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), Universidad Peruana Cayetano Heredia (UPCH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-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-Institut de Chimie du CNRS (INC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)

Subjects
Stereochemistry, Antiprotozoal Agents/chemical synthesis/chemistry/pharmacology, [SDV]Life Sciences [q-bio], Casein kinase 1, Antiprotozoal Agents, Direct arylation, Imidazo[1,2-a]pyrazines, Imidazoles/chemical synthesis/chemistry/pharmacology, Pyrazines/chemical synthesis/chemistry/pharmacology, Imidazo[1-2-a]pyrazines, Cell Line, Cell Proliferation/drug effects, Mice, Structure-Activity Relationship, Macrophages/drug effects, Drug Discovery, Moiety, Structure–activity relationship, Humans, Animals, Leishmania major, Cytotoxicity, Amastigote, Cell Proliferation, purl.org/pe-repo/ocde/ford#3.01.06 [https], Pharmacology, Mice, Inbred BALB C, biology, Molecular Structure, Dose-Response Relationship, Drug, Chemistry, Cell growth, Macrophages, Organic Chemistry, Imidazoles, General Medicine, Fibroblasts, Antileishmanial activity, biology.organism_classification, 3. Good health, Fibroblasts/drug effects, Cell culture, Pyrazines, Molecular targets, Leishmania major/drug effects
Abstract

International audience; A series of original 2-phenyl-3-(pyridin-4-yl)imidazo[1,2-a]pyrazines and the 3-iodo precursors, bearing a polar moiety at the C-8 position, was synthesized and evaluated for their antileishmanial activities. Two derivatives exhibited very good activity against the promastigote and the amastigote forms of Leishmania major in the micromolar to submicromolar ranges, coupled with a low cytotoxicity against macrophages and 3T3 mouse fibroblast cells. Through LmCK1 inhibition assay, investigations of the putative molecular target of these promising antileishmanial compounds will be discussed.

Published
2015
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13. Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors

Author

Thierry Besson, Emmanuel Deau, Laurent Meijer, Nadège Loaëc, Gaël Coadou, Pascal Marchand, Marie-Renée Nourrisson, Cédric Logé, Yvonnick Loidreau, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), 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)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), ManRos Therapeutics, Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), 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 Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed)

Subjects
Models, Molecular, Steric effects, Stereochemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Protein Serine-Threonine Kinases, Ring (chemistry), 01 natural sciences, CLK1, Structure-Activity Relationship, 03 medical and health sciences, Drug Discovery, Humans, Structure–activity relationship, Binding site, Protein Kinase Inhibitors, 030304 developmental biology, Pharmacology, 0303 health sciences, Protein-Serine-Threonine Kinases, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Kinase, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, 0104 chemical sciences, Formylation, Pyrimidines, Kinase inhibitors, Microwave-assisted chemistry, Alzheimer disease, Pyrido[3′, 2′:4, 5]thieno[3, 2-d]pyrimidin-4-amines
Abstract

International audience; This paper reports the design and synthesis of a novel series of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N′-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity.

Published
2015
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14. New N-Pyridinyl(methyl)-N1-substituted-3-indolepropanamides Acting as Topical and Systemic Anti-inflammatory Agents

Author

Guillaume Le Baut, Nicole Grimaud, Jean Yves Petit, Muriel Duflos, Anthony Gallard, and Marie-Renée Nourrisson

Subjects
Male, Indoles, Ear swelling, Pyridines, medicine.drug_class, Administration, Topical, Administration, Oral, Inflammation, Pharmacology, Carrageenan, Anti-inflammatory, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Oral administration, Drug Discovery, medicine, Animals, Edema, Potency, Ear, External, Rats, Wistar, Indole test, Molecular Structure, Foot, Anti-Inflammatory Agents, Non-Steroidal, General Medicine, Rats, chemistry, Tetradecanoylphorbol Acetate, medicine.symptom, Methyl group
Abstract

N-Pyridinyl(methyl)-N1-substituted-3-indolepropanamides (17-32) were prepared starting from the corresponding acids and screened for their anti-inflammatory activity. Pharmacomodulation was carried out on the indole and amidic nitrogens by incorporation of substituents associated with higher potency in previously synthesized related 3-indolepropanamides series. In the inhibition of topical inflammation determined by reduction of ear thickness in the acute PMA mouse ear swelling test, high levels of activity (ID50 approximately 0.030 mMol kg(-1)) were noticed for the five propanamides 17, 21, 22, 27 and 31. A comparative study showed the positive influence of a methyl group at the indole nitrogen in the 4-pyridinyl sub-series (1 --21) and of a 4-fluorobenzyl group in the 3-pyridinylmethyl sub-series (19 --31), at least after oral administration. After topical application, although compounds 17, 21, 22, 27 and 31 exerted significant (50%) ear edema inhibition at 2 x 50 microg/ear, they remained less potent than 24,29 and 30 (almost 70% inhibition). Among these eight amides, only 17, 21, 22 and 27 showed a significant activity in the carrageenan rat paw aedema model at 0.2 mMol kg(-1). Finally, although less active than the N-(4-pyridinyl) amide 21, the N-4,6-dimethyl-2-pyridinyl derivatives 17 and 27 were devoid of the toxic effects observed with 21 and to a lesser extent with 22.

Published
2003
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15. ChemInform Abstract: Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement

Author

Cécile Corbière, Muriel Duflos, Yvonnick Loidreau, Catherine Buquet, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Pascal Marchand, and Thierry Besson

Subjects
Chemistry, Amine gas treating, General Medicine, Thiophene derivatives, Medicinal chemistry, Microwave assisted, Dimroth rearrangement
Abstract

Compounds (V) and 20 compounds of type (VII) are prepared which are tested for their antiproliferative effects.

Published
2014
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16. N-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential systemic and topical inflammation inhibitors

Author

Muriel Duflos, Nicole Grimaud, Jean-Yves Petit, Jacqueline Courant, Guillaume LeBaut, Jacques Brelet, and Marie-Renée Nourrisson

Subjects
Male, Indoles, Magnetic Resonance Spectroscopy, Spectrophotometry, Infrared, Pyridines, medicine.drug_class, Stereochemistry, Administration, Topical, Drug Evaluation, Preclinical, Inflammation, Carboxamide, Pharmacology, Carrageenan, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Oral administration, Drug Discovery, medicine, Animals, Edema, Ear, External, Indole test, Bicyclic molecule, Anti-Inflammatory Agents, Non-Steroidal, Organic Chemistry, General Medicine, Propanamide, Rats, chemistry, Drug Design, Phorbol, Tetradecanoylphorbol Acetate, medicine.symptom
Abstract

N-substituted-(indol-3-yl)carboxamides 10–15 and alkanamides 16–18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM kg−1; nevertheless introduction of an alkyl chain, leading to alkanamides 16–18, induced moderate to high activity: 46–95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM kg−1, by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.

Published
2001
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17. Synthesis of novel 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases

Author

Marie-Renée Nourrisson, Laurent Meijer, Emmanuel Deau, Nadège Loaëc, Thierry Besson, Yvonnick Loidreau, Pascal Marchand, Vincent Levacher, LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etudes et de Recherches Appliquées en Sciences Sociales (LERASS), Université Paul-Valéry - Montpellier 3 (UPVM)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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), Université de Rouen Normandie (UNIROUEN), and 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)

Subjects
Formamide, Stereochemistry, Pyridines, Clinical Biochemistry, Pharmaceutical Science, Protein Serine-Threonine Kinases, Inhibitory postsynaptic potential, 01 natural sciences, Biochemistry, Dimroth rearrangement, Catalysis, CLK1, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Amines, Microwaves, Molecular Biology, IC50, Protein Kinase Inhibitors, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, 010405 organic chemistry, Kinase, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Aryl, Organic Chemistry, 0104 chemical sciences, Enzyme Activation, Pyrimidines, Cyclization, Molecular Medicine, Heterocyclic Compounds, 3-Ring, Palladium, Tricyclic, Protein Binding
Abstract

International audience; The efficient synthesis of 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki-Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases.

Published
2013
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18. Efficient New Synthesis ofN-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement

Author

Pascal Marchand, Muriel Duflos, Catherine Buquet, Marie-Renée Nourrisson, Thierry Besson, Carole Dubouilh-Benard, Yvonnick Loidreau, and Cécile Corbière

Subjects
010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, Microwave technology, 010402 general chemistry, 01 natural sciences, Dimroth rearrangement, Microwave assisted, 3. Good health, 0104 chemical sciences, Dimethyl acetal, chemistry.chemical_compound, Rapid access, Thiophene, Amine gas treating
Abstract

A useful and rapid access to libraries of N-arylbenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their novel benzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) was investigated for the first time. Title compounds were obtained via microwave-accelerated condensation and Dimroth rearrangement of suitable anilines with N′-(2-cyanaryl)-N,N-dimethylformimidamides obtained by reaction of benzo[b]furane and benzo[b]thiophene precursors with N,N-dimethylformamide dimethyl acetal. This work also demonstrates that well-controlled parameters offer comfortable use of microwave technology and are both safe and beneficial to the environment. Some products obtained in this article exhibit interesting in vitro antiproliferative effects.

Published
2013
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19. Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases

Author

Nadège Loaëc, Laurent Meijer, Marie-Renée Nourrisson, Carole Dubouilh-Benard, Yvonnick Loidreau, Thierry Besson, Muriel Duflos, Pascal Marchand, 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), Université de Rouen Normandie (UNIROUEN), 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), Laboratoire d'Etudes et de Recherches Appliquées en Sciences Sociales (LERASS), Université Paul-Valéry - Montpellier 3 (UPVM)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
DYRK1A, Stereochemistry, Thiophenes, Protein Serine-Threonine Kinases, 01 natural sciences, CLK1, Inhibitory Concentration 50, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Humans, Amines, Enzyme Inhibitors, Furans, 030304 developmental biology, Biological evaluation, Pharmacology, 0303 health sciences, Molecular Structure, 010405 organic chemistry, Kinase, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Aryl, Organic Chemistry, General Medicine, Protein-Tyrosine Kinases, 3. Good health, 0104 chemical sciences, Enzyme Activation, Inhibitory potency, Pyrimidines, chemistry, Amine gas treating, Dimethylformamide-dimethylacetal
Abstract

International audience; Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N'-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.

Published
2013
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20. Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors

Author

Olivier Lozach, Yvonnick Loidreau, Laurent Meijer, Nadège Loaëc, Muriel Duflos, Thierry Besson, Carole Dubouilh-Benard, Pascal Marchand, Marie-Renée Nourrisson, 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), Université de Rouen Normandie (UNIROUEN), 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), Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, Laboratoire d'Etudes et de Recherches Appliquées en Sciences Sociales (LERASS), Université Paul-Valéry - Montpellier 3 (UM3)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Stereochemistry, Pyridones, Swine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Thiophenes, Protein Serine-Threonine Kinases, 010402 general chemistry, 01 natural sciences, Dimroth rearrangement, CLK1, chemistry.chemical_compound, Structure-Activity Relationship, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Drug Discovery, Thiophene, Structure–activity relationship, Animals, Humans, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Pharmacology, Ser thr kinase, Dose-Response Relationship, Drug, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Kinase, Organic Chemistry, [CHIM.CATA]Chemical Sciences/Catalysis, General Medicine, 3. Good health, 0104 chemical sciences, Rats, Pyrimidines, chemistry, Pyrazines, Casein kinase 1, Dimethylformamide-dimethylacetal
Abstract

International audience; A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N'-(2-cyanoaryl)-N,N-dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ɛ, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine series of compounds (4a-j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases.

Published
2012
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23. ChemInform Abstract: N-Pyridinyl-indole-3-(alkyl)carboxamides and Derivatives as Potential Systemic and Topical Inflammation Inhibitors

Author

Guillaume LeBaut, Muriel Duflos, Jean-Yves Petit, Jacques Brelet, Nicole Grimaud, Marie-Renée Nourrisson, and Jacqueline Courant

Subjects
Indole test, chemistry.chemical_classification, Ear swelling, Inflammation, General Medicine, Pharmacology, Propanamide, chemistry.chemical_compound, chemistry, Oral administration, Phorbol, medicine, Moiety, medicine.symptom, Alkyl
Abstract

N-substituted-(indol-3-yl)carboxamides 10–15 and alkanamides 16–18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM kg−1; nevertheless introduction of an alkyl chain, leading to alkanamides 16–18, induced moderate to high activity: 46–95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM kg−1, by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.

Published
2010
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24. Structural investigation and elucidation of new communesins from a marine-derived Penicillium expansum Link by liquid chromatography/electrospray ionization mass spectrometry

Author

Isabelle, Kerzaon, Yves F, Pouchus, Fabrice, Monteau, Bruno, Le Bizec, Marie-Renée, Nourrisson, Jean-François, Biard, and Olivier, Grovel

Subjects
Spectrometry, Mass, Electrospray Ionization, Diptera, Penicillium, Animals, Seawater, Mycotoxins, Heterocyclic Compounds, 4 or More Rings, Chromatography, Liquid
Abstract

Penicillium expansum is a ubiquitous species for which there are only few reports for chemical investigation in marine environments. Among the numerous secondary metabolites produced by this species, communesins represent a new class of cytotoxic and insecticidal indole alkaloids. In this study, we investigated a marine P. expansum strain exhibiting neuroactivity on a Diptera larvae bioassay. Bio-guided purification led to the isolation and the identification of communesin B as the main active compound by HRMS and 1H and 13C NMR. Liquid chromatography analyses with detection by electrospray ionization coupled with tandem mass spectrometry (LC/ESI-MS/MS) and high-resolution tandem mass spectrometry (LC/HRMS/MS) allowed the identification and characterization of four other known communesins (A, D, E and F) in the crude extract. A fragmentation model for dimethyl epoxide communesins was proposed after detailed interpretation of their MS/MS spectra. Further analyses of the extract using the modelled fragmentations led to the detection of seven new communesins found as minor compounds. Chemical structural elucidation of these new derivatives is discussed based on their fragmentation characteristics.

Published
2009

25. Synthesis and biological evaluation of 3-(azolylmethyl)-1 H -indoles and 3-(α-azolylbenzyl)-1 H -indoles as selective aromatase inhibitors

Author

Martina Palzer, Denis Loquet, Rolf W. Hartmann, Marie-Renée Nourrisson, Pascal Marchand, Guillaume Le Baut, Marc Le Borgne, Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Saarland University [Saarbrücken]

Subjects
Azoles, Male, Indoles, Stereochemistry, medicine.drug_class, Placenta, Triazole, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, 0302 clinical medicine, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Microsomes, Drug Discovery, Testis, medicine, Imidazole, Structure–activity relationship, Moiety, Animals, Humans, Aromatase, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, Indole test, 0303 health sciences, Aromatase inhibitor, biology, Molecular Structure, Aromatase Inhibitors, Steroid 17-alpha-Hydroxylase, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Rats, Enzyme Activation, chemistry, 030220 oncology & carcinogenesis, biology.protein, Female, Selectivity
Abstract

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC50 values ranging between 0.054 and 0.050 microM. In the other sub-series, eight 3-(alpha-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC50 value of 0.052 microM. All target compounds were further evaluated against 17alpha-hydroxylase/C17,20-lyase to determine their selectivity profile.

Published
2007
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26. Potential inhibitors of angiogenesis. Part I: 3-(imidazol-4(5)-ylmethylene)indolin-2-ones

Author

Pierre Renard, Emmanuelle Braud, Bruno Pfeiffer, Carine Picot, Muriel Duflos, Guillaume Le Baut, Marie-Renée Nourrisson, Alain Tonnerre, and Tucker Gordon

Subjects
Male, Indoles, Angiogenesis, Stereochemistry, Nitrogen, Angiogenesis Inhibitors, Methylation, chemistry.chemical_compound, Aortic ring, Drug Discovery, Imidazole, Animals, Humans, Pyrroles, Mannich reaction, Aorta, Cells, Cultured, Pharmacology, General Medicine, Protein-Tyrosine Kinases, In vitro, Rats, Inbred F344, Rats, ErbB Receptors, chemistry, Models, Chemical, Knoevenagel condensation, Endothelium, Vascular, Tyrosine kinase
Abstract

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration.

Published
2003

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