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1. Imidazoquinoline Derivatives as Potential Inhibitors of InhA Enzyme and Mycobacterium tuberculosis

Author

Pascal Hoffmann, Joëlle Azéma-Despeyroux, Fernanda Goncalves, Alessandro Stamilla, Nathalie Saffon-Merceron, Frédéric Rodriguez, Giulia Degiacomi, Maria Rosalia Pasca, and Christian Lherbet

Subjects
mycobacterium tuberculosis, InhA enzyme, inhibitor, imidazoquinoline, triazolophthalazine, Organic chemistry, QD241-441
Abstract

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein’s substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth.

Published
2024
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2. Synthesis, Crystal Structure, Inhibitory Activity and Molecular Docking of Coumarins/Sulfonamides Containing Triazolyl Pyridine Moiety as Potent Selective Carbonic Anhydrase IX and XII Inhibitors

Author

Yassine Aimene, Romain Eychenne, Frédéric Rodriguez, Sonia Mallet-Ladeira, Nathalie Saffon-Merceron, Jean-Yves Winum, Alessio Nocentini, Claudiu T. Supuran, Eric Benoist, and Achour Seridi

Subjects
coumarin, sulfonamide, rhenium(I) complex, crystal structure, carbonic anhydrase inhibitor, molecular docking, Crystallography, QD901-999
Abstract

In this work, two classes of Carbonic Anhydrase (CA) inhibitors, sulfonamide and coumarin derivatives linked to pyta moiety (2a-b) and their corresponding rhenium complexes (3a-b), were designed. These compounds were synthesized and fully characterized by classical analytical methods and X-ray diffraction. All the synthesized compounds were evaluated for their inhibitory activity against the hCA isoforms I, II, IX and XII. They exhibited high inhibitory activities in the range of nanomolar for both hCA IX and hCA XII isoforms. The sulfonamide compound 2a showed the strongest inhibition against the tumour-associated hCA IX isoform with a Ki of 11.7 nM. The tumour-associated isoforms hCA IX and hCA XII were selectively inhibited by all the coumarin derivatives, with inhibition constants ranging from 12.7 nM (2b) to 44.5 nM (3b), while the hCA I and II isoforms were slightly inhibited (in the micromolar range), as expected. In terms of selectivity, compared to previously published rhenium complex-based CA inhibitors, complex 3b showed one of the highest selectivities against hCA IX and hCA XII compared to the off-target isoforms hCA I and hCA II, making it a potential anti-cancer drug candidate. Molecular docking calculations were performed to investigate the inhibition profiles of the investigated compounds at the tumour-associated hCA IX active site and to rationalize our results.

Published
2021
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3. Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors

Author

Cécile Baudoin-Dehoux, Tessa Castellan, Frédéric Rodriguez, Arnaud Rives, Fabien Stauffert, Virginie Garcia, Thierry Levade, Philippe Compain, and Yves Génisson

Subjects
iminosugars, glucocerebrosidase, pharmacological chaperones, glycosidase inhibitors, glucosylceramide synthase inhibitors, Gaucher disease, ligand docking, Organic chemistry, QD241-441
Abstract

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.

Published
2019
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4. Pares y redes de laboratorios del Centre National de la Recherche Scientifique y de sus asociados

Author

Marie-Pierre Bès, Adrien Defossez, and Frédéric Rodriguez

Subjects
Red, alianza, contrato, laboratorio, Social Sciences, Social sciences (General), H1-99
Abstract

El siguiente artículo arroja luz sobre el tema de la organización "irreversible" de las alianzas de investigación, a partir de datos longitudinales relativos a los contratos firmados por grupos de investigación del Centre National de la Recherche Scientifique (CNRS) con organismos financiadores (empresas, administraciones) entre 1986 y 2005. Los datos ponen de relieve diferentes aspectos: en primer lugar, los contratos tienden a ser volátiles y efímeros. Además, los laboratorios no presentan el mismo comportamiento que sus asociados en cuanto a cooperación, y cabe señalar que la repetición de los contratos conlleva una cierta "fidelidad" a su asociado. Por último, el análisis de estas alianzas desde el punto de vista de las redes sociales científicas ha puesto de manifiesto la convergencia de los modos de compatibilidad entre las grandes empresas y los grupos del CNRS, e igualmente la existencia de "pequeños mundos científicos".

Published
2010
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5. Synthesis, Crystal Structure, Inhibitory Activity and Molecular Docking of Coumarins/Sulfonamides Containing Triazolyl Pyridine Moiety as Potent Selective Carbonic Anhydrase IX and XII Inhibitors

Author

Jean-Yves Winum, Sonia Mallet-Ladeira, Frédéric Rodriguez, Claudiu T. Supuran, Yassine Aimene, Alessio Nocentini, Nathalie Saffon-Merceron, Eric Benoist, Achour Seridi, Romain Eychenne, Institut de Physique de Guelma, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), NEUROFARBA Department [Firenze, Italy], Università degli Studi di Firenze = University of Florence (UniFI), 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)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), and Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)

Subjects
Gene isoform, Stereochemistry, medicine.drug_class, General Chemical Engineering, Coumarin, 010402 general chemistry, Sulfonamide, 01 natural sciences, Inorganic Chemistry, chemistry.chemical_compound, Carbonic anhydrase, medicine, Moiety, [CHIM]Chemical Sciences, General Materials Science, Carbonic anhydrase inhibitor, chemistry.chemical_classification, Crystallography, biology, 010405 organic chemistry, Crystal structure, Rhenium(I) complex, Active site, Condensed Matter Physics, 0104 chemical sciences, chemistry, QD901-999, Molecular docking, biology.protein, Selectivity
Abstract

In this work, two classes of Carbonic Anhydrase (CA) inhibitors, sulfonamide and coumarin derivatives linked to pyta moiety (2a-b) and their corresponding rhenium complexes (3a-b), were designed. These compounds were synthesized and fully characterized by classical analytical methods and X-ray diffraction. All the synthesized compounds were evaluated for their inhibitory activity against the hCA isoforms I, II, IX and XII. They exhibited high inhibitory activities in the range of nanomolar for both hCA IX and hCA XII isoforms. The sulfonamide compound 2a showed the strongest inhibition against the tumour-associated hCA IX isoform with a Ki of 11.7 nM. The tumour-associated isoforms hCA IX and hCA XII were selectively inhibited by all the coumarin derivatives, with inhibition constants ranging from 12.7 nM (2b) to 44.5 nM (3b), while the hCA I and II isoforms were slightly inhibited (in the micromolar range), as expected. In terms of selectivity, compared to previously published rhenium complex-based CA inhibitors, complex 3b showed one of the highest selectivities against hCA IX and hCA XII compared to the off-target isoforms hCA I and hCA II, making it a potential anti-cancer drug candidate. Molecular docking calculations were performed to investigate the inhibition profiles of the investigated compounds at the tumour-associated hCA IX active site and to rationalize our results.

Published
2021
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10. Isolation and identification of ten new sildenafil derivatives in an alleged herbal supplement for sexual enhancement

Author

Isabelle Fabing, Frédéric Rodriguez, Gaëtan Assemat, Robert Martino, Véronique Gilard, Myriam Malet-Martino, Stéphane Balayssac, Yves Génisson, Nathalie Martins-Froment, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Service Commun de Spectrométrie de Masse (Toulouse, France), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
SFC, Sildenafil, Clinical Biochemistry, Dietary supplement, Pharmaceutical Science, High resolution, Tandem mass spectrometry, 01 natural sciences, High-performance liquid chromatography, Sildenafil Citrate, Analytical Chemistry, chemistry.chemical_compound, Methisosildenafil, Tandem Mass Spectrometry, Drug Discovery, [CHIM]Chemical Sciences, Herbal supplement, Spectroscopy, mass spectrometry, Chromatography, 010405 organic chemistry, 010401 analytical chemistry, Phosphodiesterase 5 Inhibitors, adulteration, NMR, 0104 chemical sciences, 3. Good health, respiratory tract diseases, chemistry, dietary supplement, Dietary Supplements, cardiovascular system, HPLC, Drug Contamination
Abstract

International audience; A sexual enhancer dietary supplement in pre-commercialization phase was analyzed. It 18 contained the two phosphodiesterase-5 inhibitors (PDE-5i) sildenafil and methisosildenafil as 19 major adulterants. Fourteen more sildenafil derivatives were detected and after isolation, their 20 structures were elucidated thanks to NMR, high resolution and tandem mass spectrometry, and 21 UV spectroscopy. Ten of them were never described. All these compounds are probably by-22 products of different reaction steps during the synthesis of the two PDE-5i that were not 23 properly eliminated during the purification procedure. The total amount of sildenafil-related 24 compounds was estimated at 68 mg per capsule, sildenafil and methisosildenafil accounting for 25 20 mg and 38 mg respectively.

Published
2020
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11. Concise asymmetric synthesis of new enantiomeric

Author

Tessa, Castellan, Virginie, Garcia, Frédéric, Rodriguez, Isabelle, Fabing, Yevhenii, Shchukin, My Lan, Tran, Stéphanie, Ballereau, Thierry, Levade, Yves, Génisson, and Cécile, Dehoux

Subjects
Gaucher Disease
Abstract

A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as β-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal β-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.

Published
2020

12. N,O-Dialkyl deoxynojirimycin derivatives as CERT START domain ligands

Author

Frédéric Rodriguez, Mathieu L. Lepage, Philippe Compain, Tessa Castellan, Cécile Santos, Yves Génisson, Cécile Dehoux, Anne Bodlenner, Yan Liang, Stéphanie Ballereau, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie moléculaire (LCM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), School of Automation, Northwestern Polytechnical University [Xi'an] (NPU), Institut de Chimie de Strasbourg (ICS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Chimie de Toulouse (ICT), 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)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ceramide, 1-Deoxynojirimycin, Glycoside Hydrolases, Stereochemistry, Clinical Biochemistry, Iminosugar, Pharmaceutical Science, Plasma protein binding, Protein Serine-Threonine Kinases, Ceramides, Ligands, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Protein Domains, Drug Discovery, Structural isomer, Humans, [CHIM]Chemical Sciences, Molecular Biology, Glucosamine, Binding Sites, 010405 organic chemistry, Chemistry, Ligand binding assay, Organic Chemistry, Stereoisomerism, Ceramide transport, Sphingolipid, 0104 chemical sciences, Molecular Docking Simulation, carbohydrates (lipids), 010404 medicinal & biomolecular chemistry, Docking (molecular), Molecular Medicine, Thermodynamics, lipids (amino acids, peptides, and proteins), Protein Binding
Abstract

Dysregulation of the ceramide transport protein CERT is associated to diseases such as cancer. In search for new CERT START domain ligands, N-dodecyl-deoxynojirimycin (N-dodecyl-DNJ) iminosugar was found to display, as a ceramide mimic, significant protein recognition. To reinforce the lipophilic interactions and strengthen this protein binding, a docking study was carried out in order to select the optimal position on which to introduce an additional O-alkyl chain on N-dodecyl-DNJ. Analysis of the calculated poses for three different regioisomers indicated an optimal calculated interaction pattern for N,O3-didodecyl-DNJ. The two most promising regioisomers were prepared by a divergent route and their binding to the CERT START domain was evaluated with fluorescence intensity (FLINT) binding assay. N,O3-didodecyl-DNJ was confirmed to be a new binder prototype with level of protein recognition in the FLINT assay comparable to the best known ligands from the alkylated HPA-12 series. This work opens promising perspectives for the development of new inhibitors of CERT-mediated ceramide trafficking.

Published
2020
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13. Concise asymmetric synthesis of new enantiomeric C -alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

Author

Stéphanie Ballereau, Frédéric Rodriguez, Thierry Levade, Yves Génisson, Cécile Dehoux, Yevhenii Shchukin, Isabelle Fabing, Virginie Garcia, Tessa Castellan, My Lan Tran, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and arroyo, anne-marie

Subjects
chemistry.chemical_classification, 0303 health sciences, biology, 010405 organic chemistry, Stereochemistry, Organic Chemistry, Enantioselective synthesis, Plasma protein binding, 01 natural sciences, Biochemistry, Enzyme assay, 0104 chemical sciences, 03 medical and health sciences, chemistry, Docking (molecular), [CHIM] Chemical Sciences, biology.protein, Residual activity, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, Enantiomer, Competitive inhibitor, Alkyl, 030304 developmental biology
Abstract

International audience; A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as β-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal β-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.

Published
2020
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15. Modification of endothelial nitric oxide synthase by 4-oxo-2(E)-nonenal(ONE) in preeclamptic placentas

Author

Christophe Vayssière, Olivier Parant, Paul Guerby, Koji Uchida, Frédéric Rodriguez, Anne Nègre-Salvayre, Takahiro Shibata, Oriane Tasta, Robert Salvayre, Audrey Swiader, Frédéric Pont, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Mise en Forme des Matériaux (CEMEF), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Département d'échographie et de Médecine fœtale, SIHCUS-CMCO, Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences-Nagoya University, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-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 de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Nagoya University, 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-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)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-PSL Research University (PSL)-MINES ParisTech - École nationale supérieure des mines de Paris, Institut de Recherche pour le Développement (IRD)-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 Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Régulations cellulaires: lipidoses et atherosclerose., Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), 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)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Placenta, Cell Culture Techniques, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, Biochemistry, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, Pre-Eclampsia, Enos, Pregnancy, Tandem Mass Spectrometry, Acrolein, ComputingMilieux_MISCELLANEOUS, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 3. Good health, Trophoblasts, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], embryonic structures, Female, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Adult, Nitric Oxide Synthase Type III, Cell Survival, Protein Carbonyl Content, Oxidative phosphorylation, Nitric Oxide, Preeclampsia, 4-Hydroxynonenal, Nitric oxide, Andrology, 03 medical and health sciences, Physiology (medical), medicine, Humans, Aldehydes, medicine.disease, biology.organism_classification, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Oxidative Stress, 030104 developmental biology, chemistry, Lipid Peroxidation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Chromatography, Liquid
Abstract

Preeclampsia (PE) is a leading cause of pregnancy complications, affecting 3-7% of pregnant women worldwide. The pathophysiology of preeclampsia involves a redox imbalance, oxidative stress and a reduced nitric oxide (NO) bioavailability. The molecular and cellular mechanisms leading to the dysfunction of the placental endothelial NO synthase (eNOS) are not clarified. This study was designed to investigate whether aldehydes generated by lipid peroxidation products (LPP), may contribute to placental eNOS dysfunction in PE. The analysis of placentas from PE-affected patients and normal pregnancies, showed a significant increase in protein carbonyl content, indicative of oxidative stress-induced protein modification, as shown by the accumulation of acrolein, 4-hydroxynonenal (HNE), and 4-oxo-2(E)-nonenal (ONE) adducts in PE placentas. In contrast, the levels of these LPP-adducts were low in placentas from normal pregnancies. Immunofluorescence and confocal experiments pointed out a colocalization of eNOS with ONE-Lys adducts, whereas eNOS was not modified in normal placentas. LC-MS/MS analysis of recombinant eNOS preincubated with ONE, allowed to identify several ONE-modified Lys-containing peptides, confirming that eNOS may undergo post-translational modification by LPP. The preincubation of HTR-8/SVneo human trophoblasts (HTR8) with ONE, resulted in ONE-Lys modification of eNOS and a reduced generation of NO. ONE inhibited the migration of HTR8 trophoblasts in the wound closure model, and this was partly restored by the NO donor, NOC-18, which confirmed the important role of NO in the invasive potential of trophoblasts. In conclusion, placental eNOS is modified by ONE in PE placentas, which emphasizes the sensitivity of this protein to oxidative stress in the disturbed redox environment of preeclamptic pregnancies.

Published
2019
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16. IDO1 and TDO inhibitory evaluation of analogues of the marine pyrroloiminoquinone alkaloids: Wakayin and Tsitsikammamines

Author

Laura Marchand, Benoît Van den Eynde, Luc Pilotte, Vincent Stroobant, Thomas Levy, Frédéric Rodriguez, Evelyne Delfourne, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-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-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), UCL - SSS/DDUV/GECE - Génétique cellulaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Ludwig Institute for Cancer Research [Brussels, Belgique], Université Catholique de Louvain (UCL)-Ludwig Institute for Cancer Research, Ludwig Institute for Cancer Research [Brussels, Belgium] (LICR - BRUSSELS), and Ludwig Institute for Cancer Research

Subjects
Aquatic Organisms, Protein Conformation, Clinical Biochemistry, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, Indole Alkaloids, Marine alkaloids, Tsitsikammamine, Drug Discovery, bispyrroloquinone, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Tryptophan Oxygenase, Pyrroloiminoquinone, Molecular Docking Simulation, pyrroloiminoquinone, Bispyrroloquinone, Quinolines, marine alkaloids, Molecular Medicine, IDO1 and TDO, wakayin, Protein Binding, tsitsikammamine, Inhibitory postsynaptic potential, Small Molecule Libraries, Structure-Activity Relationship, Alkaloids, Immune system, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, [CHIM]Chemical Sciences, Potency, Pyrroles, Wakayin, Molecular Biology, Pyrroloiminoquinones, 010405 organic chemistry, Cellular Assay, Organic Chemistry, HEK 293 cells, Tryptophan, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, HEK293 Cells, Enzyme, Cell culture
Abstract

International audience; Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two hemecontaining enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them being issued from an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.

Published
2021
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17. First triclosan-based macrocyclic inhibitors of InhA enzyme

Author

Nathalie Saffon, Josè Camilla Sammartino, Christian Lherbet, Maria Rosalia Pasca, Giulia Degiacomi, Frédéric Rodriguez, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative Toulousaine en Chimie Moléculaire (SFTCM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie, Università degli studi di Torino (UNITO), Universita degli Studi di Padova, Università degli Studi di Pavia, 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)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Padova = University of Padua (Unipd), and Università degli Studi di Pavia = University of Pavia (UNIPV)

Subjects
Macrocyclic Compounds, Stereochemistry, [SDV]Life Sciences [q-bio], Antitubercular Agents, Ether, Microbial Sensitivity Tests, 01 natural sciences, Biochemistry, Mycobacterium tuberculosis, Structure-Activity Relationship, chemistry.chemical_compound, InhA, Bacterial Proteins, Drug Discovery, [CHIM]Chemical Sciences, Enzyme Inhibitors, Molecular Biology, IC50, chemistry.chemical_classification, marchantin analogue, enoyl-ACP-reductase, Dose-Response Relationship, Drug, Molecular Structure, biology, 010405 organic chemistry, INHA, Organic Chemistry, Substrate (chemistry), biology.organism_classification, Triclosan, 0104 chemical sciences, 3. Good health, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Enzyme, Macrocycle, chemistry, Oxidoreductases
Abstract

International audience; Two macrocyclic derivatives based on the triclosan frame were designed and synthesized as inhibitors of Mycobacterium tuberculosis InhA enzyme. One of the two molecules M02 displayed promising inhibitory activity against InhA enzyme with an IC50 of 4.7 M. Molecular docking studies of these two compounds were performed and confirmed that M02 was more efficient as inhibitor of InhA activity. These molecules are the first macrocyclic direct inhibitors of InhA enzyme able to bind into the substrate pocket. Furthermore, these biaryl ether compounds exhibited antitubercular activities comparable to that of triclosan against M. tuberculosis H37Rv strain.

Published
2020
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18. Evaluation of heteroatom-rich derivatives as antitubercular agents with InhA inhibition properties

Author

Christian Lherbet, Mohamed Amari, Beatrice Silvia Orena, Frédéric Rodriguez, Mokhtar Fodili, Nadji Belkheiri, Bachar Rébat Moulkrere, Nathalie Saffon-Merceron, Giorgia Mori, Pascal Hoffmann, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, 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), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, chemistry.chemical_classification, biology, 010405 organic chemistry, Chemistry, Stereochemistry, INHA, Organic Chemistry, Heteroatom, Fatty Acid Biosynthesis Pathway, Pharmacology toxicology, biology.organism_classification, 01 natural sciences, 3. Good health, 0104 chemical sciences, Mycobacterium tuberculosis, 03 medical and health sciences, 030104 developmental biology, Enzyme, Docking (molecular), [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, ComputingMilieux_MISCELLANEOUS
Abstract

Two series of heterocyclic compounds derived from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (DHA) and 2-acetylbutyrolactone have been synthesized and characterized. The compounds were evaluated for their activities against Mycobacterium tuberculosis strain, and as inhibitors of InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. Among the tested compounds, one DHA derivative, compound 2, showed promising activity against both mycobacteria and InhA. Docking studies were also carried out and give some new structure-activity trends compatible with current structural knowledge.

Published
2018
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19. Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands

Author

Cécile Dehoux, Frédéric Rodriguez, Fabien Stauffert, Anne Bodlenner, Cécile Santos, Yves Génisson, Stéphanie Ballereau, Philippe Compain, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie moléculaire (LCM), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Strasbourg (ICS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
0301 basic medicine, Gene isoform, Spectrometry, Mass, Electrospray Ionization, Ceramide, Proton Magnetic Resonance Spectroscopy, Clinical Biochemistry, Iminosugar, Pharmaceutical Science, Plasma protein binding, Computational biology, Ligands, Biochemistry, Domain (software engineering), 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Protein Isoforms, [CHIM]Chemical Sciences, Carbon-13 Magnetic Resonance Spectroscopy, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Chemistry, Ligand, Molecular Mimicry, Organic Chemistry, Sphingolipid, Imino Sugars, Molecular Docking Simulation, 030104 developmental biology, Drug Design, Molecular Medicine, Function (biology)
Abstract

The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of (i) an iminoxylitol core structure and (ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.

Published
2017
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20. Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors

Author

Frédéric Rodriguez, Thierry Levade, Arnaud Rives, Cécile Baudoin-Dehoux, Yves Génisson, Fabien Stauffert, Tessa Castellan, Virginie Garcia, Philippe Compain, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Toulouse III - Paul Sabatier (UT3), 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 de Recherche pour le Développement (IRD)-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 Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de chimie moléculaire (LCM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biologie du Fruit, Institut National de la Recherche Agronomique (INRA), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-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-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and 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)

Subjects
Pyrrolidines, Mutant, Melanoma, Experimental, Iminosugar, Pharmaceutical Science, Gaucher disease, glycosidase inhibitors, 01 natural sciences, Pyrrolidine, Analytical Chemistry, Mice, chemistry.chemical_compound, Piperidines, Drug Discovery, Enzyme Inhibitors, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Molecular Structure, glucocerebrosidase, Hydrolysis, glucosylceramide synthase inhibitors, 3. Good health, Molecular Docking Simulation, Pharmacological chaperone, Chemistry (miscellaneous), ligand docking, Glucosylceramidase, Molecular Medicine, Piperidine, Imino Pyranoses, Protein Binding, medicine.drug, Ceramide, Stereochemistry, Ceramides, Ring (chemistry), Article, lcsh:QD241-441, pharmacological chaperones, Structure-Activity Relationship, 03 medical and health sciences, lcsh:Organic chemistry, Isomerism, iminosugars, medicine, Animals, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, 030304 developmental biology, 010405 organic chemistry, Organic Chemistry, Fibroblasts, Imino Sugars, 0104 chemical sciences, chemistry, Lysosomes, Glucocerebrosidase
Abstract

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal &beta, glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.

Published
2019
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21. Synthesis and In Vitro Antiproliferative Activity of Amido and Amino Analogues of the Marine Alkaloid Isogranulatimide

Author

Frédéric Rodriguez, Robert Kiss, Hubert Lavrard, Evelyne Delfourne, Béatrice Salvetti, Véronique Mathieu, Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacie, Université libre de Bruxelles (ULB), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), and Faculté de Pharmacie [Bruxelles] (ULB)

Subjects
Indoles, DNA damage, Antineoplastic Agents, Biology, Biochemistry, chemistry.chemical_compound, Cell Line, Tumor, Neoplasms, Drug Discovery, medicine, [CHIM]Chemical Sciences, Humans, CHEK1, General Pharmacology, Toxicology and Pharmaceutics, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Amination, Cell Proliferation, Pharmacology, Biological Products, Natural product, Alkaloid, Melanoma, Organic Chemistry, Imidazoles, medicine.disease, Amides, In vitro, 3. Good health, chemistry, Mechanism of action, Cell culture, Molecular Medicine, medicine.symptom
Abstract

Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.

Published
2015
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22. Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

Author

Tetiana Matviiuk, Christian Lherbet, Michel Baltas, Andrii I. Kysil, Christophe Menendez, Maria Rosalia Pasca, Frédéric Rodriguez, Beatrice Silvia Orena, Giorgia Mori, Zoia Voitenko, Jan Madacki, Christiane André-Barrès, Sonia Mallet-Ladeira, Jana Korduláková, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Comenius University in Bratislava, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Taras Shevchenko National University of Kyiv, and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, Pyrrolidines, Stereochemistry, Protein Conformation, Antitubercular Agents, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, 01 natural sciences, Pyrrolidine, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Bacterial Proteins, Drug Discovery, Escherichia coli, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, INHA, Organic Chemistry, Membrane Transport Proteins, General Medicine, biology.organism_classification, Pyrrolidinones, 0104 chemical sciences, 3. Good health, Molecular Docking Simulation, 030104 developmental biology, chemistry, Biochemistry, Drug Design, Oxidoreductases
Abstract

A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 μM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.

Published
2016
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23. Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

Author

Stéphanie Ballereau, Cécile Santos, Yves Génisson, Dušan Berkeš, Andrej Ďuriš, Frédéric Rodriguez, Adam Daïch, Laurence Fleury, Frédéric Ausseil, Unité de Recherche en Chimie Organique et Macromoléculaire (URCOM), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), PIERRE FABRE-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-Université Fédérale Toulouse Midi-Pyrénées-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)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Stereochemistry, Sonogashira coupling, Stereoisomerism, Thiophenes, Protein Serine-Threonine Kinases, Ceramides, Ligands, 010402 general chemistry, 01 natural sciences, Catalysis, Structure-Activity Relationship, Meta, Structure–activity relationship, Moiety, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, Ceramide Transfer Protein, 010405 organic chemistry, Chemistry, Ligand binding assay, Organic Chemistry, Enantioselective synthesis, Biological Transport, General Chemistry, Amides, 0104 chemical sciences, Protein Binding
Abstract

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

Published
2016
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24. Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents

Author

Christian Lherbet, Frédéric Rodriguez, Michel Baltas, Maria Rosalia Pasca, Aurélien Chollet, Cyril Inard, and Christophe Menendez

Subjects
Models, Molecular, Pharmacology, Protein Conformation, INHA, Chemistry, Stereochemistry, Organic Chemistry, Antitubercular Agents, Triazole, Mycobacterium tuberculosis, General Medicine, Triazoles, Chemical synthesis, chemistry.chemical_compound, Bacterial Proteins, Mic values, Drug Discovery, Mycobacterium tuberculosis H37Rv, Triazole derivatives, Enzyme Inhibitors, Oxidoreductases, Biological evaluation
Abstract

A series of triazoles have been prepared and evaluated as inhibitors of InhA as well as inhibitors of Mycobacterium tuberculosis H37Rv. Several of these new compounds possess a good activity against InhA, particularly compounds 17 and 18 for which molecular docking has been performed. Concerning their activities against M. tuberculosis H37RV strain, two of them, 3 and 12, were found to be good inhibitors with MIC values of 0.50 and 0.25 μg/mL, respectively. Particularly, compound 12 presenting the best MIC value of all compounds tested (0.6 μM) is totally inactive against InhA.

Published
2012
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25. Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents

Author

Frédéric Rodriguez, Christian Lherbet, Sylvain Gau, Christophe Menendez, Maria Rosalia Pasca, Michel Baltas, and Cyril Inard

Subjects
Models, Molecular, Stereochemistry, Antitubercular Agents, Triazole, Chemistry Techniques, Synthetic, Microbial Sensitivity Tests, Reductase, chemistry.chemical_compound, Minimum inhibitory concentration, Bacterial Proteins, Catalytic Domain, Drug Discovery, Enzyme Inhibitors, Pharmacology, INHA, Organic Chemistry, Substrate (chemistry), Mycobacterium tuberculosis, General Medicine, Triazoles, Triclosan, Cycloaddition, chemistry, Drug Design, Mycobacterium tuberculosis H37Rv, Triazole derivatives, Oxidoreductases
Abstract

InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target for the development of novel drugs against tuberculosis. We exploited copper-catalyzed [3+2] cycloaddition between alkynes and different azides to afford 1,4-disubstituted triazole or α-ketotriazole derivatives. Several compounds bearing a lipophilic chain mimicking the substrate were able to inhibit InhA. Among them, 1-dodecyl-4-phenethyl-1H-1,2,3-triazole displayed a minimum inhibitory concentration inferior to 2 μg/mL against Mycobacterium tuberculosis H37Rv.

Published
2011
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26. New Potent Bisubstrate Inhibitors of Histone Acetyltransferase p300: Design, Synthesis and Biological Evaluation

Author

Cécile Baudoin-Dehoux, Casimir Blonski, Frédéric Rodriguez, David Soupaya, Pascal Hoffmann, Martine Briet, Franciane Ho A Kwie, Marie Maturano, and Christian Lherbet

Subjects
Pharmacology, Histone Acetyltransferases, Histone Acetyltransferase p300, biology, Chemistry, Stereochemistry, Organic Chemistry, Active site, Biochemistry, Combinatorial chemistry, chemistry.chemical_compound, Histone, Docking (molecular), Drug Discovery, biology.protein, Molecular Medicine, Transferase, Linker, Lead compound
Abstract

Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.

Published
2010
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27. Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues

Author

Georges Hilal, Frédéric Rodriguez, Youssef Diab, Marwan El-Sabban, Evelyne Delfourne, Fadia Najjar, Rémi Safi, Mona Diab-Assaf, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Lebanese University [Beirut] (LU), Université Paris-Est, EIVP, affiliation inconnue, Department of Human Morphology, and American University of Beirut [Beyrouth] (AUB)

Subjects
0301 basic medicine, Agonist, Magnetic Resonance Spectroscopy, Spectrophotometry, Infrared, medicine.drug_class, Estrogen receptor, Pharmacology, Biochemistry, Benzoates, Mass Spectrometry, 03 medical and health sciences, chemistry.chemical_compound, Bridged Bicyclo Compounds, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, Medicine, [CHIM]Chemical Sciences, Humans, Cycloheptanes, IC50, ComputingMilieux_MISCELLANEOUS, Natural product, business.industry, Organic Chemistry, Antagonist, In vitro, 3. Good health, Molecular Docking Simulation, 030104 developmental biology, chemistry, Docking (molecular), 030220 oncology & carcinogenesis, Molecular Medicine, Antagonism, business, Sesquiterpenes
Abstract

The natural product ferutinin was shown to act as an agonist to estrogen receptor ERα and agonist/antagonist to ERβ featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c' exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1 μM. Docking simulation of 3c' in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c' binds as an antagonist to ERα protein while ferutinin acts as an agonist.

Published
2015
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28. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

Author

Giorgia Mori, Michel Baltas, Vania Bernardes-Génisson, Aurélien Chollet, Jana Korduláková, Frédéric Rodriguez, Jan Madacki, Isabelle Fabing, Maria Rosalia Pasca, Christian Lherbet, Annaïk Quémard, Patricia Constant, Christophe Menendez, Laboratoire de chimie de coordination (LCC), 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)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Comenius University in Bratislava, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), 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), 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)-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), Institut de Chimie de Toulouse (ICT-FR 2599), 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)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Models, Molecular, Indoles, Stereochemistry, efflux pumps, Medicinal chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Piperazines, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, InhA, Bacterial Proteins, Amide, Drug Discovery, inhibitors, Moiety, Enzyme Inhibitors, 030304 developmental biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, INHA, Organic Chemistry, General Medicine, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 0104 chemical sciences, Anti-Bacterial Agents, Piperazine, Enzyme, chemistry, Docking (molecular), Drug Design, Efflux, Oxidoreductases
Abstract

A series of fluorene-based derivatives was synthesized and evaluated for inhibiting both InhA and Mycobacterium tuberculosis growth. These compounds were inspired by the previously reported Genz-10850 molecule, a good InhA inhibitor, but with a poor activity against M. tuberculosis growth. Structure activity relationships were performed by introducing the following chemical modifications: 1) the piperazine ring; 2) the amide group; 3) the aryl moiety; and 4) the fluorene moiety. Among these new derivatives, one of them was more effective against both the InhA activity and mycobacterial growth, compared to the hit compound. Docking studies were also performed to rationalize activities of these derivatives. Furthermore, we showed for the first time that efflux pump inhibitors potentiated the efficacy of Genz-10850 (GEQ) derivatives against M. tuberculosis growth, demonstrating that these compounds could be substrates of some efflux pumps. (C) 2015 Elsevier Masson SAS. All rights reserved.

Published
2015
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29. The CERT antagonist HPA-12: first practical synthesis and individual binding evaluation of the four stereoisomers

Author

Cécile Baudoin-Dehoux, Laurence Fleury, Adam Daïch, Dušan Berkeš, Jozef Markus, Stéphanie Ballereau, Frédéric Ausseil, Cécile Santos, Yves Génisson, Frédéric Rodriguez, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Chimie Organique et Macromoléculaire (URCOM), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU), Institut de Recherche pour le Développement (IRD)-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 Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Stereochemistry, High-throughput screening, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Stereoisomerism, Protein Serine-Threonine Kinases, Biochemistry, Stereocenter, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, [CHIM]Chemical Sciences, Humans, Binding site, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Binding Sites, Dose-Response Relationship, Drug, Chemistry, Organic Chemistry, Antagonist, Combinatorial chemistry, Amides, Enantiopure drug, Molecular Medicine, Stereoselectivity
Abstract

The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC₅₀. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening.

Published
2015
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30. Design of granulatimide and isogranulatimide analogues as potential Chk1 inhibitors: Study of amino-platforms for their synthesis

Author

Hubert Lavrard, Evelyne Delfourne, Frédéric Rodriguez, Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Granulatimide, Indoles, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, 010402 general chemistry, 01 natural sciences, Biochemistry, Structure-Activity Relationship, Alkaloids, Drug Discovery, [CHIM]Chemical Sciences, CHEK1, Molecular Biology, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Isogranulatimide, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Imidazoles, Combinatorial chemistry, 3. Good health, 0104 chemical sciences, Cancer treatment, Drug Design, Checkpoint Kinase 1, Molecular Medicine, biological phenomena, cell phenomena, and immunity, Protein Kinases
Abstract

The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described.

Published
2014
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31. Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis

Author

Michel Baltas, Christian Lherbet, Frédéric Rodriguez, Giorgia Mori, Brigitte Guidetti, Zoia Voitenko, Maria Rosalia Pasca, Tetiana Matviiuk, Marian V. Gorichko, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, and Taras Shevchenko National University of Kyiv

Subjects
Models, Molecular, Pyrrolidines, Stereochemistry, Antitubercular Agents, Microbial Sensitivity Tests, Pyrrolidine, Catalysis, Mycobacterium tuberculosis, Structure-Activity Relationship, chemistry.chemical_compound, Bacterial Proteins, Succinimide, Drug Discovery, Humans, Tuberculosis, Structure–activity relationship, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, Chemistry, INHA, Organic Chemistry, General Medicine, biology.organism_classification, 3. Good health, Mycobacterium tuberculosis H37Rv, Michael reaction, Oxidoreductases
Abstract

In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.

Published
2014
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32. Electrooptics Studies of Escherichia coli Electropulsation: Orientation, Permeabilization, and Gene Transfer

Author

Frédéric Rodriguez, Justin Teissié, N. Eynard, and J. Trotard

Subjects
Cell Membrane Permeability, Light, Kinetics, Biophysics, Analytical chemistry, Biology, Transfection, medicine.disease_cause, Plasmid, Nephelometry and Turbidimetry, Escherichia coli, medicine, Microscopy, Video, Pulse (signal processing), Electroporation, Gene Transfer Techniques, Pulse duration, DNA, biology.organism_classification, Transformation (genetics), Bacteria, Plasmids, Research Article
Abstract

Fast optical transient signals are suitable approaches to the investigation of the behavior of bacteria during an electric pulse. In a previous work, by a dual approach taking advantage of a video method and a fast kinetic study of the light transmitted across a cell suspension, we showed that a field-induced orientation phenomenon was affecting the rod-shaped bacteria during the pulse (Eynard et al., 1992. Eur. J. Biochem. 209:431-436). In the present work, time courses of electro-induced responses of bacteria during a single square-wave pulse are analyzed. Observations of both the orientation step and the permeabilization process are relevant. These two steps are affected by the addition of DNA. They both obey to a first-order kinetic. The conclusion of this work is that Escherichia coli permeabilization and transformation are multistep processes: orientation (step 1) is followed by an envelope alteration (step 2), all steps being affected by plasmid addition. In the case of E. coli, a rod-shaped bacteria, the orientation process (step 1) brings the cell parallel to the field direction. The pulse duration must be longer than the orientation characteristic time (approximately 1 ms) to trigger an effective permeabilization and its associated events. The permeabilization process (step 2) is associated with a field-induced dipole effect.

Published
1998
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33. Design, chemical synthesis of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives and biological activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis

Author

Zoia Voitenko, Tetiana Matviiuk, Michel Baltas, Ana Luisa de Jesus Lopes Ribeiro, Christian Lherbet, Frédéric Rodriguez, Maria Rosalia Pasca, Nathalie Saffon, Sonia Mallet-Ladeira, and Marian V. Gorichko

Subjects
Models, Molecular, Stereochemistry, Enoyl-acyl carrier protein reductase, Antitubercular Agents, Microbial Sensitivity Tests, Reductase, Chemical synthesis, Pyrrolidine, Mycobacterium tuberculosis, chemistry.chemical_compound, Structure-Activity Relationship, Bacterial Proteins, Drug Discovery, Enzyme Inhibitors, Pharmacology, chemistry.chemical_classification, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, INHA, Organic Chemistry, Biological activity, General Medicine, biology.organism_classification, Pyrrolidinones, Kinetics, Enzyme, Biochemistry, Drug Design, Oxidoreductases
Abstract

We report here the discovery, synthesis and screening results of a series of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives as a novel class of potent inhibitors of Mycobacterium tuberculosis H37Rv strain as well as the enoyl acyl carrier protein reductase (ENR) InhA. Among them, several compounds displayed good activities against InhA which is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of the mycobacteria cell wall. Furthermore, some exhibited promising activities against M. tuberculosis and multi-drug resistant M. tuberculosis strains.

Published
2013

34. Synthesis and evaluation of α-ketotriazoles and α,β-diketotriazoles as inhibitors of Mycobacterium tuberculosis

Author

Céline Frongia, Frédéric Rodriguez, Maria Rosalia Pasca, Ana Luisa de Jesus Lopes Ribeiro, Valérie Lobjois, Christian Lherbet, Christophe Menendez, Francesca Zara, Michel Baltas, and Nathalie Saffon

Subjects
Tuberculosis, Colorectal cancer, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Structure-Activity Relationship, Drug Discovery, medicine, Cytotoxic T cell, Humans, Fibroblast, Cytotoxicity, Pharmacology, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, General Medicine, Ketones, Triazoles, medicine.disease, biology.organism_classification, HCT116 Cells, Anti-Bacterial Agents, medicine.anatomical_structure, Biochemistry, Cell culture
Abstract

Two series of α-ketotriazole and α,β-diketotriazole derivatives were synthesized and evaluated for antitubercular and cytotoxic activities. Among them, two α,β-diketotriazole compounds, 6b and 9b, exhibited good activities (minimum inhibitory concentration = 7.6 μM and 6.9 μM, respectively) on Mycobacterium tuberculosis and multi-drug resistant M. tuberculosis strains and presented no cytotoxicity (IC50 > 50 μM) on colorectal cancer HCT116 and normal fibroblast GM637H cell lines. These two compounds represent promising leads for further optimization.

Published
2013

35. ChemInform Abstract: Synthesis and Biological Activities of Triazole Derivatives as Inhibitors of InhA and Antituberculosis Agents

Author

Frédéric Rodriguez, Maria Rosalia Pasca, Michel Baltas, Sylvain Gau, Christophe Menendez, Christian Lherbet, and Cyril Inard

Subjects
Chemistry, INHA, Triazole derivatives, General Medicine, Combinatorial chemistry, Cycloaddition
Abstract

α-Ketotriazoles (V) are obtained in a one-pot cycloaddition reaction between ethynyl ketones (III) and azides (IV) mediated by Cu(II) without prior deprotection.

Published
2012
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36. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: structure activity relationships

Author

Michelle Mazallon, Frédéric Rodriguez, Sylvaine Lecoeur, Caroline Prouillac, Farah Koraichi, Bernadette Videmann, Michel Baltas, Mycotoxines et Toxicologie Comparée des Xénobiotiques (MET), Ecole Nationale Vétérinaire de Lyon (ENVL)-Institut National de la Recherche Agronomique (INRA), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
EXPRESSION, medicine.medical_specialty, medicine.drug_class, Placenta, [SDV]Life Sciences [q-bio], Cellular differentiation, Receptors, Cytoplasmic and Nuclear, Biology, Toxicology, Cell Line, Structure-Activity Relationship, HUMAN CHORIONIC-GONADOTROPIN, FUSION, Internal medicine, medicine, Humans, Estrogens, Non-Steroidal, Liver X receptor, Receptor, LINE BEWO, Pharmacology, Pregnane X receptor, RECEPTOR, fungi, Trophoblast, Cell Differentiation, PROGESTERONE, Mycotoxins, TRANSPORTERS, BEWO CELLS, Cell biology, Trophoblasts, DIFFERENTIATION, Endocrinology, medicine.anatomical_structure, Nuclear receptor, Estrogen, Cell culture, Zearalenone, Zeranol, ABC transporter, Biomarkers
Abstract

Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to alpha- and beta-zearalenol (alpha ZEL and beta zEL). These reduced metabolites possess estrogenic properties, alpha ZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of alpha ZEL and beta ZEL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPAR gamma). Our results demonstrated that in spite of structure similarities between ZEN, alpha ZEL and beta zEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. (C) 2012 Elsevier Inc. All rights reserved.

Published
2011
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37. New potent bisubstrate inhibitors of histone acetyltransferase p300: design, synthesis and biological evaluation

Author

Franciane Ho A, Kwie, Martine, Briet, David, Soupaya, Pascal, Hoffmann, Marie, Maturano, Frédéric, Rodriguez, Casimir, Blonski, Christian, Lherbet, and Cécile, Baudoin-Dehoux

Subjects
Models, Molecular, Research Design, Reproducibility of Results, Coenzyme A, Enzyme Inhibitors, Molecular Dynamics Simulation, Amides, Histone Acetyltransferases, Protein Binding
Abstract

Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.

Published
2010

38. Watson–Crick Base-Pairing Properties of Nucleic Acid Analogues with Stereocontrolled α and β Torsion Angles (α,β-D-CNAs)

Author

Frédéric Rodriguez, Nathalie Iché-Tarrat, Christelle Dupouy, Marie-Pierre Durrieu, Alain Vigroux, Jean-Marc Escudier, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Solidarités, Sociétés, Territoires (LISST), and École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
010405 organic chemistry, Oligonucleotide, Chemistry, Base pair, Stereochemistry, [SDV]Life Sciences [q-bio], Alpha (ethology), Torsion (mechanics), General Chemistry, General Medicine, 010402 general chemistry, 01 natural sciences, Catalysis, 0104 chemical sciences, Crystallography, Nucleic acid thermodynamics, Torsion (algebra), Nucleic acid, [CHIM]Chemical Sciences, [PHYS.PHYS.PHYS-CHEM-PH]Physics [physics]/Physics [physics]/Chemical Physics [physics.chem-ph], Nucleic acid structure, Beta (finance), Nucleic acid analogue
Abstract

International audience; Constrained nucleic acids (α,β‐D‐CNAs) have an ethylene bridge that locks the α and β backbone torsion angles of DNA in the canonical (gauche(−),trans) conformation, as in B‐form DNA (see picture), or in the noncanonical (gauche(+),trans) conformation. Canonical α,β‐D‐CNAs enhance the duplex‐forming ability of oligonucleotides with complementary DNA, while noncanonical α,β‐D‐CNAs stabilize distorted B‐DNA structures.

Published
2006
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40. Effect of Zearalenone gestational exposure: Modulation of placenta cell differentiation and transport function

Author

Caroline Prouillac, Sylvaine Lecoeur, Michel Baltas, Michelle Mazallon, Mohamed Benahmed, Frédéric Rodriguez, Farah Koraichi, Bernadette Videmann, Rongeurs sauvages, risques sanitaires et gestion des populations, Institut National de la Recherche Agronomique (INRA)-ISARA-Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Université de Lyon (COMUE), UPE, European Union Reference Laboratory for equine diseases (EURL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon

Subjects
0303 health sciences, Gestational exposure, Chemistry, [SDV]Life Sciences [q-bio], Cellular differentiation, zearalenone, General Medicine, Toxicology, 3. Good health, Andrology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine.anatomical_structure, Placenta, medicine, Zearalenone, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology
Abstract

International audience

Published
2013
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43. A biologically relevant ceramide fluorescent probe to assess the binding of potential ligands to the CERT transfer protein

Author

Chantal Galaup, Cécile Baudoin-Dehoux, Céline Frongia, Stéphanie Ballereau, Frédéric Rodriguez, Thierry Levade, Cécile Santos, Yves Génisson, Stéphanie Combemale, Valérie Lobjois, and Virginie Garcia

Subjects
chemistry.chemical_compound, Ceramide, Sphingosine, chemistry, Stereochemistry, Ligand, General Chemical Engineering, Amide, Lipophilicity, Moiety, General Chemistry, Sphingomyelin, Fluorescence
Abstract

The conversion of ceramide into sphingomyelin (SM) was only recently considered in relation to cancer. Overexpression of the CERT protein, responsible for a highly specific inter-organelle ceramide transfer step along the de novo SM synthesis pathway, has been associated with multi-drug resistance of cancer cells. Identification of new CERT antagonists may therefore lead to potential resensitizing agents. This work describes the first attempt to design a ceramide-based fluorescent probe optimised to evaluate the binding of potential CERT ligands. A prototypical structure with an ω-labelled sphingosine backbone was selected. Its possible recognition mode by CERT was first evaluated by means of a precursory molecular modelling study. Three derivatives with various amide chain lengths were prepared and tested. The binding efficiency was shown to be proportional to the lipophilicity of the acyl moiety. The best compound bearing a C16 amide fragment was used to implement a practical binding experiment. Facile assessment of the recognition by the CERT START domain of various structures was thus ensured. Metabolism and imaging experiments were also used to illustrate the capacity of the proposed fluorescent ceramide analogue to mimic the natural ceramide cellular behaviour. This work led to the synthesis and evaluation as an efficient CERT START domain ligand of a ω-biotinylated ceramide, a potential probe to develop the screening of new CERT antagonists.

Published
2013
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44. Self-association processes involving anthracene labeled phosphatidylcholines in model membrane

Author

Jean-François Tocanne, Frédéric Rodriguez, and André Lopez

Subjects
Anthracene, Vesicle, Organic Chemistry, Biophysics, Phospholipid, Analytical chemistry, Biochemistry, Fluorescence, chemistry.chemical_compound, Membrane, chemistry, Phosphatidylcholine, Lipid bilayer, Equilibrium constant
Abstract

When studying lipid-lipid or lipid-protein interaction in membranes, the correct interpretation of data obtained when using fluorescent phospholipid probes requires the best possible knowledge of probe behaviour in phosopholipid membranes. Analysis of the translational dynamics and photochemical properties of the anthracene-labeled phosphatidylcholine (EAPC) shows that a self-association process occurs with this probe in the membrane at the ground state. This anthracene self-association is characterized and leads to a hypochromic effect which has been studied by means of ultraviolet absorption spectroscopy in unilamellar egg-yolk phosphatidylcholine (EggPC) vesicles. A model with indefinite linear self-association, in which each step has the same equilibrium constant, best describes the data. The equilibrium constant was found to be in the 300–500 M−1 range and the complex lateral distribution pattern of EAPC in model membranes, which results from this self-association process, is characterized and seems to be mainly controlled by the amount of EAPC incorporated into the lipid bilayer.

Published
1993

45. Pares y redes de laboratorios del Centre National de la Recherche Scientifique y de sus asociados

Author

Adrien Defossez, Marie Pierre Bès, and Frédéric Rodriguez

Subjects
H1-99, contrato, Communication, alianza, partnership, Social Sciences, Network, Red, Social sciences (General), lcsh:Social Sciences, lcsh:H, lcsh:H1-99, lcsh:Social sciences (General), contract, laboratory, laboratorio, Social Sciences (miscellaneous)
Abstract

El siguiente artículo arroja luz sobre el tema de la organización "irreversible" de las alianzas de investigación, a partir de datos longitudinales relativos a los contratos firmados por grupos de investigación del Centre National de la Recherche Scientifique (CNRS) con organismos financiadores (empresas, administraciones) entre 1986 y 2005. Los datos ponen de relieve diferentes aspectos: en primer lugar, los contratos tienden a ser volátiles y efímeros. Además, los laboratorios no presentan el mismo comportamiento que sus asociados en cuanto a cooperación, y cabe señalar que la repetición de los contratos conlleva una cierta "fidelidad" a su asociado. Por último, el análisis de estas alianzas desde el punto de vista de las redes sociales científicas ha puesto de manifiesto la convergencia de los modos de compatibilidad entre las grandes empresas y los grupos del CNRS, e igualmente la existencia de "pequeños mundos científicos".

Published
2010
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46. Watson–Crick Base-Pairing Properties of Nucleic Acid Analogues with Stereocontrolled α and β Torsion Angles (α,β-D-CNAs)We thank the Centre Informatique National de l'Enseignement Supérieur (CINES) and the Centre Interuniversitaire de Calcul de Toulouse (CALMIP) for the generous allocation of computer time and Dr. M. Erard for assistance with the CD experiments. D-CNAs=constrained nucleic acids with dioxaphosphorinane ring.

Author

Christelle Dupouy, Nathalie Iché-Tarrat, Marie-Pierre Durrieu, Frédéric Rodriguez, Jean-Marc Escudier, and Alain Vigroux

Published
2006
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47. Methods for obtaining the midpoint potential E(m,pH) of a bacterial chromophore

Author

Frédéric Rodriguez and Michel Prats

Subjects
chemistry.chemical_classification, Rhodobacter, biology, Biochemistry, chemistry, Stereochemistry, General Chemistry, Chromophore, biology.organism_classification, Chromatophore, Carotenoid, Education
Abstract

The authors present a critical analysis of three methods that are used to determine the carotenoid midpoint potential of chromatophores extracted from Rhodobacter capsulatus.

Published
1992
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48. Comparutions immédiates : quelle Justice ? Regards citoyens sur une justice du quotidien

Author

Welzer-Lang, Daniel, Castex, Patrick, WELZER-LANG, Daniel, Laboratoire Interdisciplinaire Solidarités, Sociétés, Territoires (LISST), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA), financement associatif et militant, Ligue des droits de l'Homme, Américo Mariani, Frédéric Rodriguez, Sébastien Saetta, Rémi Cochard, Hervé Dubost, Préface de Serge PORTELLI Postface de Pascal NAKACHE, and École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
comparutions immédiates, recherche citoyenne, [SHS] Humanities and Social Sciences, citoyenneté, justice, [SHS]Humanities and Social Sciences
Abstract

International audience; L’Observatoire des comparutions immédiates a été créé par la Ligue des droits de l’Homme de Toulouse, associée à des universitaires. Du 1er février au 30 juin 2011, 47 auditeurs et auditrices ont observé 543 affaires au terme de 112 audiences, auditionné avocat-e-s, magistrats, et autres professionnel-le-s du droit. Des observations réalisées et de l’étude statistique, il ressort que cette procédure revêt un caractère expéditif (les affaires sont jugées en 36 minutes en moyenne), peu respectueux des droits des personnes prévenues ET des victimes. Cette procédure met à mal les principes de la justice républicaine : présomption d’innocence, procès équitable, individualisation et sens de la peine.La population étudiée est surtout jeune, pauvre, précaire et masculine, souvent en mauvaise santé ; en un mot des « mauvais pauvres ». Plus de la moitié d’entre-elle est « colorée » ; les auteurs s’interrogent sur les mesures discriminatoires que subissent « Beurs » et « Blacks » en situation régulière ou non (sans papiers), moins concernés par les délits avec violence, les atteintes aux biens et aux personnes, mais plus envoyés en prison.Bras armé de la politique pénale, la judiciarisation du quotidien que sont les comparutions immédiates donne à voir les effets destructeurs de la précarité et de la petite délinquance. Le livre montre aussi à travers les récidives (massives dans les délits de circulation, les violences conjugales, comme les atteintes aux biens) l’échec de cette procédure et de l’exemplarité de la peine.L’analyse des affaires après et avant le 15 avril 2011 (date de la réforme de la garde à vue), comme la comparaison des chiffres entre Lyon et Toulouse, met en évidence un « effet système » qui semble s’imposer à l’ensemble des acteurs et actrices de la chaine pénale des comparutions immédiates ; « effet système » qui pourrait bien relativiser l’impact de la participation des Citoyens assesseurs en cours d’expérimentation dans quelques juridictions (dont Toulouse).Le livre est aussi enrichi par les apports de responsables de centre de réinsertion pour sortants de prison, d’association pour femmes victimes de violences, d’avocats et magistrats. Serge Portelli, Gilles Sainati, magistrats et Laurent Mucchielli sociologue, qui ont développé des analyses sur les comparutions immédiates et sur le thème de l’insécurité ont aussi contribué à cet ouvrage.

Published
2012

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