Search

Your search keyword '"MESH: Molecular Structure"' showing total 265 results
Start Over Descriptor "MESH: Molecular Structure"
265 results on '"MESH: Molecular Structure"'

1. Voatriafricanines A and B, Trimeric Vobasine-Aspidosperma-Aspidosperma Alkaloids from Voacanga africana

Author

Jérôme Vanheuverzwijn, Franck Meyer, Augustin Ephrem Nkengfack, Véronique Fontaine, Jean-François Gallard, Pierre Le Pogam, Erwan Poupon, Mehdi A. Beniddir, Karine Leblanc, Pierre Mkounga, Zhiyu Zhou, Somia Rharrabti, Hugues Fouotsa, Guillaume Bernadat, Alain Meli Lannang, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Université de Yaoundé I - UY1 (CAMEROON), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Transfrontalière BioEcoAgro - UMR 1158 (BioEcoAgro), Université d'Artois (UA)-Université de Liège-Université de Picardie Jules Verne (UPJV)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Faculté de Pharmacie [Bruxelles] (ULB), and Université libre de Bruxelles (ULB)

Subjects
medicine.drug_class, Stereochemistry, Monoterpene, MESH: Molecular Structure, Pharmaceutical Science, MESH: Voacanga, 010402 general chemistry, Antimycobacterial, 01 natural sciences, Homonuclear molecule, Analytical Chemistry, MESH: Anti-Bacterial Agents, Immunologie, Drug Discovery, medicine, [CHIM]Chemical Sciences, MESH: Phytochemicals, Pharmacology, biology, 010405 organic chemistry, Hydrogen bond, Chemistry, Organic Chemistry, Biologie moléculaire, MESH: Cameroon, biology.organism_classification, 0104 chemical sciences, MESH: Indole Alkaloids, Voacanga africana, Complementary and alternative medicine, Heteronuclear molecule, Intramolecular force, Aspidosperma, Molecular Medicine, Biologie cellulaire, Microbiologie et protistologie [bacteriol.virolog.mycolog.], MESH: Plant Bark
Abstract

International audience; Voatriafricanines A and B (1 and 2), the first examples of vobasine-aspidosperma-aspidosperma monoterpene trisindole alkaloids, were isolated from the stem barks of Voacanga africana, guided by a molecular networking strategy. Their structures, including absolute configurations, were elucidated by spectroscopic methods and ECD calculations. Compounds 1 and 2 possess intramolecular hydrogen bonding, sufficiently robust to transfer homonuclear and heteronuclear magnetizations. Compound 1 exhibited potent antimycobacterial activity with no discernible cytotoxic activity.

Published
2021
Full Text
View/download PDF

2. Porphyrin Binding and Irradiation Promote G-Quadruplex DNA Dimeric Structure

Author

Aurelien Thureau, M. Longo, Anne Martel, Alessandro Paciaroni, Caterina Petrillo, Valeria Libera, Giorgio Schirò, Lucia Comez, Elena A. Andreeva, Dipartimento di Fisica e Geologia [Perugia], Università degli Studi di Perugia (UNIPG), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), European Synchrotron Radiation Facility (ESRF), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Jülich Centre for Neutron Science (JCNS), Forschungszentrum Jülich GmbH at Heinz Maier-Leibnitz Zentrum (MLZ), and Università degli Studi di Perugia = University of Perugia (UNIPG)

Subjects
Porphyrins, Dimer, MESH: Molecular Structure, 010402 general chemistry, G-quadruplex, SEQUENCE, 01 natural sciences, MESH: Circular Dichroism, Scattering, 03 medical and health sciences, chemistry.chemical_compound, MESH: X-Rays, ABSORPTION, Scattering, Radiation, General Materials Science, Physical and Theoretical Chemistry, MESH: Scattering, Radiation, Protein secondary structure, 030304 developmental biology, 0303 health sciences, MESH: Porphyrins, Radiation, Molecular Structure, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Circular Dichroism, X-Rays, MESH: DNA, CATIONIC PORPHYRINS, DNA, Telomere, Porphyrin, Small molecule, 0104 chemical sciences, G-Quadruplexes, chemistry, MESH: Dimerization, Nucleic acid, Biophysics, Protein quaternary structure, LIGAND, MESH: Telomere, TELOMERE G-QUADRUPLEX, Dimerization, TMPYP4, MESH: G-Quadruplexes
Abstract

International audience; Nucleic acid sequences rich in guanines can organize into noncanonical DNA G-quadruplexes (G4s) of variable size. The design of small molecules stabilizing the structure of G4s is a rapidly growing area for the development of novel anticancer therapeutic strategies and bottom-up nanotechnologies. Among a multitude of binders, porphyrins are very attractive due to their light activation that can make them valuable conformational regulators of G4s. Here, a structure-based strategy, integrating complementary probes, is employed to study the interaction between TMPyP4 porphyrin and a 22-base human telomeric sequence (Tel22) before and after irradiation with blue light. Porphyrin binding is discovered to promote Tel22 dimerization, while light irradiation of the Tel22-TMPyP4 complex controls dimer fraction. Such a change in quaternary structure is found to be strictly correlated with modifications at the secondary structure level, thus providing an unprecedented link between the degree of dimerization and the underlying conformational changes in G4s.

Published
2021
Full Text
View/download PDF

3. Streamlined targeting of Amaryllidaceae alkaloids from the bulbs of Crinum scillifolium using spectrometric and taxonomically-informed scoring metabolite annotations

Author

Aboua Timothée Okpekon, Pierre Le Pogam, Blandine Séon-Méniel, Pierre Champy, Nicaise F. Bony, Amon Diane N'Tamon, Jean-François Gallard, Tapé Kouamé, Michèle Aké, Somia Rharrabti, Guillaume Bernadat, Mehdi A. Beniddir, Philippe Grellier, N’Cho Christophe Amin, Karine Leblanc, Elisabeth Mouray, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Laboratoire de Chimie Organique et de Substances Naturelles (LCOSN), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Félix Houphouët-Boigny (UFHB), Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Institut méditerranéen d'océanologie (MIO), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, Stereochemistry, In silico, Metabolite, MESH: Molecular Structure, MESH: Plant Extracts, MESH: Plant Roots, MESH: Amaryllidaceae Alkaloids, Plant Science, Horticulture, Plant Roots, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Alkaloids, MESH: Alkaloids, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Crinum, Humans, [CHIM]Chemical Sciences, Crinum scillifolium, Molecular networking, Amaryllidaceae Alkaloids, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Pretazettine, MESH: Humans, Molecular Structure, biology, MESH: Crinum, Plant Extracts, 010405 organic chemistry, Amaryllidaceae, General Medicine, biology.organism_classification, In silico data base, 0104 chemical sciences, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Two-dimensional nuclear magnetic resonance spectroscopy, 010606 plant biology & botany
Abstract

International audience; Four undescribed alkaloids have been isolated from the bulbs of the previously unstudied Crinum scillifolium. These compounds were targeted following a state-of-the-art molecular networking strategy comprising a dereplication against in silico databases and re-ranking of the candidate structures based on taxonomically informed scoring. The unreported structures span across a variety of Amaryllidaceae alkaloids appendages. Their structures were unambiguously elucidated by thorough interpretation of their HRESIMS and 1D and 2D NMR data, and comparison to literature data. DFT-NMR calculations were performed to support the determined relative configurations of scillitazettine and scilli-N-desmethylpretazettine and their absolute configurations were mitigated by comparison between experimental and theoretically calculated ECD spectra. The lack of a methyl group on the nitrogen atom in the structure of scilli-N-desmethylpretazettine series is highly unusual in the pretazettine/tazettine series but the most original structural feature in it lies in its 11α disposed hydrogen, which is new to pretazettines. The antiplasmodial as well as the cytotoxic activities against the human colon cancer cell line HCT116 were evaluated, revealing mild to null activities.

Published
2020
Full Text
View/download PDF

4. Stealth fluorescence labeling for live microscopy imaging of mRNA delivery

Author

Elin K. Esbjörner, Jesper R. Nilsson, Audrey Gallud, Marcel Hollenstein, Cécile Gasse, Emanuele Celauro, Anders Dahlén, Fabienne Levi-Acobas, Tom Baladi, Ivo Sarac, L. Marcus Wilhelmsson, Chalmers University of Technology [Gothenburg, Sweden], AstraZeneca, Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Chimie bioorganique des acides nucléiques - Bioorganic chemistry of nucleic acids, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was conducted as part of the FoRmulaEx research center for nucleotide delivery and with associated financial support to E.K.E. and L.M.W. from the Swedish Foundation for Strategic Research (SSF, Grant No. IRC15-0065). F.L.-A., I.S., and M.H. acknowledge funding from Institut Pasteur., Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cytosine, translation, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, fluorescence labeling, Biochemistry, 01 natural sciences, law.invention, Green fluorescent protein, Histones, chemistry.chemical_compound, Colloid and Surface Chemistry, law, MESH: COVID-19, nucleobase triphosphate, MESH: Histones, 0303 health sciences, Molecular Structure, medicine.diagnostic_test, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Electroporation, Translation (biology), Transfection, MESH: Fluorescent Dyes, Molecular Imaging, Cell biology, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, MESH: Spectrometry, Fluorescence, Cytosine, MESH: Cell Line, Tumor, mRNA, Green Fluorescent Proteins, MESH: Molecular Structure, 010402 general chemistry, Fluorescence, Article, Catalysis, Flow cytometry, 03 medical and health sciences, MESH: Green Fluorescent Proteins, Confocal microscopy, Cell Line, Tumor, medicine, Humans, [CHIM]Chemical Sciences, RNA, Messenger, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Fluorescent Dyes, MESH: RNA, Messenger, 030304 developmental biology, Messenger RNA, MESH: Humans, MESH: Molecular Imaging, MESH: Fluorescence, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, COVID-19 Drug Treatment, 0104 chemical sciences, live cell imaging, Spectrometry, Fluorescence, drug delivery, Nucleic acid
Abstract

International audience; Methods for tracking RNA molecules inside living cells without perturbing their natural interactions and functions are critical within biology and, in particular, to facilitate studies of therapeutic RNA delivery. We present a stealth labeling approach that can efficiently, and with high fidelity, generate RNA transcripts of any length, through enzymatic incorporation of the triphosphate of tC O-a fluorescent tricyclic cytosine analogue. We demonstrate this by incorporation of tC O in up to 100% of the natural cytosine positions of a 1.2 kb mRNA encoding for the histone H2B fused to GFP (H2B:GFP). Spectroscopic characterization of this mRNA shows that the incorporation rate of tC O is similar to cytosine, which not only indicates tC O 's excellent nucleotide analogue properties, but also the possibility for efficient labeling and controlled tuning of labeling ratios for different applications. Using live cell confocal microscopy and flow cytometry, we show that the tC Olabeled mRNA is efficiently and correctly translated into H2B:GFP inside human cells. Hence, we not only pioneer the use of fluorescent base analogue labeling of nucleic acids in live-cell microscopy but also, importantly, show that the resulting transcript can be correctly translated. Moreover, the spectral properties of our transcripts and their translation product allow for their straightforward, simultaneous visualization in live cells. Finally, we find that transfected tC O-labeled RNA, unlike the corresponding state-of-the-art fluorescently labeled RNA, translates equally efficient as its natural counterpart, hence representing a methodology for studying natural, unperturbed processing of mRNA used in RNA therapeutics as well as in vaccines, like the ones currently under development against SARS-CoV-2.

Published
2020
Full Text
View/download PDF

5. Corynanthean-Epicatechin Flavoalkaloids from Corynanthe pachyceras

Author

Kouamé, Tapé, Okpekon, Aboua Timothée, Bony, Nicaise, N'Tamon, Amon Diane, Gallard, Jean-François, Rharrabti, Somia, Leblanc, Karine, Mouray, Elisabeth, Grellier, Philippe, Champy, Pierre, Beniddir, Mehdi, Le Pogam, Pierre, N’tamon, Amon Diane, Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Laboratoire de Chimie Organique et de Substances Naturelles (LCOSN), Université Félix Houphouët-Boigny (UFHB), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'océanographie et de biogéochimie (LOB), Université de la Méditerranée - Aix-Marseille 2-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)

Subjects
Magnetic Resonance Spectroscopy, Monoterpene, [SDV]Life Sciences [q-bio], Flavonoid, Pharmaceutical Science, Corynanthean, Corynanthe pachyceras, 01 natural sciences, Catechin, Mass Spectrometry, Indole Alkaloids, Analytical Chemistry, Pausinystalia, Drug Discovery, MESH: Pausinystalia, ComputingMilieux_MISCELLANEOUS, rubiaceae, MESH: Inhibitory Concentration 50, Anthelmintics, chemistry.chemical_classification, 0303 health sciences, molecular networking, MESH: Plant Stems, Molecular Structure, Plant Stems, Chemistry, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Anthelmintics, Chemistry (miscellaneous), Molecular networking, Plant Bark, Molecular Medicine, MESH: Monoterpenes, Two-dimensional nuclear magnetic resonance spectroscopy, MESH: Plant Bark, Stereochemistry, MESH: Catechin, MESH: Molecular Structure, Article, lcsh:QD241-441, Inhibitory Concentration 50, 03 medical and health sciences, lcsh:Organic chemistry, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, 030304 developmental biology, Flavonoids, monoterpene indole alkaloids, MESH: Mass Spectrometry, Stem bark, Indole alkaloid, 010405 organic chemistry, MESH: Magnetic Resonance Spectroscopy, Organic Chemistry, 0104 chemical sciences, MESH: Indole Alkaloids, flavoalkaloids, Monoterpenes, MESH: Flavonoids
Abstract

International audience; Epicatechocorynantheines A and B, and epicatechocorynantheidine were isolated from the stem bark of Corynanthe pachyceras. These molecules were pinpointed, and their isolation streamlined, by a molecular networking strategy. The structural elucidation was unambiguously accomplished from HRMS and 1D/2D NMR data. These compounds represent the first examples of corynanthean-type alkaloids tethered with a flavonoid. Epicatechocorynantheidine notably instigated two connections between the monoterpene indole alkaloid and the flavonoid, yielding an unprecedented octacyclic appendage. These flavoalkaloids exerted moderate antiplasmodial activities.

Published
2020
Full Text
View/download PDF

6. Molecular Networking Reveals Serpentinine-Related Bisindole Alkaloids from Picralima nitida , a Previously Well-Investigated Species

Author

Karine Leblanc, Elisabeth Mouray, Mehdi A. Beniddir, Charlotte Fox Alcover, Jean-François Gallard, Alexander E. Fox Ramos, Philippe Grellier, Faustin Aka Kabran, Guillaume Bernadat, Erwan Poupon, Pierre Le Pogam, Institut national des sciences de l'Univers (INSU - CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Laboratoire d'océanographie et de biogéochimie (LOB), Université de la Méditerranée - Aix-Marseille 2-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Équipe 'Pharmacognosie-Chimie des Substances Naturelles' BioCIS, Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Université Félix Houphouët-Boigny (UFHB), Institut méditerranéen d'océanologie (MIO), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stereochemistry, MESH: Secologanin Tryptamine Alkaloids, [SDV]Life Sciences [q-bio], Monoterpene, MESH: Molecular Structure, Pharmaceutical Science, 01 natural sciences, Alstonine, Analytical Chemistry, chemistry.chemical_compound, MESH: Apocynaceae, Drug Discovery, [CHIM]Chemical Sciences, MESH: Plasmodium falciparum, ComputingMilieux_MISCELLANEOUS, MESH: Antiparasitic Agents, Pharmacology, Picralima, Indole test, biology, 010405 organic chemistry, Organic Chemistry, biology.organism_classification, 0104 chemical sciences, MESH: Indole Alkaloids, 010404 medicinal & biomolecular chemistry, Monomer, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Complementary and alternative medicine, chemistry, Molecular networking, Molecular Medicine, MESH: Monoterpenes, Derivative (chemistry)
Abstract

International audience; Five new monoterpene indole alkaloids (1-5), including four serpentinine-related bisindoles and one alstonine derivative monomer, have been isolated from the aerial parts of Picralima nitida. Their structures were elucidated by analysis of their HRMS and NMR spectroscopic data, and their absolute configurations were deduced from the comparison of experimental and simulated ECD spectra. In addition, two known compounds (6 and 7), previously undescribed from P. nitida, have also been purified. The compound isolation workflow was guided by a molecular networking-based dereplication strategy. Twenty-three compounds were dereplicated from the EtOH extract of P. nitida and fractions network and were assigned various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum as well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1-7.

Published
2020
Full Text
View/download PDF

7. Molecular docking studies and in vitro degradation of four aflatoxins (AFB 1 , AFB 2 , AFG 1 , and AFG 2 ) by a recombinant laccase from Saccharomyces cerevisiae

Author

Liu, Yingli, Mao, Huijia, Hu, Chuanqin, Tron, Thierry, Lin, Junfang, Wang, Jing, Sun, Baoguo, Beijing Technology and Business University, Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The University of Texas M.D. Anderson Cancer Center [Houston], and Aix Marseille Université (AMU)

Subjects
aflatoxins, degradability, laccases, MESH: Aflatoxin B1, MESH: Molecular Structure, food and beverages, in vitro assays, molecular docking, Saccharomyces cerevisiae, [CHIM.CATA]Chemical Sciences/Catalysis, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, MESH: Food Contamination, MESH: Saccharomyces cerevisiae, MESH: Trametes, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, MESH: Computer Simulation, [SDV.IDA]Life Sciences [q-bio]/Food engineering, MESH: Molecular Docking Simulation, MESH: Aflatoxins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Laccase, MESH: Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, MESH: Models, Molecular
Abstract

International audience; Here, molecular docking simulation was used to predict and compare interactions between a recombinant Trametes sp. C30 laccase from Saccharomyces cerevisiae and four aflatoxins (AFB1 , AFB2 , AFG1 , and AFG2 ) as well as their degradation at a molecular level. The computational result of docking simulation indicates that each of the aflatoxins tested can interact with laccase with a binding ability of AFB1 >AFG2 >AFG1 >AFB2 . Simultaneously, it also demonstrated that aflatoxin B1 ， B2 ， G1 ， G2 may interact near the T1 copper center of the enzyme through H-bonds and hydrophobic interactions with amino acid residues His481 and Asn288; His481； Asn288, and Asp230; His481 and Asn288. Biological degradation test was performed in vitro in the presence of a recombinant laccase. Degradation increased as incubation time increased from 12 to 60 hr and the maximum degradation obtained for AFB1 , AFB2 , AFG1 , and AFG2 was 90.33%, 74.23%, 85.24%, and 87.58%, respectively. Maximum degradation of aflatoxins was determined with a total activity 3 U laccase at 30 °C in 0.1 M phosphate buffer, pH 5.7 after 48-hr incubation. The experimental results are consistent with that of docking calculation on the biological degradation test of four aflatoxins by laccase. PRACTICAL APPLICATION: In this study, the degradation efficiencies of laccase for B and G series of aflatoxins were determined by computer simulation and verified by performing in vitro experiments. It can provide reference for rapid screening of aflatoxin degradation-related enzymes.

Published
2020
Full Text
View/download PDF

8. Eumitrins C-E: Structurally diverse xanthone dimers from the vietnamese lichen Usnea baileyi

Author

Pierre Le Pogam, Grégory Genta-Jouve, Solenn Ferron, Joël Boustie, Mehdi A. Beniddir, Van-Kieu Nguyen, Philippe Grellier, Warinthorn Chavasiri, Jean-François Gallard, Elisabeth Mouray, Thuc-Huy Duong, Chulalongkorn University [Bangkok], Laboratoire Ecologie, Evolution, Interactions des Systèmes amazoniens (LEEISA), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS), Hétérocycles et Peptides (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vietnam National University - Ho Chi Minh City (VNU-HCM), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Equipe C-TAC (UMR 8638), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Graduate School, University of Texas, Austin, Chulalongkorn University, Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)

Subjects
Circular dichroism, Magnetic Resonance Spectroscopy, Antiparasitic, medicine.drug_class, Stereochemistry, Xanthones, MESH: Molecular Structure, MESH: Plant Extracts, MESH: Usnea, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, MESH: Circular Dichroism, chemistry.chemical_compound, Drug Discovery, Xanthone, medicine, [CHIM]Chemical Sciences, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Pharmacology, Molecular Structure, Plant Extracts, 010405 organic chemistry, Depsidone, MESH: Magnetic Resonance Spectroscopy, Circular Dichroism, MESH: Xanthones, Absolute configuration, General Medicine, Nuclear magnetic resonance spectroscopy, 0104 chemical sciences, Thallus, 010404 medicinal & biomolecular chemistry, Usnea, Vietnam, chemistry, MESH: Vietnam, Two-dimensional nuclear magnetic resonance spectroscopy
Abstract

International audience; Three new xanthone dimers, eumitrins C - E (1-3), along with a new depsidone, 3'-O-demethylcryptostictinolide (4) were isolated from the acetone extract of the whole thallus of the lichen Usnea baileyi collected in Vietnam. Their structures were unambiguously established by spectroscopic analyses (HRESIMS, 1D and 2D NMR), as well as comparison to literature data. The absolute configurations of 1-3 were elucidated through electronic circular dichroism (ECD) analyses. The absolute configuration of 2 was validated by comparison between experimental and TDDFT-calculated ECD spectra while that of 3 was based on DFT-NMR calculations and subsequent DP4 probability score. The antiparasitic activities against Plasmodium falciparum as well as the cytotoxic activity against seven cell lines were determined for the new compounds 1-3, and led from null to mild bioactivities.

Published
2020
Full Text
View/download PDF

9. Crystallographic analysis of Staphylococcus aureus LcpA, the primary wall teichoic acid ligase

Author

Federico I. Rosell, Jean-Pierre Simorre, Natalie C. J. Strynadka, Eric D. Brown, Robert T. Gale, Franco K.K. Li, Centre for Blood Research (CBR), University of British Columbia (UBC), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, size-exclusion chromatography with multiangle light scattering, MESH: Molecular Structure, MESH: Catalytic Domain, Bacillus, Bacillus subtilis, peptidoglycan, Biochemistry, Bacterial cell structure, oligomerization, Cell wall, 03 medical and health sciences, chemistry.chemical_compound, MESH: Cell Wall, Arabinogalactan, MESH: Staphylococcus aureus, MESH: Protein Binding, Molecular Biology, MESH: Bacterial Proteins, X-ray crystallography, chemistry.chemical_classification, Teichoic acid, DNA ligase, 030102 biochemistry & molecular biology, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Peptidoglycan, Cell Biology, MESH: Bacillus subtilis, biology.organism_classification, MESH: Crystallography, X-Ray, teichoic acid, LytR–CpsA–Psr, Staphylococcus aureus (S. aureus), 030104 developmental biology, Enzyme, chemistry, MESH: Ligases, gram-positive bacteria, MESH: Teichoic Acids, cell wall, Peptidoglycan
Abstract

International audience; Gram-positive bacteria, including major clinical pathogens such as Staphylococcus aureus, are becoming increasingly drug-resistant. Their cell walls are composed of a thick layer of peptidoglycan (PG) modified by the attachment of wall teichoic acid (WTA), an anionic glycopolymer that is linked to pathogenicity and regulation of cell division and PG synthesis. The transfer of WTA from lipid carriers to PG, catalyzed by the LytR-CpsA-Psr (LCP) enzyme family, offers a unique extracellular target for the development of new anti-infective agents. Inhibitors of LCP enzymes have the potential to manage a wide range of bacterial infections because the target enzymes are implicated in the assembly of many other bacterial cell wall polymers, including capsular polysaccharide of streptococcal species and arabinogalactan of mycobacterial species. In this study, we present the first crystal structure of S. aureus LcpA with bound substrate at 1.9 Å resolution and those of Bacillus subtilis LCP enzymes, TagT, TagU, and TagV, in the apo form at 1.6-2.8 Å resolution. The structures of these WTA transferases provide new insight into the binding of lipid-linked WTA and enable assignment of the catalytic roles of conserved active-site residues. Furthermore, we identified potential subsites for binding the saccharide core of PG using computational docking experiments, and multiangle light-scattering experiments disclosed novel oligomeric states of the LCP enzymes. The crystal structures and modeled substrate-bound complexes of the LCP enzymes reported here provide insights into key features linked to substrate binding and catalysis and may aid the structure-guided design of specific LCP inhibitors.

Published
2020
Full Text
View/download PDF

10. Note of Caution for the Aqueous Behaviour of Metal‐Based Drug Candidates

Author

Anna Notaro, Annie Castonguay, Gilles Gasser, Institute of Chemistry for Life and Health Sciences (iCLeHS), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), This work was financially supported by an ERC Consolidator Grant PhotoMedMet to G.G. (GA 681679) and has received support under the program Investissements d'Avenir launched by the French Government and implemented by the ANR with the reference ANR-10-IDEX-0001-02 PSL (G.G.). Ile de France Region is gratefully acknowledged for financial support of 500 MHz NMR spectrometer of Chimie ParisTech in the framework of the SESAME equipment project. We acknowledge the loan of Agilent's equipment to Chimie ParisTech. This work was also supported by INRS University, the Natural Sciences and Engineering Research Council of Canada (Discovery 06336 to A.C.), the Fonds de Recherche du Québec Santé (Junior 1 Research Scholar, Établissement de Jeunes Chercheurs 32622 to A.C.) and the Canada Foundation for Innovation (John Evans Leaders Fund 34846 to A.C.)., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), and European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017)

Subjects
Drug, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Inorganic chemistry, MESH: Molecular Structure, chemistry.chemical_element, Antineoplastic Agents, 01 natural sciences, Biochemistry, Metal, bioinorganic chemistry, Colloid, Microscopy, Electron, Transmission, Coordination Complexes, MESH: Coordination Complexes, Neoplasms, Drug Discovery, Aqueous solubility, MESH: Water, Humans, cancer, MESH: Neoplasms, General Pharmacology, Toxicology and Pharmaceutics, ruthenium, medicinal inorganic chemistry, media_common, Pharmacology, Aqueous solution, MESH: Humans, Molecular Structure, 010405 organic chemistry, Organic solvent, Organic Chemistry, Water, aqueous behaviour, MESH: Ruthenium, 0104 chemical sciences, Ruthenium, 010404 medicinal & biomolecular chemistry, chemistry, visual_art, visual_art.visual_art_medium, MESH: Microscopy, Electron, Transmission, Molecular Medicine, MESH: Antineoplastic Agents
Abstract

International audience; Poor aqueous solubility is one of the recurrent drawbacks of many compounds in medicinal chemistry. To overcome this limitation, the dilution of drug candidates from stock solutions of an organic solvent is common practice. However, the precise characterisation of these compounds in aqueous solutions is often neglected, leading to some uncertainties regarding the nature of the actual active species. In this communication, we demonstrate that two ruthenium complexes previously reported by our group for their chemotherapeutic potential against cancer, namely [Ru(DIP)2 (sq)](PF6 ) and [Ru(DIP)2 (3-methoxysq)](PF6 ), where DIP is 4,7-diphenyl-1,10-phenanthroline, sq=semiquinonate and 3-methoxysq=3-methoxysemiquinonate, form colloids in water-DMSO (1 % v/v) mixtures that are invisible to the naked eyes. [Ru(DIP)2 (3-methoxysq)](PF6 ) was found to form a highly stable and monodispersed colloid with nanoaggregates of ∼25 nm. In contrast, [Ru(DIP)2 (sq)](PF6 ) was found to form large reticulates of mostly spherical aggregates which size was found to increase over time. The difference in size and shape distribution of drug candidates is of tremendous significance as the study of their biological activity might be severely affected. Overall, we strongly believe that these observations should be taken into account by the scientific community working on the development of metal-based drugs with poor water solubility.

Published
2020
Full Text
View/download PDF

11. Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes

Author

Xavier Brazzolotto, Florian Nachon, Marko Živin, Jure Stojan, Maja Zorović, Damijan Knez, Jacques-Philippe Colletier, Urban Košak, Stanislav Gobec, Stane Pajk, Nicolas Coquelle, Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut Laue-Langevin (ILL), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de Recherche Biomédicale des Armées (IRBA), ILL, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia, Faculty of Pharmacy, University of Ljubljana, Département de Toxicologie et Risques Chimiques, and Institute of Biochemistry, Faculty of Medicine

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Crystallography, X-Ray, 01 natural sciences, Mice, chemistry.chemical_compound, Drug Discovery, MESH: Animals, Butyrylcholinesterase, chemistry.chemical_classification, zaviralci, Molecular Structure, biology, MESH: Butyrylcholinesterase, General Medicine, MESH: Fluorescent Dyes, Fluorescence, Acetylcholinesterase, MESH: Amides, 3. Good health, inhibitor, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Fluorescence intensity, Biochemistry, butyrylcholinesterase, fluorescence, patogeneza Alzheimerjeve bolezni, MESH: Cholinesterase Inhibitors, MESH: Models, Molecular, Research Paper, MESH: Molecular Structure, Mixed inhibition, RM1-950, probe, butiriliholinesteraza, Hydrolase, Animals, Humans, [CHIM]Chemical Sciences, udc:616.894+616.892.3:615.2, MESH: Mice, Fluorescent Dyes, Pharmacology, MESH: Humans, 010405 organic chemistry, Active site, MESH: Crystallography, X-Ray, Amides, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, biology.protein, Therapeutics. Pharmacology, Cholinesterase Inhibitors
Abstract

International audience; Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer’s disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.

Published
2020
Full Text
View/download PDF

12. Paclitaxel Response Can Be Predicted With Interpretable Multi-Variate Classifiers Exploiting DNA-Methylation and miRNA Data

Author

Borazjani, Nassim, Sepehri, Saghi, Behzadi, Maryam, Jarrahpour, Aliasghar, Rad, Javad Ameri, Sasanipour, Maryam, Mohkam, Milad, Ghasemi, Younes, Akbarizadeh, Amin Reza, Digiorgio, Carole, Brunel, Jean Michel, Ghanbari, Mohammad Mehdi, Batta, Gyula, Turos, Edward, Shiraz University (Shiraz University ), Ardabil University of Medical Sciences, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Islamic Azad University, University of Debrecen Egyetem [Debrecen], University of South Florida [Tampa] (USF), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and University of South Florida (USF)

Subjects
0301 basic medicine, MESH: Inflammation, Cytotoxicity, [SDV]Life Sciences [q-bio], β-Lactams, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, 0302 clinical medicine, MESH: Structure-Activity Relationship, biomarker discovery, MESH: RAW 264.7 Cells, MESH: Animals, MESH: Neoplasms, Biomarker discovery, Genetics (clinical), Original Research, MESH: Drug Screening Assays, Antitumor, Methylation, artificial intelligence, MESH: Anti-Inflammatory Agents, Non-Steroidal, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], tumor profiling, 3. Good health, Colon cancer, machine learning, Anticancer, Paclitaxel, CpG site, MESH: Cell Survival, 030220 oncology & carcinogenesis, precision oncology, DNA methylation, Molecular Medicine, MESH: Drug Evaluation, Preclinical, lcsh:QH426-470, MESH: Molecular Structure, Decision tree, MESH: Hep G2 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, 03 medical and health sciences, Breast cancer, MESH: beta-Lactams, MESH: Cell Proliferation, microRNA, medicine, Genetics, MESH: Tumor Cells, Cultured, MESH: Mice, DABCO, MESH: Humans, medicine.disease, lcsh:Genetics, 030104 developmental biology, chemistry, MESH: Benzopyrans, MESH: Antineoplastic Agents, Anti-inflammatory, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; To address the problem of resistance to paclitaxel treatment, we have investigated to which extent is possible to predict Breast Cancer (BC) patient response to this drug. We carried out a large-scale tumor-based prediction analysis using data from the US National Cancer Institute's Genomic Data Commons. These data sets comprise the responses of BC patients to paclitaxel along with six molecular profiles of their tumors. We assessed 10 Machine Learning (ML) algorithms on each of these profiles and evaluated the resulting 60 classifiers on the same BC patients. DNA methylation and miRNA profiles were the most informative overall. In combination with these two profiles, ML algorithms selecting the smallest subset of molecular features generated the most predictive classifiers: a complexity-optimized XGBoost classifier based on CpG island methylation extracted a subset of molecular factors relevant to predict paclitaxel response (AUC = 0.74). A CpG site methylation-based Decision Tree (DT) combining only 2 of the 22,941 considered CpG sites (AUC = 0.89) and a miRNA expression-based DT employing just 4 of the 337 analyzed mature miRNAs (AUC = 0.72) reveal the molecular types associated to paclitaxel-sensitive and resistant BC tumors. A literature review shows that features selected by these three classifiers have been individually linked to the cytotoxic-drug sensitivities and prognosis of BC patients. Our work leads to several molecular signatures, unearthed from methylome and miRNome, able to anticipate to some extent which BC tumors respond or not to paclitaxel. These results may provide insights to optimize paclitaxel-therapies in clinical practice.

Published
2019
Full Text
View/download PDF

13. Poly ethylene glycol (PEG)-Related controllable and sustainable antidiabetic drug delivery systems

Author

Ding Ying, Jiang Liu, Litao Zhang, Peng Yu, Yongmin Zhang, Yupeng Fu, Tianjin University of Science and Technology (TUST), Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Poly ethylene glycol, MESH: Diabetes Mellitus, Biocompatibility, MESH: Drug Delivery Systems, MESH: Molecular Structure, Nanotechnology, macromolecular substances, Polyethylene glycol, stimulating responsive release, 01 natural sciences, Micelle, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, Drug Delivery Systems, MESH: Hypoglycemic Agents, Drug Discovery, PEG ratio, Diabetes Mellitus, Humans, Hypoglycemic Agents, drug delivery system, sustainable release, Therapy efficacy, Micelles, 030304 developmental biology, Pharmacology, Drug Carriers, 0303 health sciences, MESH: Humans, Molecular Structure, antidiabetic, 010405 organic chemistry, Chemistry, Organic Chemistry, MESH: Micelles, technology, industry, and agriculture, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, PEG, 0104 chemical sciences, 3. Good health, MESH: Drug Carriers, MESH: Polyethylene Glycols, Drug delivery, Self-healing hydrogels
Abstract

International audience; Diabetes mellitus is one of the most challenging threats to global public health. To improve the therapy efficacy of antidiabetic drugs, numerous drug delivery systems have been developed. Polyethylene glycol (PEG) is a polymeric family sharing the same skeleton but with different molecular weights which is considered as a promising material for drug delivery. In the delivery of antidiabetic drugs, PEG captures much attention in the designing and preparation of sustainable and controllable release systems due to its unique features including hydrophilicity, biocompatibility and biodegradability. Due to the unique architecture, PEG molecules are also able to shelter delivery systems to decrease their immunogenicity and avoid undesirable enzymolysis. PEG has been applied in plenty of delivery systems such as micelles, vesicles, nanoparticles and hydrogels. In this review, we summarized several commonly used PEG-contained antidiabetic drug delivery systems and emphasized the advantages of stimuli-responsive function in these sustainable and controllable formations.

Published
2021
Full Text
View/download PDF

14. Guttiferone A Aggregates Modulate Silent Information Regulator 1 (SIRT1) Activity

Author

Cottet, Kévin, Xu, Bin, Coric, Pascale, Bouaziz, Serge, Michel, Michel, Vidal, Michel, Lallemand, Marie-Christine, Broussy, Sylvain, Michel, Sylvie, Yangtze Delta Region Institute of Tsinghua University [Zhejiang], Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe Pharmacognosie (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire de chimie de coordination (LCC), 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), Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), 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 Bouaziz, Serge

Subjects
Models, Molecular, 0301 basic medicine, MESH: Benzophenones, Magnetic Resonance Spectroscopy, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Biological Products, MESH: Molecular Structure, Regulator, MESH: Dynamic Light Scattering, MESH: Dose-Response Relationship, Drug, Benzophenones, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Sirtuin 1, Clusiaceae, Drug Discovery, Humans, Structure–activity relationship, MESH: Sirtuin 1, Enzyme Inhibitors, chemistry.chemical_classification, Biological Products, MESH: Humans, Natural product, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Dose-Response Relationship, Drug, Molecular Structure, MESH: Magnetic Resonance Spectroscopy, Nuclear magnetic resonance spectroscopy, Dynamic Light Scattering, In vitro, 3. Good health, MESH: Clusiaceae, Hyperforin, 030104 developmental biology, Enzyme, chemistry, Biochemistry, MESH: Enzyme Inhibitors, Biological target, Molecular Medicine, MESH: Models, Molecular
Abstract

International audience; Natural products guttiferone A, hyperforin, and aristoforin were able to inhibit or increase SIRT1 catalytic activity, depending on protein concentration and presence of detergent. On the basis of NMR data for guttiferone A, we demonstrated that the aggregation state of the natural product played a crucial role for its interaction with the enzyme. These results are useful to interpret future in vitro structure-activity relationship studies on these natural products in the quest of their biological target(s).

Published
2016
Full Text
View/download PDF

15. Structures of Nahuoic Acids B–E Produced in Culture by a Streptomyces sp. Isolated from a Marine Sediment and Evidence for the Inhibition of the Histone Methyl Transferase SETD8 in Human Cancer Cells by Nahuoic Acid A

Author

Teatulohi Matainaho, Doralyn S. Dalisay, Eric Julien, Cholpisut Tantapakul, David E. Williams, Stéphanie Arnould, Fanny Izard, Raymond J. Andersen, Wisanu Maneerat, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Geologic Sediments, MESH: Histone Methyltransferases, MESH: Streptomyces, MESH: Molecular Structure, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, Streptomyces, Cell Line, Histones, 03 medical and health sciences, MESH: Cell Proliferation, Humans, IC50, MESH: Polyketides, Cell Proliferation, MESH: Histones, MESH: Humans, Molecular Structure, biology, 010405 organic chemistry, Cell growth, Chemistry, Organic Chemistry, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, MESH: Geologic Sediments, biology.organism_classification, Molecular biology, In vitro, MESH: Cell Line, 0104 chemical sciences, 3. Good health, 030104 developmental biology, Histone, Biochemistry, Cell culture, Polyketides, Histone methyltransferase, Cancer cell, Histone Methyltransferases, biology.protein, MESH: Antineoplastic Agents, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Nahuoic acids A-E (1-5) have been isolated from laboratory cultures of a Streptomyces sp. obtained from a tropical marine sediment. The structures of the new polyketides 2-5 were elucidated by analysis of spectroscopic data of the natural products and the chemical derivatives 6 and 7. Nahuoic acids 1-5 are in vitro inhibitors of the histone methyltransferase SETD8, and nahuoic acid A (1) and its pentaacetate derivative 8 inhibit the proliferation of several cancer cells lines in vitro with modest potency. At the IC50 for cancer cell proliferation, nahuoic acid A (1) showed selective inhibition of SETD8 in U2OS osteosarcoma cells that reflect its selectivity against a panel of pure histone methyl transferases. A cell cycle analysis revealed that the cellular toxicity of nahuoic acid A (1) is likely linked to its ability to inhibit SETD8 activity.

Published
2016
Full Text
View/download PDF

16. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Author

Salvador Fernández-Arroyo, Lukas Werner, Jorge Joven, Laura Llorach-Parés, Javier A. Menendez, Noemí Cabré, Benoit Viollet, Sara Verdura, Elisabet Cuyàs, Fedra Luciano-Mateo, Jan Stursa, Alfons Nonell-Canals, Jiri Neuzil, Begoña Martin-Castillo, Melchor Sanchez-Martinez, Program Against Cancer Therapeutic Resistance/Metabolism & Cancer Group [Catalonia, Spain] (ProCURE), Catalan Institute of Oncology-Girona (ICO-Girona), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Mind the Byte [Barcelona, Spain], Unitat de Recerca Biomedica [Reus, Spain], Hospital Universitari de Sant Joan [Reus, Spain]-Rovira i Virgili University [Reus, Spain] (IISPV), Institute of Chemical Technology [Prague, Czech Republic], Institute of Biotechnology [Prague-West, Czech Republic], Czech Academy of Sciences [Prague] (CAS), Girona Biomedical Research Institute (IdIBGi), Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute (IDIBGI), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Menzies Health Institute Queensland [Queensland, Australia], Griffith University [Brisbane], This work was supported by grants from the Ministerio de Ciencia e Innovacion (Grant SAF2016-80639-P to J. A. Menendez), Plan Nacional de I+D+I, Spain, the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR) (Grant 2014 SGR229 to J. A. Menendez), Departament d’Economia i Coneixement, Catalonia, Spain, and the Czech Health Council Foundation (Grant 16- 31604A to J. Neuzil). Elisabet Cuyas is supported by the Sara Borrell postdoctoral contract (CD15/00033) from the Ministerio de Sanidad y Consumo, Fondo de Investigacion Sanitaria (FIS), Spain. This study was supported also by unrestricted research grants from Roche Pharma (Spain) and Astellas Pharma (Spain) to the Program Against Cancer Therapeutic Resistance (ProCURE, Catalan Institute of Oncology), and the Armangue family (Girona, Catalonia) to the Metabolism and Cancer Group (Girona Biomedical Research Institute), and Viollet, Benoit

Subjects
0301 basic medicine, Models, Molecular, Aging, Pharmacology, Ligands, MESH: Metformin, MESH: Mice, Knockout, computational screening, MESH: Dose-Response Relationship, Drug, Mice, MESH: Ligands, MESH: Animals, Enzyme Inhibitors, Càncer, Cancer, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Histone Demethylases, Mice, Knockout, Molecular Structure, Nuclear Proteins, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Metformin, Chromatin, MESH: Neoplasms, Experimental, MESH: Enzyme Inhibitors, Original Article, Female, MESH: Biocatalysis, MESH: Models, Molecular, medicine.drug, Premature aging, MESH: Molecular Structure, macromolecular substances, Biology, chemoinformatics, 03 medical and health sciences, Envelliment, MESH: Histone Demethylases, medicine, Animals, Humans, cancer, Epigenetics, MESH: Mice, MESH: Humans, Dose-Response Relationship, Drug, aging, AMPK, Cell Biology, Epigenome, Original Articles, Neoplasms, Experimental, medicine.disease, 030104 developmental biology, biology.protein, Biocatalysis, Demethylase, metformin, MESH: Nuclear Proteins, MESH: Female
Abstract

International audience; Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low-density lipoprotein receptor-deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft-bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

Published
2018
Full Text
View/download PDF

17. Attraction of Rhodnius prolixus males to a synthetic female-pheromone blend

Author

Bohman, Bjorn, Weinstein, Alyssa, Unelius, C. Rikard, Lorenzo, Marcelo, The University of Western Australia (UWA), Australian National University (ANU), Linneaus University, Le Studium Loire Valley Institute for Advanced Studies, 45000 Orléans, France, Fiocruz Minas - René Rachou Research Center / Instituto René Rachou [Belo Horizonte, Brésil], Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and This project has been supported by LE STUDIUM Loire Valley Institute for Advanced Studies, Orléans & Tours, France with funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 665790

Subjects
Male, Volatiles, MESH: Sexual Behavior, Animal, Chagas disease, MESH: Sex Attractants/chemical synthesis, MESH: Molecular Structure, Pheromone, Insect Control, MESH: Rhodnius/physiology, lcsh:Infectious and parasitic diseases, Sexual Behavior, Animal, Animals, MESH: Animals, lcsh:RC109-216, Biologiska vetenskaper, Sex Attractants, MESH: Insect Control, Molecular Structure, Research, Metasternal gland, Kemi, Biological Sciences, Rhodnius prolixus, SSR, MESH: Male, Trap, MESH: Sex Attractants/pharmacology, MESH: Rhodnius/drug effects, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Rhodnius, Chemical Sciences, Female, MESH: Female, Olfactometer
Abstract

This is the final version of the following article: "Attraction of Rhodnius prolixus males to a synthetic female-pheromone blend", which has been published in final form at https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-018-2997-z; International audience; Background: The triatomine bug Rhodnius prolixus Stål, 1859 (Heteroptera: Reduviidae) is the primary vector of Chagas disease in Colombia and Venezuela. An important step in controlling Chagas disease is monitoring the growth and spread of bug populations to inform effective management. Such monitoring could be carried out using pheromone traps. To develop effective pheromone traps, it is vital to understand the pheromone chemistry of R. prolixus. Previous studies have found that female R. prolixus metasternal gland secretions induce males to: leave shelters, take off, orientate during walking, aggregate around mating pairs, and mate. This study aims to identify a synthetic blend of female metasternal gland compounds that could be used to attract R. prolixus. Results: We investigated the electrophysiological activity of the ten most abundant compounds in female R. prolixus metasternal glands using single sensillum recordings. In total we obtained 60 recordings from basiconic sensilla in male R. prolixus. In 31 of these recordings, responses to individual compounds were observed. Each of the ten tested compounds elicited neuron responses in a minimum of eight recordings. Having confirmed their electrophysiological activity, we tested these ten compounds by presenting them to male Rhodnius prolixus in a "T" olfactometer. Male bugs showed a significant preference for the blend of metasternal gland compounds compared to the clean air control. Conclusions: A simple blend of ten compounds found in female R. prolixus metasternal glands is attractive to conspecific males. All compounds in the blend are either commercially available at low cost, or easily synthetically prepared from simple precursors. We hope that this blend will be evaluated as a lure for pheromone traps in field bioassays.

Published
2018
Full Text
View/download PDF

18. 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a] pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Author

Maxime D. Crozet, Alan H. Fairlamb, Geneviève Pratviel, Alexis Valentin, Pascal Rathelot, Alix Sournia-Saquet, Clotilde Boudot, Anita Cohen, Patrice Vanelle, Julien Pedron, Jean-Luc Stigliani, Sandra Bourgeade-Delmas, Susan Wyllie, Pierre Verhaeghe, Nadine Azas, Caroline Castera-Ducros, Cyril Fersing, Alain Moreau, Sébastien Hutter, Nicolas Primas, Bertrand Courtioux, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire de chimie de coordination (LCC), 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), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee, 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 Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), and Université de Toulouse (UT)

Subjects
Models, Molecular, 0301 basic medicine, SARs, Redox potentials, HepG2 cytotoxicity, Crystallography, X-Ray, MESH: Parasitic Sensitivity Tests, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, In vitro activity, Drug Discovery, Nitroheterocycles, Moiety, MESH: Trypanocidal Agents, Imidazo[1, Leishmania, 2-a]pyridine, Molecular Structure, MESH: Drug Screening Assays, Antitumor, Hep G2 Cells, General Medicine, Trypanocidal Agents, 3. Good health, MESH: Nitroreductases, MESH: Cell Survival, Imidazo[1,2-a]pyridine, Pharmacophore, MESH: Models, Molecular, Trypanosoma, MESH: Cell Line, Tumor, Cell Survival, Stereochemistry, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, 030106 microbiology, MESH: Molecular Structure, Substituent, Antineoplastic Agents, MESH: Hep G2 Cells, Article, Structure-Activity Relationship, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, Amastigote, Cell Proliferation, Pharmacology, MESH: Humans, MESH: Leishmania donovani, Dose-Response Relationship, Drug, Aryl, Organic Chemistry, MESH: Trypanosoma brucei brucei, Nitroreductases, MESH: Crystallography, X-Ray, 030104 developmental biology, chemistry, Nitro, Suzuki-Miyaura cross-coupling reaction, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Screening Assays, Antitumor, Leishmania donovani, Fexinidazole
Abstract

International audience; Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

Published
2018
Full Text
View/download PDF

19. Biological small-angle neutron scattering: recent results and development

Author

Frank Gabel, Emilie Mahieu, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, Materials science, Macromolecular Substances, MESH: Molecular Structure, Context (language use), Nanotechnology, Neutron scattering, 03 medical and health sciences, RNA/DNA, Biopolymers, detergent, Structural Biology, Scattering, Small Angle, MESH: Scattering, Small Angle, deuteration, small-angle neutron scattering, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, Scattering, Small-angle X-ray scattering, MESH: Macromolecular Substances, Small-angle neutron scattering, MESH: Neutron Diffraction, MESH: Biopolymers, Neutron Diffraction, 030104 developmental biology, Structural biology, Deuterium, Solubilization, protein
Abstract

Small-angle neutron scattering (SANS) has increasingly been used by the structural biology community in recent years to obtain low-resolution information on solubilized biomacromolecular complexes in solution. In combination with deuterium labelling and solvent-contrast variation (H2O/D2O exchange), SANS provides unique information on individual components in large heterogeneous complexes that is perfectly complementary to the structural restraints provided by crystallography, nuclear magnetic resonance and electron microscopy. Typical systems studied include multi-protein or protein–DNA/RNA complexes and solubilized membrane proteins. The internal features of these systems are less accessible to the more broadly used small-angle X-ray scattering (SAXS) technique owing to a limited range of intra-complex and solvent electron-density variation. Here, the progress and developments of biological applications of SANS in the past decade are reviewed. The review covers scientific results from selected biological systems, including protein–protein complexes, protein–RNA/DNA complexes and membrane proteins. Moreover, an overview of recent developments in instruments, sample environment, deuterium labelling and software is presented. Finally, the perspectives for biological SANS in the context of integrated structural biology approaches are discussed.

Published
2017
Full Text
View/download PDF

20. BF 2 -azadipyrromethene NIR-emissive fluorophores with research and clinical potential

Author

Gonzalo Sampedro, Ghazi Ismail, Harrison C. Daly, Donal F. O'Shea, Ronan Cahill, Corentin Bon, Dan Wu, Royal College of Surgeons in Ireland (RCSI), and University College Dublin [Dublin] (UCD)

Subjects
Azadipyrromethene, Fluorescence-lifetime imaging microscopy, Fluorescence guided surgery, Fluorophore, MESH: Porphobilinogen, [SDV]Life Sciences [q-bio], MESH: Boron Compounds, MESH: Molecular Structure, Analytical chemistry, 010402 general chemistry, 01 natural sciences, Tattoo, MESH: Spectroscopy, Near-Infrared, MESH: Dose-Response Relationship, Drug, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Structure-Activity Relationship, Drug Discovery, Bathochromic shift, [CHIM]Chemical Sciences, Clinical imaging, MESH: Colon, Pharmacology, MESH: Humans, Organic Chemistry, Near-infrared spectroscopy, General Medicine, NIR-fluorescence, MESH: Fluorescent Dyes, Fluorescence, 0104 chemical sciences, chemistry, 030220 oncology & carcinogenesis, MESH: Aza Compounds, Lymph node, Preclinical imaging, Biomedical engineering
Abstract

International audience; The use of near-infrared fluorescence for in vivo research and intraoperative clinical imaging is rapidly expanding, with new applications being proposed and developed. While imaging hardware and software have significantly progressed in recent times, the molecular fluorescent agents remain a limiting factor. In this report, the design, synthesis, photophysical characterization and bio-medical imaging assessment of two new NIR-fluorophores based on the BF2-azadipyrromethene fluorophore class are described. Inclusion of dimethylamino substituents on these BF2-azadipyrromethene probes results in very large bathochromic shifts with photophysical measurements showing absorption and emission maxima between 757 and 818 nm within the desired NIR spectra region. Testing of the probes shows that they are suitable for fluorescence imaging with both research and clinical instrumentation. Preclinical imaging assessment shows their suitability as fluorescent markers (tattoos) of lesions for intraoperative identification and lymphatic mapping in ex vivo human colonic tissue. These new clinical wavelength-compatible fluorophores may contribute towards the on-going expansion of medical uses for NIR-fluorescence.

Published
2017
Full Text
View/download PDF

21. Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles

Author

Justine Evrard, Flavie Soubigou, Cécile Voisset, Nathalie Desban, Pascale Lemoine, Nassima Oumata, Marc Blondel, Serge Bouaziz, Phuhai Nguyen, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), ManRos Therapeutics, Systèmes d'Elevage, Nutrition Animale et Humaine (SENAH), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure Agronomique de Rennes, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), INSERM Unit 1018, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Bouaziz, Serge, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, MESH: Heterocyclic Compounds, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Prions, MESH: Mice, Transgenic, MESH: Molecular Structure, Cell, Mice, Transgenic, Saccharomyces cerevisiae, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, MESH: Prions, MESH: Structure-Activity Relationship, 0302 clinical medicine, Heterocyclic Compounds, Mammalian cell, Drug Discovery, medicine, Animals, MESH: Animals, MESH: Mice, IC50, Phenanthridine, 030304 developmental biology, Pharmacology, 0303 health sciences, Molecular Structure, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Neurodegenerative diseases, Organic Chemistry, Aromaticity, General Medicine, MESH: Phenanthridines, MESH: Saccharomyces cerevisiae, Yeast, Phenanthridines, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], medicine.anatomical_structure, chemistry, Biochemistry, Protein folding, MESH: Models, Molecular, 030217 neurology & neurosurgery, Ex vivo, Protein misfolding
Abstract

International audience; Series of 6-aminophenanthridines and related heterocyclic compounds such as benzonaphtyridines were prepared. Reduction of one of the three aromatic rings was also performed. The compounds were first tested for their antiprion activity in a previously described yeast-based colourimetric prion assay. The most potent derivatives were then assayed ex vivo against the mammalian prion PrP(Sc) in a cell-based assay. Several of the new compounds were found more potent than the parent lead 6-aminophenanthridine. The most promising compounds against yeast and mammalian prions were 8-azido-6-aminophenanthridine (3m), and 7,10-dihydrophenanthridin-6-amine (14). In the mammalian cell-based assay, the IC50 of these two compounds were around 5 μM and 1.8 μM, respectively.

Published
2014
Full Text
View/download PDF

22. Selective Targeting of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin (DC-SIGN) with Mannose-Based Glycomimetics: Synthesis and Interaction Studies of Bis(benzylamide) Derivatives of a Pseudomannobioside

Author

Thépaut, Michel, Guzzi, Cinzia, Sutkeviciute, Ieva, Sattin, Sara, Ribeiro-Viana, Renato, Varga, Norbert, Chabrol, Eric, Rojo, Javier, Bernardi, Anna, Angulo, Jesus, Nieto, Pedro M, Fieschi, Franck, Università degli Studi di Milano [Milano] (UNIMI), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Morphologie Mathématique (CMM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Università degli Studi di Milano = University of Milan (UNIMI), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Instituto de Investigaciones Químicas (IIQ), and Universidad de Sevilla / University of Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)

Subjects
Mannose, HIV Infections, Ligands, 01 natural sciences, chemistry.chemical_compound, Glycomimetic, MESH: Nuclear Magnetic Resonance, Biomolecular, MESH: Ligands, Combinatorial Chemistry Techniques, MESH: Antigens, CD, MESH: Receptors, Cell Surface, Molecular Structure, MESH: Dendritic Cells, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Chemistry, MESH: Models, Chemical, Glycopeptides, MESH: HIV Infections, Intercellular adhesion molecule, 3. Good health, DC-SIGN, MESH: Mannose, MESH: Cell Adhesion Molecules, MESH: Combinatorial Chemistry Techniques, Langerin, Stereochemistry, MESH: Molecular Structure, Receptors, Cell Surface, 010402 general chemistry, Catalysis, Antigens, CD, MESH: Mannose-Binding Lectins, Lectins, C-Type, Binding site, Nuclear Magnetic Resonance, Biomolecular, MESH: Glycopeptides, Binding Sites, 010405 organic chemistry, Ligand, Organic Chemistry, Dendritic Cells, General Chemistry, Dendritic cell, 0104 chemical sciences, Mannose-Binding Lectins, Models, Chemical, MESH: Binding Sites, biology.protein, Cell Adhesion Molecules, MESH: Lectins, C-Type
Abstract

International audience; Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3-4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN.

Published
2013
Full Text
View/download PDF

23. Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

Author

Song, Lijun, Risseeuw, Martijn D.P., Froeyen, Matheus, Karalic, Izet, Goeman, Jan, Cappoen, Davie, Van der Eycken, Johan, Cos, Paul, Munier-Lehmann, Hélène, Van Calenbergh, Serge, Risseeuw, Martijn, Froeyen, Mathy, Universiteit Gent = Ghent University [Belgium] (UGENT), Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Antwerp (UA), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This project is financially supported by China Scholarship Council (CSC)., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, MESH: Mycobacterium tuberculosis, [SDV]Life Sciences [q-bio], Clinical Biochemistry, POTENT INHIBITORS, Antitubercular Agents, Pharmaceutical Science, 01 natural sciences, Biochemistry, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, Thymidine monophosphate kinase, MESH: Structure-Activity Relationship, DESIGN, Piperidines, Drug Discovery, Medicine and Health Sciences, thymine derivatives, MESH: Protein Kinase Inhibitors, Thymidine monophosphate, MESH: Microbial Sensitivity Tests, Nucleoside-phosphate kinase, biology, Molecular Structure, Kinase, Pharmacology. Therapy, 3. Good health, Chemistry, MESH: Piperidines, ANTIBACTERIAL INHIBITORS, NUCLEOSIDE ANALOGS, Molecular Medicine, MYCOBACTERIUM-TUBERCULOSIS, MESH: Models, Molecular, medicine.drug, MESH: Molecular Structure, Microbial Sensitivity Tests, Thymidylate kinase, Mycobacterium tuberculosis, Structure-Activity Relationship, medicine, Structure–activity relationship, Humans, extensively drug-resistant tuberculosis, [CHIM]Chemical Sciences, XDR-TB, Biology, Molecular Biology, Protein Kinase Inhibitors, MESH: Humans, Nucleoside analogue, Dose-Response Relationship, Drug, 010405 organic chemistry, Inhibitors, Organic Chemistry, thymidine monophosphate kinase, biology.organism_classification, TMK, MESH: Antitubercular Agents, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, DISCOVERY, CHIMERA, Thymine derivatives, Nucleoside-Phosphate Kinase, Nucleoside, MESH: Nucleoside-Phosphate Kinase, SYSTEM
Abstract

We report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization. (C) 2016 Elsevier Ltd. All rights reserved.

Published
2016
Full Text
View/download PDF

24. In silico analysis and in vitro evaluation of immunogenic and immunomodulatory properties of promiscuous peptides derived from Leishmania infantum eukaryotic initiation factor

Author

Mourad Barhoumi, Athanassios Tsakris, Olga S. Koutsoni, Eleni Dotsika, John G. Routsias, Ioannis D. Kyriazis, Ikram Guizani, Laboratory of Cellular Immunology [Athens], Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), National and Kapodistrian University of Athens (NKUA), Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée aux Maladies Infectieuses (LR11IPT04), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, and The financial support for the conduct of this study was provided by the Hellenic Pasteur Institute.

Subjects
0301 basic medicine, Models, Molecular, Clinical Biochemistry, MESH: Eukaryotic Initiation Factors/chemistry, Pharmaceutical Science, MESH: Peptides/immunology, In silico analysis, Biochemistry, Dendritic cells, Epitope, Immunogenicity, Vaccine, Eukaryotic initiation factor, MESH: Immunogenicity, Vaccine/immunology, Drug Discovery, Eukaryotic Initiation Factors, Leishmania infantum, MESH: Leishmania infantum/immunology, biology, Molecular Structure, Chemistry, Synthetic peptides, MESH: Immunomodulation/immunology, Immunogenicity, 3. Good health, Molecular Medicine, MESH: Eukaryotic Initiation Factors/immunology, MESH: Models, Molecular, Algorithms, In silico, MESH: Molecular Structure, Leishmania eukaryotic initiation factor (LeIF), MESH: Algorithms, Major histocompatibility complex, MESH: Peptides/chemistry, Immunomodulation, 03 medical and health sciences, Immune system, MHC class I, Molecular Biology, Organic Chemistry, MESH: Peptides/chemical synthesis, biology.organism_classification, Molecular biology, 030104 developmental biology, biology.protein, Peptides, MESH: Leishmania infantum/chemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; It is generally considered as imperative the ability to control leishmaniasis through the development of a protective vaccine capable of inducing long-lasting and protective cell-mediated immune responses. In this current study, we demonstrated potential epitopes that bind to H2 MHC class I and II molecules by conducting the in silico analysis of Leishmania infantum eukaryotic Initiation Factor (LieIF) protein, using online available algorithms. Moreover, we synthesized five peptides (16-18 amino acids long) which are part of the N-terminal portion of LieIF and contain promising MHC class I and II-restricted epitopes and afterwards, their predicted immunogenicity was evaluated in vitro by monitoring peptide-specific T-cell responses. Additionally, the immunomodulatory properties of these peptides were investigated in vitro by exploring their potential of inducing phenotypic maturation and functional differentiation of murine Bone-Marrow derived Dendritic Cells (BM-DCs). It was revealed by our data that all the synthetic peptides predicted for H2 alleles; present the property of immunogenicity. Among the synthetic peptides which contained T-cell epitopes, the peptide 52-68 aa (LieIF_2) exhibited immunomodulatory properties with the larger potential. LieIF_2-pulsed BM-DCs up-regulated the expression of the co-stimulatory surface molecules CD80 and CD86, as well as the production of the proinflammatory cytokine TNF-α and of the Th1-polarizing cytokines IL-12 and IFN-γ. The aforementioned data suggest that selected parts of LieIF could be used to develop innovative subunit protective vaccines able to induce effective immunity mediated by MHC class I-restricted as well as class II-restricted T-cell responses.

Published
2016
Full Text
View/download PDF

25. The natural cytokinin 2OH3MeOBAR induces cell death by a mechanism that is different from that of the 'classical' cytokinin ribosides

Author

Petr Džubák, Tibor Béres, Percy Niemann, Miroslav Strnad, Karel Doležal, Marian Hajduch, Jiří Voller, Pierre Alexandre Kaminski, Marek Zatloukal, Palacky University Olomouc, Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), BIOLOG Life Science Institute [Bremen], and The research was supported by the Czech Grant Agency (project 14-19590S) and Ministry of Education, Youth and Sports, Czech Republic (National Program of Sustainability I grants L01204 - Sustainable Development of Research in the Centre of Region Haná and LO1304 - Sustainable development of Institute of Molecular and Translational Medicine, projects EATRIS-CZ [LM2015064] and CZ-OPENSCREEN [LM2015063]).

Subjects
MESH: Cell Death, 0301 basic medicine, Programmed cell death, Adenosine, Cytokinins, MESH: Isopentenyladenosine, [SDV]Life Sciences [q-bio], Metabolite, MESH: Molecular Structure, Cytokinin, Apoptosis, Plant Science, Horticulture, Biology, MESH: Glycosides, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Isopentenyladenosine, Phytohormone, NCI60 panel, medicine, Glycosides, Molecular Biology, Cancer, Leukemia, Cell Death, Molecular Structure, MESH: Apoptosis, General Medicine, Riboside, Kinetin, MESH: Adenosine, 030104 developmental biology, MESH: Kinetin, chemistry, Cancer cell, MESH: Cytokinins, medicine.drug
Abstract

International audience; Cytokinin ribosides (N6-substituted adenosines) have demonstrated anticancer activity in various cultured cell lines, several xenografts and even a small clinical trial. Effects of kinetin riboside, N6-benzyladenosine (BAR) and N6-isopentenyladenosine on various parameters related to apoptosis have also been reported, but not directly compared with those of the highly active naturally occurring aromatic cytokinins oTR (ortho-topolin riboside) and 2OH3MeOBAR (N6-(2-hydroxy-3-methoxybenzyl)adenosine). Here we show that 2OH3MeOBAR is the most active cytokinin riboside studied to date (median, 1st quartile, 3rd quartile and range of GI50 in tests with the NCI60 cell panel: 0.19, 0.10, 0.43 and 0.02 to 15.7 μM, respectively) and it differs from other cytokinins by inducing cell death without causing pronounced ATP depletion. Analysis of NCI60 test data suggests that its activity is independent of p53 status. Further we demonstrate that its 5'-monophosphate, the dominant cancer cell metabolite, inhibits the candidate oncogene DNPH1. Synthesis, purification, HPLC-MS identification and HPLC-UV quantification of 2OH3MeOBAR metabolites are also reported.

Published
2016
Full Text
View/download PDF

26. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential

Author

Delphine Rigault, Francine Acher, Nadia Oueslati, Hervé Daniel, Marianne Amalric, Isabelle Brabet, Jean-Philippe Pin, Heather McLean, Hugues-Olivier Bertrand, Tiphanie Courtiol, Bruno Vilar, Thomas Bessiron, Cyril Goudet, Thierry Deltheil, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Accelrys SARL, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS) - Université Montpellier 2 - Sciences et Techniques (UM2) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université de Montpellier (UM), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU) - Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Patch-Clamp Techniques, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Antiparkinson Agents, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH : Dose-Response Relationship, Drug, Pharmacology, Ligands, Receptors, Metabotropic Glutamate, Synaptic Transmission, Biochemistry, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, Antiparkinson Agents, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH : Structure-Activity Relationship, Excitatory Amino Acid Agonists, MESH: Ligands, MESH: Animals, MESH : Patch-Clamp Techniques, Receptor, Mice, Knockout, MESH : Synaptic Transmission, MESH : Ligands, 0303 health sciences, Molecular Structure, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH : Rats, Chemistry, Metabotropic glutamate receptor 4, MESH : Receptors, Metabotropic Glutamate, Glutamate receptor, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Glutamate binding, MESH : Antiparkinson Agents, MESH : Phosphinic Acids, Recombinant Proteins, MESH : Mutagenesis, Site-Directed, MESH: Mutagenesis, Site-Directed, MESH: HEK293 Cells, Metabotropic glutamate receptor 1, MESH: Phosphinic Acids, Biotechnology, Agonist, MESH: Rats, MESH : Recombinant Proteins, medicine.drug_class, MESH : Male, MESH: Molecular Structure, MESH : Rats, Wistar, Structure-Activity Relationship, 03 medical and health sciences, MESH : Mice, MESH: Patch-Clamp Techniques, Genetics, medicine, MESH: Synaptic Transmission, Animals, Humans, Rats, Wistar, MESH: Receptors, Metabotropic Glutamate, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH : Excitatory Amino Acid Agonists, Binding Sites, MESH: Humans, Dose-Response Relationship, Drug, MESH : Humans, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Rats, Wistar, Phosphinic Acids, MESH: Male, Rats, MESH : HEK293 Cells, HEK293 Cells, Metabotropic receptor, MESH: Binding Sites, Metabotropic glutamate receptor, Mutagenesis, Site-Directed, MESH : Mice, Knockout, MESH : Animals, MESH: Excitatory Amino Acid Agonists, MESH : Molecular Structure, MESH : Binding Sites, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery
Abstract

International audience; Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC(50): 0.11 ± 0.02, 11.6 ± 1.9, 29.2 ± 4.2 μM (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 μM]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor-knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential.

Published
2016
Full Text
View/download PDF

27. Highly solvatochromic and tunable fluorophores based on a 4,5-quinolimide scaffold: novel CDK5 probes

Author

May C. Morris, Juan A. González-Vera, Ibon Alkorta, Francisco Fueyo-González, Marion Peyressatre, Rosario Herranz, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Spanish National Research Council [Madrid] (CSIC), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Instituto de Quimica Médica (CSIC), and Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)

Subjects
Scaffold, Stereochemistry, MESH: Molecular Structure, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Catalysis, Materials Chemistry, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Fluorescent Dyes / chemistry, MESH: Quinolines / chemistry, Fluorescent Dyes, chemistry.chemical_classification, MESH: Humans, Molecular Structure, 010405 organic chemistry, Cyclin-dependent kinase 5, Solvatochromism, Metals and Alloys, Cyclin-Dependent Kinase 5, General Chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, female genital diseases and pregnancy complications, eye diseases, 3. Good health, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, chemistry, Ceramics and Composites, Biophysics, MESH: Cyclin-Dependent Kinase 5 / chemistry, Quinolines, Solvents, Glioblastoma
Abstract

Novel 4,5-quinolimide-based fluorophores are more solvatochromic and red-shifted than known naphthalimide analogues. Conjugation of one of these fluorophores to a peptide derived from CDK5 kinase demonstrated its sensitivity for monitoring the interaction with its regulatory partner p25. Introduction of the quinolimide-labelled peptide into living glioblastoma cells probed the interaction with endogenous p25., The work was supported by the Spanish Ministerio de Economía y Competividad grant SAF2012-32209 and the CSIC grant 2012280E096. J. A. G.-V. held a JAEdoc research contract from the CSIC and now is supported by a Marie-Curie fellowship EC-FP7 Framework (PIEF-GA-2013-623151). The work was also supported by the CNRS and a grant from Canceropole GSO 2015-E03 to MCM and has benefited from the facilities and expertise of the Montpellier RIO imaging facility (www.mri.cnrs.fr) at the Centre de Recherches en Biochimie Macromoléculaire, Montpellier

Published
2016
Full Text
View/download PDF

28. New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure–activity relationships

Author

Nicole Bec, Jean-François Guichou, Georges Moarbess, Carine Deleuze-Masquéfa, Christian Larroque, Stéphanie Paniagua-Gayraud, Zahraa Zghaib, Mona Diab-Assaf, Pierre-Antoine Bonnet, Issam Kassab, Kamel Hadj-Kaddour, Pierre Cuq, Laure-Anaïs Vincent, Johanna Vappiani, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Lebanese University [Beirut] (LU), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Tubulin depolymerization, Clinical Biochemistry, Pharmaceutical Science, Structure–activity relationship, Antiproliferative activity, MESH: Tubulin, Bioinformatics, 01 natural sciences, Biochemistry, Polymerization, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Tubulin, Drug Discovery, Tumor Cells, Cultured, Melanoma, Imidazo[1, Molecular Structure, biology, Chemistry, Human melanoma cancer cell line (A375), MESH: Drug Screening Assays, Antitumor, Imidazoles, 3. Good health, Molecular Docking Simulation, MESH: Polymerization, Molecular docking, Molecular Medicine, MESH: Imidazoles, MESH: Melanoma, MESH: Molecular Structure, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Structure-Activity Relationship, 03 medical and health sciences, Quinoxaline, MESH: Quinoxalines, Microtubule, Quinoxalines, medicine, MESH: Molecular Docking Simulation, Humans, MESH: Tumor Cells, Cultured, Molecular Biology, IC50, MESH: Humans, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, medicine.disease, 2-a]quinoxaline, In vitro, 0104 chemical sciences, 030104 developmental biology, Cell culture, biology.protein, MESH: Antineoplastic Agents, Drug Screening Assays, Antitumor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.

Published
2016
Full Text
View/download PDF

29. Urocontrin, a novel UT receptor ligand with a unique pharmacological profile

Author

Jocelyn Dupuis, David Chatenet, Alain Fournier, Myriam Létourneau, Quang-Trinh Nguyen, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), International Associated laboratory Samuel de Champlain, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Montreal Heart Institute, Department of Medicine, and This work was supported by the Canadian Institutes of Health Research. JD is a National Researcher from the Fonds de la Recherche en Santé du Québec

Subjects
Male, MESH: Endothelin-1, MESH: Sequence Homology, Amino Acid, Peptide Hormones, MESH: Cricetinae, MESH: Hypotension, MESH: Rats, Sprague-Dawley, MESH: Receptors, G-Protein-Coupled, Pharmacology, Biochemistry, Receptors, G-Protein-Coupled, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cricetinae, MESH: Animals, MESH: Phylogeny, Aorta, 0303 health sciences, Endothelin-1, Molecular Structure, Chemistry, MESH: Models, Chemical, Intracellular Signaling Peptides and Proteins, MESH: Aorta, Biological activity, Ligand (biochemistry), 3. Good health, MESH: Vasoconstriction, Hypotension, Protein Binding, Agonist, MESH: Rats, medicine.drug_class, Urotensins, MESH: Molecular Structure, CHO Cells, Urotensin-II receptor, MESH: Cation Transport Proteins, 03 medical and health sciences, MESH: CHO Cells, In vivo, medicine, Animals, MESH: Protein Binding, Antihypertensive Agents, 030304 developmental biology, MESH: Antihypertensive Agents, MESH: Humans, MESH: Metals, MESH: Urotensins, MESH: Molecular Sequence Data, Rational design, MESH: Male, Rats, Vasoconstriction, MESH: Peptide Hormones, Urotensin-II, 030217 neurology & neurosurgery, Ex vivo
Abstract

International audience; In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP.

Published
2012
Full Text
View/download PDF

30. The Prins Reaction Using Ketones: Rationalization and Application toward the Synthesis of the Portentol Skeleton

Author

Pierre van de Weghe, Nicolas Levoin, Maiwenn Jacolot, Mickael Jean, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Rennes Métropole, Région Bretagne, Université de Rennes 1, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)

Subjects
MESH: Molecular Structure, MESH: Ketones, 010402 general chemistry, 01 natural sciences, Biochemistry, Kinetic resolution, Computational chemistry, Spiro Compounds, MESH: Cyclization, MESH: Pyrans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Physical and Theoretical Chemistry, Pyrans, Molecular Structure, MESH: Kinetics, 010405 organic chemistry, Chemistry, Organic Chemistry, Rationalization (psychology), Stereoisomerism, Ketones, Prins reaction, MESH: Stereoisomerism, 0104 chemical sciences, Kinetics, MESH: Spiro Compounds, Cyclization
Abstract

International audience; We report a TMSI-promoted Prins cyclization reaction with ketones as carbonyl partners to prepare polysubstituted chiral spirotetrahydropyrans. In the presence of racemic 2-methylcyclohexanone a dynamic kinetic resolution occurred affording one stereoisomer. The observed enantiospecificity has been rationalized by DFT calculation.

Published
2011
Full Text
View/download PDF

31. Protonation of Lipids Impacts the Supramolecular and Biological Properties of Their Self-Assembly

Author

Marie Breton, Nathalie Mignet, Martin Hof, Daniel Scherman, Jean-François Berret, Michel Bessodes, Chantal Pichon, Teresa Kral, Claudie Bourgaux, Unité de pharmacologie chimique et génétique et d'imagerie ( UPCGI - UMR 8151 / UMR_S 1022 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Matière et Systèmes Complexes ( MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de biophysique moléculaire ( CBM ), Université d'Orléans ( UO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Matière et Systèmes Complexes (MSC (UMR_7057)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
MESH : DNA, 01 natural sciences, chemistry.chemical_compound, Computational chemistry, MESH : Particle Size, Electrochemistry, Organic chemistry, MESH: Animals, General Materials Science, Spectroscopy, Liposome, Molecular Structure, Chemistry, Thiourea, MESH: DNA, Surfaces and Interfaces, Condensed Matter Physics, Lipids, MESH : Microscopy, Electron, Transmission, MESH: Microscopy, Electron, Transmission, lipids (amino acids, peptides, and proteins), Protons, MESH: Cell Line, Tumor, Chemical structure, MESH: Molecular Structure, Supramolecular chemistry, Protonation, 010402 general chemistry, MESH: Hydrodynamics, MESH: Thiourea, Microscopy, Electron, Transmission, Cell Line, Tumor, MESH : Hydrodynamics, Amphiphile, Animals, Humans, MESH : Protons, Molecule, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Thiourea, MESH: Particle Size, Particle Size, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, MESH : Cell Line, Tumor, 010405 organic chemistry, MESH : Humans, MESH : Lipids, DNA, MESH: Lipids, 0104 chemical sciences, Hydrodynamics, MESH: Protons, MESH : Animals, Self-assembly, MESH : Molecular Structure
Abstract

International audience; We assessed in this work how a chemical structure difference could influence a supramolecular organization and then its biological properties. In our case study, we considered two amphiphilic lipidic gene vectors. The chemical difference was situated on their hydrophilic part which was either a pure neutral thiourea head or a mixture of three thiourea function derivatives, thiourea, iminothiol, and charged iminothiol. This small difference was obtained thanks to the last chemical deprotection conditions of the polar head hydroxyl groups. Light, neutron, and X-ray scattering techniques have been used to investigate the spatial structure of the liposomes and lipoplexes formed by the lipids. The chemical structure difference impacts the supramolecular assemblies of the lipids and with DNA as shown by fluorescence correlation spectroscopy (FCS), X-ray, and neutron scattering. Hence the structures formed were found to be highly different in terms of liposomes to DNA ratio and size and polydispersity of the aggregates. Finally, the transfection and internalization results proved that the differences in the structure of the lipid aggregates fully affect the biological properties of the lipopolythiourea compounds. The lipid containing three functions is a better gene transfection agent than the lipid which only contains one thiourea moiety. As a conclusion, we showed that the conditions of the last chemical step can influence the lipidic supramolecular structure which in turn strongly impacts their biological properties.

Published
2011
Full Text
View/download PDF

32. Stable interactions between DNA polymerase δ catalytic and structural subunits are essential for efficient DNA repair

Author

Laurent Maloisel, Serge Gangloff, Jean-Baptiste Charbonnier, Clémentine Brocas, Claudine Dherin, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Biologie Structurale et Radiobiologie (LBSR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d'Etudes de la Réparation de l'ADN (LERA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Radiobiologie moléculaire et cellulaire (RMC), Système membranaires, photobiologie, stress et détoxication (SMPSD), and Laboratoire de Radiobiologie de l'ADN (LRD)

Subjects
DNA Repair, DNA polymerase, MESH: DNA Polymerase III, [SDV]Life Sciences [q-bio], MESH: Protein Structure, Secondary, MESH: Catalytic Domain, MESH: DNA Replication, DNA-Directed DNA Polymerase, MESH: Amino Acid Sequence, Biochemistry, DNA polymerase delta, Protein Structure, Secondary, MESH: Saccharomyces cerevisiae Proteins, 0302 clinical medicine, Catalytic Domain, MESH: DNA-Directed DNA Polymerase, Pol3, Recombination, Genetic, MESH: DNA Repair, Genetics, 0303 health sciences, DNA clamp, Molecular Structure, biology, MESH: Saccharomyces cerevisiae, Cell biology, MESH: Mutagenesis, Site-Directed, MESH: Recombination, Genetic, DNA polymerase mu, Protein Binding, DNA Replication, Saccharomyces cerevisiae Proteins, DNA polymerase II, Molecular Sequence Data, MESH: Molecular Structure, Saccharomyces cerevisiae, 03 medical and health sciences, Proliferating Cell Nuclear Antigen, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Molecular Biology, Replication protein A, Alleles, DNA Polymerase III, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Alleles, DNA replication, Pol32, Cell Biology, Processivity, Pol31, MESH: Proliferating Cell Nuclear Antigen, Mutagenesis, Site-Directed, biology.protein, Genes, Lethal, MESH: Genes, Lethal, 030217 neurology & neurosurgery
Abstract

International audience; Eukaryotic DNA polymerase δ (Pol δ) activity is crucial for chromosome replication and DNA repair and thus, plays an essential role in genome stability. In Saccharomyces cerevisiae, Pol δ is a heterotrimeric complex composed of the catalytic subunit Pol3, the structural B subunit Pol31, and Pol32, an additional auxiliary subunit. Pol3 interacts with Pol31 thanks to its C-terminal domain (CTD) and this interaction is of functional importance both in DNA replication and DNA repair. Interestingly, deletion of the last four C-terminal Pol3 residues, LSKW, in the pol3-ct mutant does not affect DNA replication but leads to defects in homologous recombination and in break-induced replication (BIR) repair pathways. The defect associated with pol3-ct could result from a defective interaction between Pol δ and a protein involved in recombination. However, we show that the LSKW motif is required for the interaction between Pol3 C-terminal end and Pol31. This loss of interaction is relevant in vivo since we found that pol3-ct confers HU sensitivity on its own and synthetic lethality with a POL32 deletion. Moreover, pol3-ct shows genetic interactions, both suppression and synthetic lethality, with POL31 mutant alleles. Structural analyses indicate that the B subunit of Pol δ displays a major conserved region at its surface and that pol31 alleles interacting with pol3-ct, correspond to substitutions of Pol31 amino acids that are situated in this particular region. Superimposition of our Pol31 model on the 3D architecture of the phylogenetically related DNA polymerase α (Pol α) suggests that Pol3 CTD interacts with the conserved region of Pol31, thus providing a molecular basis to understand the defects associated with pol3-ct. Taken together, our data highlight a stringent dependence on Pol δ complex stability in DNA repair.

Published
2010
Full Text
View/download PDF

33. Rearranged Diterpenoids from the Biotransformation of ent-Trachyloban-18-oic Acid by Rhizopus arrhizus

Author

Françoise Guéritte, Marc Litaudon, Jamal Ouazzani, Mat Ropi Mukhtar, Claudine Servy, Pascal Retailleau, Khalijah Awang, Marie-Thérèse Martin, Aurélie Leverrier, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
MESH: Diterpenes, Pharmaceutical Science, Pharmacognosy, 01 natural sciences, KB Cells, Analytical Chemistry, chemistry.chemical_compound, Biotransformation, Drug Discovery, MESH: Rhizopus, MESH: Inhibitory Concentration 50, Molecular Structure, biology, MESH: Drug Screening Assays, Antitumor, Biological activity, Xylopia, 3. Good health, MESH: Malaysia, Plant Bark, Molecular Medicine, Diterpenes, Rhizopus, MESH: Plant Bark, MESH: HCT116 Cells, Stereochemistry, Chemical structure, MESH: Molecular Structure, education, bcl-X Protein, MESH: KB Cells, MESH: Xylopia, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, MESH: bcl-X Protein, Inhibitory Concentration 50, otorhinolaryngologic diseases, Humans, Rhizopus arrhizus, MESH: Biotransformation, Pharmacology, MESH: Humans, 010405 organic chemistry, Organic Chemistry, Malaysia, HCT116 Cells, biology.organism_classification, Terpenoid, 0104 chemical sciences, Complementary and alternative medicine, chemistry, Drug Screening Assays, Antitumor, Diterpene
Abstract

International audience; In our search for inhibitors of the antiapoptotic protein Bcl-xL, investigation of Xylopia caudata afforded a new diterpenoid, ent-trachyloban-4beta-ol (2), and five known ent-trachylobane or ent-atisane compounds. Only ent-trachyloban-18-oic acid (1) exhibited weak binding activity to Bcl-xL. These compounds exhibited cytotoxicity against KB and HCT-116 cell lines with IC(50) values between 10 and 30 microM. Bioconversion of compound 1 by Rhizopus arrhizus afforded new hydroxylated metabolites (3-7) of the ent-trachylobane and ent-kaurene type and compound 8, with a rearranged pentacyclic carbon framework that was named rhizopene. Compounds 3-8 were noncytotoxic to the two cancer cell lines, and compounds 3 and 5 exhibited only weak binding affinity for Bcl-xL.

Published
2010
Full Text
View/download PDF

34. Asymmetric Total Syntheses of (−)-Renieramycin M and G and (−)-Jorumycin Using Aziridine as a Lynchpin

Author

Jieping Zhu, Yan-Chao Wu, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Stereochemistry, MESH: Molecular Structure, MESH: Porifera, Aziridines, Heterocyclic compounds Role: RCT (Reactant), and (-)-jorunnamycin A using ring opening and Pictet-Spengler reactions of nonracemic amino acid-derived aziridine building blocks as key steps), Stereoselective synthesis (stereoselective prepn. of (-)-renieramycins G and M, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, aziridines, stereoselective prepn. of (-)-renieramycins G and M, 010402 general chemistry, 01 natural sciences, Biochemistry, Catalysis, MESH: Tetrahydroisoquinolines, chemistry.chemical_compound, Nucleophile, Tetrahydroisoquinolines, PREP (Preparation), renieramycin G M stereoselective nonracemic prepn, jorumycin stereoselective nonracemic prepn, jorunnamycin A stereoselective nonracemic prepn, ring opening reaction amino acid derived aziridine prepn renieramycin, Pictet Spengler reaction amino acid derived aziridine prepn renieramycin, Animals, Organic chemistry, MESH: Animals, Reactivity (chemistry), Pictet-Spengler cyclocondensation reaction, Ring opening (stereoselective, Physical and Theoretical Chemistry, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, SPN (Synthetic preparation), Stereoisomerism, Aziridine, MESH: Catalysis, MESH: Stereoisomerism, Porifera, 0104 chemical sciences, 3. Good health, Renieramycin M, RACT (Reactant or reagent) (nitrogen, MESH: Aziridines, (-)-jorumycin
Abstract

Using ring opening and Pictet-Spengler reactions of nonracemic amino acid-derived aziridine building blocks as key steps, (-)-renieramycin M I [R = (Z)-MeCH:CMeCO; R = NC; R1 = H], (-)-renieramycin G I [R = (Z)-MeCH:CMeCO; RR1 = O], (-)-jorumycin I (R = MeCO; R1 = HO; R2 = H), and (-)-jorunnamycin A I (R = H; R1 = NC; R2 = H) are prepd. convergently. [on SciFinder (R)]

Published
2009
Full Text
View/download PDF

35. Retinoid receptor subtype-selective modulators through synthetic modifications of RARγ agonists

Author

Hinrich Gronemeyer, Pierre Germain, Harshal Khanwalkar, Géraldine Lemaire, Rosana Alvarez, Fátima Rodríguez-Barrios, Angel R. de Lera, Susana Alvarez, Peney, Maité, Departamento de Química Orgánica, Universidade de Vigo, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Transcriptional Activation, Agonist, medicine.drug_class, Recombinant Fusion Proteins, MESH: Molecular Structure, Clinical Biochemistry, Pharmaceutical Science, Retinoid receptor, MESH: Carrier Proteins, Retinoid X receptor, Ligands, Biochemistry, Partial agonist, Retinoids, Transactivation, Genes, Reporter, Drug Discovery, MESH: Ligands, MESH: Recombinant Fusion Proteins, medicine, Humans, MESH: Retinoids, Retinoid, Molecular Biology, Reporter gene, MESH: Humans, Molecular Structure, Chemistry, MESH: Genes, Reporter, Organic Chemistry, Antagonist, Cell biology, MESH: Hela Cells, Retinoid X Receptors, MESH: Transcriptional Activation, MESH: Retinoid X Receptors, Molecular Medicine, Carrier Proteins, MESH: Models, Molecular, HeLa Cells
Abstract

International audience; A series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARgamma antagonists based on the structure of known RARgamma agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARgamma antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARalpha than TTNPB and synergizes at low concentration with TTNPB-bound RARalpha but not RARbeta or RARgamma. Similarly, 24c synergizes with TTNPB-bound RARgamma and exhibits RARalpha,beta antagonist activity. Compounds 24b and 25b are strong RARalpha,beta-selective antagonists without agonist or antagonist activities for RARgamma. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined.

Published
2009
Full Text
View/download PDF

36. Microcalorimetric study of the inhibition of butyrylcholinesterase by paraoxon

Author

Jean Debord, Thierry Dantoine, Jean-Claude Bollinger, Bernard Verneuil, Michel Harel, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Institut universitaire de formation des maîtres - Limousin (IUFM Limousin), Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Groupement de Recherche Eau, Sol, Environnement (GRESE), Service de Médecine Gériatrique [CHU Limoges], Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Microchemistry, Tris, Isothermal microcalorimetry, Stereochemistry, MESH: Molecular Structure, MESH: Paraoxon, Kinetics, Biophysics, Calorimetry, Biochemistry, Paraoxon, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Reaction rate constant, medicine, Organophosphorus compound, Animals, MESH: Animals, Horses, Butyrylcholine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Calorimetry, MESH: Horses, Molecular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Molecular Structure, MESH: Butyrylcholinesterase, MESH: Kinetics, Microchemistry, Substrate (chemistry), Cell Biology, chemistry, Butyrylcholinesterase, 030220 oncology & carcinogenesis, Physical chemistry, Cholinesterase Inhibitors, MESH: Cholinesterase Inhibitors, medicine.drug
Abstract

International audience; The inhibition of horse serum butyrylcholinesterase (EC 3.1.1.8) by the organophosphorus compound paraoxon (diethyl 4-nitrophenyl phosphate) was studied by flow microcalorimetry at 37 degrees C in Tris buffer (pH 7.5) using a modification of the kinetic model described by Stojan and coworkers [J. Stojan, V. Marcel, S. Estrada-Mondaca, A. Klaebe, P. Masson, D. Fournier, A putative kinetic model for substrate metabolisation by Drosophila acetylcholinesterase, FEBS Lett. 440 (1998) 85-88]. The reversible steps of the inhibition were studied in the mixing cell of the calorimeter, whereas the irreversible step was studied in the flow-through cell. A new pseudo-first-order approximation was developed to allow the kinetic analysis of inhibition progress curves in the presence of substrate when a significant amount of substrate is transformed. This approximation also allowed one to compute an analytical expression of the calorimetric curves using a gamma distribution to describe the impulse response of the calorimeter. Fitting models to data by nonlinear regression, with simulated annealing as a stochastic optimization method, allowed the determination of all kinetic parameters. It was found that paraoxon binds to both the enzyme and acyl-enzyme, but with weak affinities (K(i) = 0.123 mM and K'(i) = 5.5 mM). A slight activation was observed at the lowest paraoxon concentrations and was attributed to the binding of the substrate to the enzyme-inhibitor complex. The bimolecular inhibition rate constant k(i) = 2.8 x 10(4) M(-1) s(-1) was in agreement with previous studies. It is hoped that the methods developed in this work will contribute to extending the application range of microcalorimetry in the field of irreversible inhibitors.

Published
2009
Full Text
View/download PDF

37. Useful Sialic Acid Modifications Catalyzed by Palladium

Author

Stéphanie Norsikian, Jean-Marie Beau, Chih-Wei Chang, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Models, Molecular, Allylic rearrangement, Stereochemistry, MESH: Molecular Structure, Carbohydrates, chemistry.chemical_element, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ligands, 010402 general chemistry, 01 natural sciences, Catalysis, Structure-Activity Relationship, chemistry.chemical_compound, MESH: Structure-Activity Relationship, MESH: Allyl Compounds, MESH: Ligands, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Regioselectivity, Stereoisomerism, General Chemistry, MESH: Catalysis, MESH: Stereoisomerism, N-Acetylneuraminic Acid, 0104 chemical sciences, Sialic acid, Allyl Compounds, MESH: N-Acetylneuraminic Acid, MESH: Palladium, Palladium, MESH: Models, Molecular, MESH: Carbohydrates
Abstract

International audience; A regio- and stereocontrolled solution for a selective modification at the C-2 or C-4 position of N-acetylneuraminic acid involves the use of allylic substitution catalyzed by palladium. As illustrated in the scheme, regioselective malonylation is under the strict influence of the ligands associated with the allylpalladium complex.

Published
2009
Full Text
View/download PDF

38. Phycourobilin in Trichromatic Phycocyanin from Oceanic Cyanobacteria Is Formed Post-translationally by a Phycoerythrobilin Lyase-Isomerase

Author

Matthias Plöscher, Kai-Hong Zhao, Ming Zhou, Nicolas Blot, Laurence Garczarek, Jun-Ming Tu, Juan Zhang, Frédéric Partensky, Lutz A. Eichacker, Hugo Scheer, Stephan H. Bohm, Jean-Claude Thomas, Xian-Jun Wu, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), MArine Phototrophic Prokaryotes (MAPP), Adaptation et diversité en milieu marin (AD2M), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Biologie moléculaire des organismes photosynthétiques (UMR8186), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department Biologie I, Universität München, SILS-CNS, University of Amsterdam [Amsterdam] (UvA), University of Stavanger, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Procaryotes Phototrophes Marins = MArine Phototrophic Prokaryotes (MAPP), Huazhong Agricultural University [Wuhan] (HZAU), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL)

Subjects
MESH: Phycoerythrin, Phycoerythrobilin, Biochemistry, Substrate Specificity, MESH: Circular Dichroism, chemistry.chemical_compound, Phycocyanobilin, Phycobilins, Isomerases, MESH: Phylogeny, Phylogeny, MESH: Evolution, Molecular, 0303 health sciences, Molecular Structure, Phycourobilin, Circular Dichroism, Phycobiliprotein, 030302 biochemistry & molecular biology, MESH: Cyanobacteria, Chromatin, Metabolism and Bioenergetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDE]Environmental Sciences, MESH: Phycobilins, Phycoerythrin, MESH: Molecular Structure, Lyases, MESH: Isomerases, Biology, Cyanobacteria, MESH: Chromatin, Evolution, Molecular, 03 medical and health sciences, Phycocyanin, Seawater, Phycobilin, Molecular Biology, 030304 developmental biology, MESH: Seawater, Cell Biology, MESH: Phycocyanin, MESH: Lyases, chemistry, MESH: Protein Processing, Post-Translational, biology.protein, MESH: Substrate Specificity, Phycobilisome, Protein Processing, Post-Translational
Abstract

International audience; Most cyanobacteria harvest light with large antenna complexes called phycobilisomes. The diversity of their constituting phycobiliproteins contributes to optimize the photosynthetic capacity of these microorganisms. Phycobiliprotein biosynthesis, which involves several post-translational modifications including covalent attachment of the linear tetrapyrrole chromophores (phycobilins) to apoproteins, begins to be well understood. However, the biosynthetic pathway to the blue-green-absorbing phycourobilin (lambda(max) approximately 495 nm) remained unknown, although it is the major phycobilin of cyanobacteria living in oceanic areas where blue light penetrates deeply into the water column. We describe a unique trichromatic phycocyanin, R-PC V, extracted from phycobilisomes of Synechococcus sp. strain WH8102. It is evolutionarily remarkable as the only chromoprotein known so far that absorbs the whole wavelength range between 450 and 650 nm. R-PC V carries a phycourobilin chromophore on its alpha-subunit, and this can be considered an extreme case of adaptation to blue-green light. We also discovered the enzyme, RpcG, responsible for its biosynthesis. This monomeric enzyme catalyzes binding of the green-absorbing phycoerythrobilin at cysteine 84 with concomitant isomerization to phycourobilin. This reaction is analogous to formation of the orange-absorbing phycoviolobilin from the red-absorbing phycocyanobilin that is catalyzed by the lyase-isomerase PecE/F in some freshwater cyanobacteria. The fusion protein, RpcG, and the heterodimeric PecE/F are mutually interchangeable in a heterologous expression system in Escherichia coli. The novel R-PC V likely optimizes rod-core energy transfer in phycobilisomes and thereby adaptation of a major phytoplankton group to the blue-green light prevailing in oceanic waters.

Published
2009
Full Text
View/download PDF

39. Grandine A, a New Proaporphine Alkaloid from the Bark of Phoebe grandis

Author

Mat Ropi Mukhtar, Noel F. Thomas, Ahmad Nazif Aziz, Khalijah Awang, Marc Litaudon, A. Hamid A. Hadi, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Magnetic Resonance Spectroscopy, Aporphine, Pharmaceutical Science, 01 natural sciences, Analytical Chemistry, chemistry.chemical_compound, Dihydrolinearisine, Drug Discovery, Organic chemistry, Oxoproaporphine, Molecular Structure, Alkaloid, Chemistry (miscellaneous), visual_art, Plant Bark, visual_art.visual_art_medium, Molecular Medicine, Bark, High field, NMR, Phoebe grandis, MESH: Plant Bark, Aporphines, Stereochemistry, MESH: Molecular Structure, MESH: Lauraceae, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, lcsh:QD241-441, Lauraceae, Alkaloids, lcsh:Organic chemistry, MESH: Alkaloids, MESH: Isoquinolines, Boldine, Physical and Theoretical Chemistry, Isoquinoline, Spectral data, Stem bark, MESH: Aporphines, MESH: Magnetic Resonance Spectroscopy, 010405 organic chemistry, Organic Chemistry, Isoquinolines, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry
Abstract

International audience; The stem bark of Phoebe grandis afforded one new oxoproaporphine; (-)-grandine A (1), along with six known isoquinoline alkaloids: (-)-8,9-dihydrolinearisine (2), boldine, norboldine, lauformine, scortechiniine A and scortechiniine B. In addition to that of the new compound, complete 1H- and 13C-NMR data of the tetrahydroproaporphine (-)-8,9-dihydrolinearisine (2) is also reported. The alkaloids' structures were elucidated primarily by means of high field 1D- and 2D-NMR and HRMS spectral data.

Published
2009
Full Text
View/download PDF

40. Novel Chiral Molecular Tweezer from (+)-Usnic Acid

Author

Loïc Toupet, Pierre van de Weghe, Béatrice Legouin, Philippe Uriac, Sophie Tomasi, Arnaud Bondon, Substances Lichéniques et Photoprotection, Université de Rennes (UR), Institut de Physique de Rennes (IPR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Plate-forme Rennaise d'Imagerie et Spectroscopie Structurale et Métabolique (PRISM), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Interactions cellulaires et moléculaires (ICM), De Villemeur, Hervé, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre National de la Recherche Scientifique (CNRS)-IFR140-Université de Rennes 1 (UR1)

Subjects
Models, Molecular, Stereochemistry, MESH: Molecular Structure, Molecular Conformation, Stereoisomerism, Crystallography, X-Ray, 010402 general chemistry, Heterocyclic Compounds, 4 or More Rings, 01 natural sciences, Biochemistry, Molecular conformation, chemistry.chemical_compound, Cyclohexanes, Models, MESH: Fluorenes, Molecule, Physical and Theoretical Chemistry, Binding site, Benzofurans, MESH: Heterocyclic Compounds with 4 or More Rings, Fluorenes, MESH: Molecular Conformation, Binding Sites, Crystallography, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, Usnic acid, Molecular, MESH: Benzofurans, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [CHIM.ORGA] Chemical Sciences/Organic chemistry, MESH: Crystallography, X-Ray, MESH: Cyclohexanes, MESH: Stereoisomerism, 0104 chemical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Binding Sites, X-Ray, Heterocyclic Compounds with 4 or More Rings, MESH: Models, Molecular
Abstract

International audience; A new chiral molecular tweezer was synthesized with (1R,2R)-1,2-diaminocyclohexane as spacer and two molecules of (+)-usnic acid as pincers. The ability of this molecular tweezer to bind 2,4,7-trinitrofluorenone was studied. A charge-transfer complex was formed in which TNF was sandwiched between the two usnic acid units with pi-pi-stacked aromatic interactions.

Published
2009
Full Text
View/download PDF

41. High-Throughput Screening Assays to Discover Small-Molecule Inhibitors of Protein Interactions

Author

Pierre Colas, Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
Magnetic Resonance Spectroscopy, MESH: Molecular Structure, Druggability, Enzyme-Linked Immunosorbent Assay, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Computational biology, Biology, MESH: Two-Hybrid System Techniques, 01 natural sciences, Mass Spectrometry, Protein–protein interaction, 03 medical and health sciences, MESH: Drug Discovery, Two-Hybrid System Techniques, Protein Interaction Mapping, Drug Discovery, High-Throughput Screening Assays, Screening method, Animals, Humans, MESH: Animals, 030304 developmental biology, MESH: Mass Spectrometry, 0303 health sciences, MESH: Humans, Molecular Structure, MESH: Magnetic Resonance Spectroscopy, Drug discovery, MESH: Protein Interaction Mapping, MESH: Enzyme-Linked Immunosorbent Assay, Small molecule, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry
Abstract

International audience; The availability of large collections of small-molecule inhibitors of protein interactions would bear a tremendous impact both on academic and therapeutic research. The past recent years have seen a marked acceleration in the discovery of protein interaction inhibitors, through structure-based drug design but mostly through screening efforts. This article attempts to review the impressive number and variety of in vitro and cellular screening assays that have been developed and, for most of them, used successfully to identify small-molecule inhibitors of protein interactions. Various strategies aimed at improving hit rates are also reviewed, and future challenges to improve discovery success rates are discussed. The growing list of protein interaction inhibitors and the large arsenal of screening methods, now available to most laboratories or screening facilities, will probably convince an increasing number of academic and industrial scientists that protein interactions are more druggable than once feared, and that their respective research interests would greatly benefit from the discovery of protein interaction inhibitors.

Published
2008
Full Text
View/download PDF

42. Molecular Field Analysis and 3D-Quantitative Structure−Activity Relationship Study (MFA 3D-QSAR) Unveil Novel Features of Bile Acid Recognition at TGR5

Author

Alberto Massarotti, Charles Thomas, Johan Auwerx, Emiliano Rosatelli, Antonio Macchiarulo, Paola Sabbatini, Roberto Nuti, Kristina Schoonjans, Antimo Gioiello, Roberto Pellicciari, Department of Chemistry and Pharmaceutical Technology, Università degli Studi di Perugia = University of Perugia (UNIPG), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Peney, Maité, Università degli Studi di Perugia (UNIPG), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Quantitative structure–activity relationship, medicine.drug_class, General Chemical Engineering, MESH: Molecular Structure, Quantitative Structure-Activity Relationship, Chemical, MESH: Bile Acids and Salts, MESH: Imaging, Three-Dimensional, MESH: Receptors, G-Protein-Coupled, Library and Information Sciences, Biology, Cyclase, Receptors, G-Protein-Coupled, Bile Acids and Salts, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, MESH: Computer Simulation, Models, Cell surface receptor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, bile acids, TGR5, FXR, QSAR, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Luciferase, Receptor, 030304 developmental biology, MESH: Quantitative Structure-Activity Relationship, 0303 health sciences, Molecular Structure, Bile acid, MESH: Models, Chemical, General Chemistry, G protein-coupled bile acid receptor, In vitro, Computer Science Applications, Models, Chemical, Biochemistry, 030220 oncology & carcinogenesis
Abstract

International audience; Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

Published
2008
Full Text
View/download PDF

43. Structure–activity relationships of urotensin II and URP

Author

Hubert Vaudry, David Chatenet, Daniel Davoust, Pierre Pacaud, Christophe Dubessy, Laure Guilhaudis, Alain Fournier, Bruno Pfeiffer, Hassan Oulyadi, Marie-Christine Tonon, Jérôme Leprince, Pierre Renard, Elizabeth Scalbert, Isabelle Ségalas-Milazzo, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Montreal Heart Institute (MONTREAL HEART INSTITUTE), Les Laboratoires SERVIER, Institut de Recherche Servier, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)

Subjects
Protein Conformation, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peptide Hormones, Peptide, Endogeny, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, MESH: Tyrosine, chemistry.chemical_compound, MESH: Protein Conformation, MESH: Structure-Activity Relationship, 0302 clinical medicine, Endocrinology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Disulfides, MESH: Peptide Fragments, Receptor, chemistry.chemical_classification, 0303 health sciences, Alanine, Molecular Structure, Biological activity, 3. Good health, Amino acid, MESH: Alanine, Urotensins, MESH: Molecular Structure, Molecular Sequence Data, MESH: Sequence Alignment, Structure-Activity Relationship, 03 medical and health sciences, Cellular and Molecular Neuroscience, Animals, Humans, Structure–activity relationship, MESH: Disulfides, Amino Acid Sequence, Cysteine, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, MESH: Urotensins, Rational design, MESH: Cysteine, Peptide Fragments, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Tyrosine, Urotensin-II, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

International audience; Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.

Published
2008
Full Text
View/download PDF

44. A New Generation of SpecificTrypanosoma cruzi trans-Sialidase Inhibitors

Author

Stephen G. Withers, Alejandro Buschiazzo, Sabrina Buchini, University of British Columbia (UBC), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), and Canadian Institutes for Health ResearchSwiss National Science Foundation

Subjects
Models, Molecular, Stereochemistry, Trypanosoma cruzi, MESH: Molecular Structure, MESH: Glycoproteins, Neuraminidase, Crystallography, X-Ray, 010402 general chemistry, Sensitivity and Specificity, 01 natural sciences, Catalysis, Trans-sialidase, Hydrolase, [CHIM.CRIS]Chemical Sciences/Cristallography, Animals, Bioorganic chemistry, Protease Inhibitors, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Glycoproteins, chemistry.chemical_classification, MESH: Protease Inhibitors, Molecular Structure, biology, MESH: Kinetics, 010405 organic chemistry, Chemistry, MESH: Neuraminidase, General Chemistry, General Medicine, biology.organism_classification, MESH: Crystallography, X-Ray, MESH: Sensitivity and Specificity, 0104 chemical sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Kinetics, Enzyme, Biochemistry, MESH: Trypanosoma cruzi, MESH: Models, Molecular
Abstract

International audience

Published
2008
Full Text
View/download PDF

45. Cinnamic Acid, an Autoinducer of Its Own Biosynthesis, Is Processed via Hca Enzymes in Photorhabdus luminescens

Author

Antoine Danchin, Christelle Ganneau, Jean-François Charles, Emma Brito-Fravallo, Sylvie Bay, Sabina Chalabaev, Evelyne Turlin, Francis Biville, Génétique des Génomes Bactériens, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chimie Organique, Membranes bactériennes, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Molecular Structure, Phenylalanine ammonia-lyase, Models, Biological, Applied Microbiology and Biotechnology, Cinnamic acid, Microbiology, MESH: Phenylalanine Ammonia-Lyase, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Biosynthesis, Dioxygenase, MESH: Reverse Transcriptase Polymerase Chain Reaction, Photorhabdus luminescens, Invertebrate Microbiology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Models, Genetic, MESH: Chromatography, High Pressure Liquid, MESH: Bacterial Proteins, Chromatography, High Pressure Liquid, Phenylalanine Ammonia-Lyase, MESH: Phenylpropionates, 030304 developmental biology, chemistry.chemical_classification, MESH: Gene Expression Regulation, Bacterial, 0303 health sciences, Models, Genetic, Molecular Structure, Phenylpropionates, Ecology, biology, Reverse Transcriptase Polymerase Chain Reaction, 030306 microbiology, MESH: Models, Biological, MESH: Photorhabdus, Gene Expression Regulation, Bacterial, biology.organism_classification, MESH: Cinnamates, Enzyme, Biochemistry, chemistry, Cinnamates, Autoinducer, Photorhabdus, Signal Transduction, Food Science, Biotechnology
Abstract

Photorhabdus luminescens , an entomopathogenic bacterium and nematode symbiont, has homologues of the Hca and Mhp enzymes. In Escherichia coli , these enzymes catalyze the degradation of the aromatic compounds 3-phenylpropionate (3PP) and cinnamic acid (CA) and allow the use of 3PP as sole carbon source. P. luminescens is not able to use 3PP and CA as sole carbon sources but can degrade them. Hca dioxygenase is involved in this degradation pathway. P. luminescens synthesizes CA from phenylalanine via a phenylalanine ammonia-lyase (PAL) and degrades it via the not-yet-characterized biosynthetic pathway of 3,5-dihydroxy-4-isopropylstilbene (ST) antibiotic. CA induces its own synthesis by enhancing the expression of the stlA gene that codes for PAL. P. luminescens bacteria release endogenous CA into the medium at the end of exponential growth and then consume it. Hca dioxygenase is involved in the consumption of endogenous CA but is not required for ST production. This suggests that CA is consumed via at least two separate pathways in P. luminescens : the biosynthesis of ST and a pathway involving the Hca and Mhp enzymes.

Published
2008
Full Text
View/download PDF

46. Environmentally Friendly Chemoselective Oxidation of Primary Aliphatic Amines by Using a Biomimetic Electrocatalytic System

Author

Angèle Chiaroni, Martine Largeron, Maurice-Bernard Fleury, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, MESH: Oxidation-Reduction, Crystallography, X-Ray, Electrochemistry, 01 natural sciences, chemistry.chemical_compound, Biomimetic Materials, Organic chemistry, ComputingMilieux_MISCELLANEOUS, Primary (chemistry), Molecular Structure, enzyme models, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, MESH: Biomimetic Materials, Quinones, MESH: Amines, Environmentally friendly, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, chemoselectivity, Amine gas treating, Amine Oxidase (Copper-Containing), Imines, Oxidation-Reduction, MESH: Models, Molecular, oxidation, amines, MESH: Molecular Structure, Imine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, MESH: Quinones, Catalysis, electrocatalysis, [CHIM]Chemical Sciences, Reactivity (chemistry), MESH: Hydrogen Bonding, Chemoselectivity, MESH: Electrochemistry, 010405 organic chemistry, Organic Chemistry, Hydrogen Bonding, [CHIM.CATA]Chemical Sciences/Catalysis, General Chemistry, MESH: Catalysis, MESH: Crystallography, X-Ray, 0104 chemical sciences, MESH: Imines, MESH: Amine Oxidase (Copper-Containing)
Abstract

International audience; Environmentally friendly oxidation of primary aliphatic amines to imines has been successfully achieved, under metal-free conditions, by the use of diverse electrogenerated o-azaquinone mediators. High catalytic performance, together with high chemoselectivity, were observed with electron-poor o-azaquinone catalysts generated from 2-aminoresorcinol derivatives. Similar to copper amine oxidase enzymes, these mediators exhibited lower reactivity toward alpha-branched primary amines and no reactivity toward secondary amines. In the case of 3,4-aminophenol derivatives lacking a 2-hydroxy group, the generated o-azaquinone species failed to catalyze the oxidation of the amine to the corresponding imine. Further mechanistic considerations allowed a rationalization of the crucial role of the 2-hydroxy group in converting a catalytically inert species into a highly effective biomimetic catalyst.

Published
2008
Full Text
View/download PDF

47. N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) Acts through a Novel Site as a Positive Allosteric Modulator of Group 1 Metabotropic Glutamate Receptors

Author

P. Jeffrey Conn, Cyril Goudet, Yelin Chen, Jean-Philippe Pin, Department of Pharmacology, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville]-Vanderbilt University [Nashville], Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Goudet, Cyril, and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Sequence Homology, Amino Acid, Cell Culture Techniques, MESH: Cricetinae, MESH: Amino Acid Sequence, Kidney, Ligands, Receptors, Metabotropic Glutamate, MESH: Allosteric Regulation, MESH: Radioligand Assay, MESH: Dose-Response Relationship, Drug, Radioligand Assay, MESH: Protein Structure, Tertiary, MESH: Valine, MESH: Benzamides, 0302 clinical medicine, Cricetinae, MESH: Ligands, Radioligand, MESH: Animals, MESH: Allosteric Site, Cells, Cultured, Cerebral Cortex, 0303 health sciences, Molecular Structure, Metabotropic glutamate receptor 5, Chemistry, Valine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Amino Acid Substitution, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Calcium, Benzamides, Molecular Medicine, Metabotropic glutamate receptor 1, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Allosteric Site, MESH: Cells, Cultured, Allosteric modulator, MESH: Rats, Stereochemistry, Molecular Sequence Data, MESH: Molecular Structure, Allosteric regulation, CDPPB, Transfection, Cell Line, 03 medical and health sciences, Allosteric Regulation, mental disorders, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, Binding site, MESH: Receptors, Metabotropic Glutamate, 030304 developmental biology, Pharmacology, MESH: Cell Culture Techniques, MESH: Humans, MESH: Molecular Sequence Data, Dose-Response Relationship, Drug, Sequence Homology, Amino Acid, MESH: Transfection, MESH: Kidney, MESH: Cerebral Cortex, Protein Structure, Tertiary, Rats, MESH: Cell Line, MESH: Astrocytes, Amino Acid Substitution, Metabotropic glutamate receptor, Astrocytes, Calcium, 030217 neurology & neurosurgery
Abstract

International audience; Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.

Published
2007
Full Text
View/download PDF

48. Small Multivalent Architectures Mimicking Homotrimers of the TNF Superfamily Member CD40L: Delineating the Relationship between Structure and Effector Function

Author

Johan Hoebeke, Olivier Chaloin, Gilles Guichard, Nathalie Trouche, Sylvie Fournel, Weimin Sun, Sébastien Wieckowski, Immunologie et chimie thérapeutiques (ICT), and Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Scaffold, Time Factors, Protein Conformation, CD40 Ligand, MESH: Molecular Structure, Nanotechnology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Ligands, 01 natural sciences, Biochemistry, Catalysis, MESH: Antigens, CD40, law.invention, Structure-Activity Relationship, MESH: Protein Structure, Tertiary, 03 medical and health sciences, MESH: Protein Conformation, MESH: Structure-Activity Relationship, Colloid and Surface Chemistry, In vivo, Cell surface receptor, law, MESH: Ligands, CD40 Antigens, MESH: CD40 Ligand, 030304 developmental biology, 0303 health sciences, Binding Sites, CD40, Molecular Structure, biology, 010405 organic chemistry, Effector, Chemistry, Intracellular parasite, MESH: Time Factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Protein Structure, Tertiary, 0104 chemical sciences, Cell biology, MESH: Binding Sites, biology.protein, Recombinant DNA, Linker, MESH: Models, Molecular
Abstract

Synthetic multivalent ligands, owing to the presence of multiple copies of a recognition motif attached to a central scaffold, can mediate clustering of cell surface receptors and thereby function as effector molecules. This paper dissects the relationship between structure and effector function of synthetic multivalent ligands targeting CD40, a cell surface receptor of the tumor necrosis factor receptor (TNF-R) superfamily. Triggering CD40 signaling in vivo can be used to enhance immunity against intracellular pathogens or tumors. A series of multimeric molecules has been prepared by systematically varying the shape and the valency of the central scaffold, the nature and the length of the linker as well as the sequence of the receptor binding motif. The data reported here (i) suggest that radial distribution of CD40-binding units and C3-symmetry are preferred for optimal binding to CD40 and signaling, (ii) underscore the importance of choosing an appropriate linker to connect the receptor binding motif to the central scaffold, and (iii) show the versatility of planar cyclic alpha- and beta-peptides as templates for the design of CD40L mimetics. In particular, the (Ahx)3-B trimeric scaffold-linker combination equally accommodated binding elements derived from distinct CD40L hot-spot regions including AA" loop and beta-strand E. The use of miniCD40Ls such as those reported here is complementary to other approaches (recombinant ligands, agonistic anti-receptor antibodies) and may find interesting therapeutic applications. Furthermore, the results disclosed in this paper provide the basis for future design of other TNF family member mimetics.

Published
2007
Full Text
View/download PDF

49. Nongenomic Actions of Bile Acids. Synthesis and Preliminary Characterization of 23- and 6,23-Alkyl-Substituted Bile Acid Derivatives as Selective Modulators for the G-Protein Coupled Receptor TGR5

Author

Johan Auwerx, Roberto Pellicciari, Gianluca Giorgi, Kristina Schoonjans, Hiroyuki Sato, Bahman M. Sadeghpour, Gabriele Costantino, Antimo Gioiello, Antonio Macchiarulo, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Models, Molecular, medicine.medical_treatment, Receptors, Cytoplasmic and Nuclear, MESH: Cricetinae, MESH: Receptors, G-Protein-Coupled, Crystallography, X-Ray, Ligands, Receptors, G-Protein-Coupled, chemistry.chemical_compound, MESH: Structure-Activity Relationship, 0302 clinical medicine, MESH: Cricetulus, Cricetinae, Chenodeoxycholic acid, Drug Discovery, MESH: Ligands, MESH: Animals, Receptor, 0303 health sciences, Molecular Structure, Bile acid, Chemistry, Ursodeoxycholic Acid, TGR5, Stereoisomerism, MESH: Transcription Factors, G protein-coupled bile acid receptor, DNA-Binding Proteins, FXR, Biochemistry, 030220 oncology & carcinogenesis, Molecular Medicine, MESH: Models, Molecular, Agonist, medicine.drug_class, Stereochemistry, MESH: Molecular Structure, CHO Cells, MESH: Bile Acids and Salts, MESH: Receptors, Cytoplasmic and Nuclear, Methylation, Steroid, Bile Acids and Salts, MESH: Methylation, Structure-Activity Relationship, 03 medical and health sciences, Cricetulus, MESH: CHO Cells, medicine, Animals, Humans, bile acid, Structure–activity relationship, 030304 developmental biology, G protein-coupled receptor, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Crystallography, X-Ray, MESH: Stereoisomerism, MESH: Ursodeoxycholic Acid, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

23-Alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid are identified as potent and selective agonists of TGR5, a G-protein coupled receptor for bile acids (BAs). In particular, we show that methylation at the C-23(S) position of natural BAs confers a marked selectivity for TGR5 over FXR, while the 6alpha-alkyl substitution increases the potency at both receptors. The present results allow for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by BA derivatives.

Published
2007
Full Text
View/download PDF

50. Highly Efficient and Stereoselective N-Vinylation of Oxiranecarboxamides and Unprecedented 8-endo-Epoxy-arene Cyclization: Expedient and Biomimetic Synthesis of Some Clausena Alkaloids

Author

De-Xian Wang, Mei-Xiang Wang, Zhi-Tang Huang, Gang Deng, Luo Yang, Jieping Zhu, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Models, Molecular, MESH: Epoxy Compounds, Vinyl Compounds, Stereochemistry, MESH: Molecular Structure, Ligands, 010402 general chemistry, 01 natural sciences, Biochemistry, Catalysis, chemistry.chemical_compound, Alkaloids, Clausena, MESH: Alkaloids, Biomimetic synthesis, MESH: Ligands, Organic chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cyclization, Physical and Theoretical Chemistry, Rutaceae, Natural product, Molecular Structure, biology, 010405 organic chemistry, Molecular Mimicry, Organic Chemistry, Stereoisomerism, General Medicine, Epoxy, MESH: Catalysis, biology.organism_classification, Amides, MESH: Amides, MESH: Stereoisomerism, 0104 chemical sciences, chemistry, Cyclization, visual_art, Intramolecular force, MESH: Rutaceae, visual_art.visual_art_medium, Epoxy Compounds, MESH: Molecular Mimicry, MESH: Vinyl Compounds, Stereoselectivity, Enantiomer, MESH: Models, Molecular
Abstract

[structure: see text]. Catalyzed by CuI/N,N-dimethylglycine, oxiranecarboxamides underwent a highly efficient and stereoselective N-vinylation reaction with (Z)-1-aryl-2-bromoethenes to afford the corresponding enamides. The method has been applied to a straightforward synthesis of (-)-(2R,3S)-SB204900, the enantiomer of the natural product. Following a hypothetic biomimetic pathway, both (+)-(5R,6S)-xi-Clausenamide and (-)-(5R,6S)-balasubramide have been efficiently synthesized for the first time through the unprecedented intramolecular 8-endo-epoxy-arene cyclization of (Z)-N-(phenylvinyl)oxiranecarboxamides.

Published
2007
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results