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59 results on '"Peyrottes A"'

1. Lead optimization and biological evaluation of fragment-based cN-II inhibitors

Author

Rahila Rahimova, David Egron, Suzanne Peyrottes, Sonia Rouanet, Charles Dumontet, Lars Petter Jordheim, Laurent Chaloin, Nushin Aghajari, Preeti, Rémi Guillon, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), BCI Pharma, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases moléculaires et structurales des systèmes infectieux (BMSSI), Equipe 14, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Models, Molecular, Purine, Cell Survival, [SDV]Life Sciences [q-bio], enzyme inhibitor, Antineoplastic Agents, HL-60 Cells, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Crystallography, X-Ray, 01 natural sciences, 5'-nucleotidase, law.invention, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, law, Cell Line, Tumor, Drug Discovery, Hydrolase, Humans, cancer, Cytotoxic T cell, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Pharmacology, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, General Medicine, 0104 chemical sciences, 3. Good health, Biochemistry, Purines, Enzyme inhibitor, Cancer cell, biology.protein, Recombinant DNA, Drug Screening Assays, Antitumor, Nucleoside
Abstract

The development of cytosolic 5′-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50–75% inhibition on the purified recombinant protein at 200 μM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.

Published
2019
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2. Mononucleoside phosphorodithiolates as mononucleotide prodrugs

Author

Nathalie Schlienger, Anne-Marie Aubertin, Christian Périgaud, I. Lefebvre, and Suzanne Peyrottes

Subjects
Anti-HIV Agents, Microbial Sensitivity Tests, Virus Replication, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Humans, Prodrugs, Sulfhydryl Compounds, Cells, Cultured, EC50, Pharmacology, Dose-Response Relationship, Drug, Molecular Structure, Organic Chemistry, Nucleosides, General Medicine, Prodrug, Phosphate, Combinatorial chemistry, chemistry, Cell culture, HIV-1, Selectivity, Nucleoside, Derivative (chemistry), Intracellular
Abstract

The synthesis and in vitro anti-HIV activity of a novel series of pronucleotides are reported. These prodrugs were characterized by a phosphorodithiolate structure, incorporating two O-pivaloyl-2-oxyethyl substituents as biolabile phosphate protections. The compounds were obtained following an original one-pot three-step procedure, involving the formation of a phosphorodithioite intermediate which is in situ oxidized. In vitro, comparative anti-HIV evaluations demonstrate that such original prodrugs are able to allow the efficient intracellular release of the corresponding 5′-mononucleotide. The pronucleotide of 2′,3′-dideoxyadenosine (ddA) 3 exhibited a very potent antiretroviral effect with 50% effective concentration (EC50) values in nanomolar concentration range in various cell lines. In primary monocytes/macrophages, this derivative was 500 times more potent in inhibiting HIV replication (EC50 0.23 pM) than ddA and the selectivity index of the prodrug is fifty times higher than the one of the parent nucleoside.

Published
2021

4. Cytotoxic and Antitumoral Activity of N-(9H-purin-6-yl) Benzamide Derivatives and Related Water-soluble Prodrugs

Author

Suzanne Peyrottes, Laurent Chaloin, Muhammad Zawwad Raza, Charles Dumontet, Lars Petter Jordheim, Rémi Charmelot, David Egron, Emeline Cros-Perrial, Steve Saulnier, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and CHALOIN, Laurent

Subjects
Cell death, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Antineoplastic Agents, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, chemistry, chemistry.chemical_compound, Structure-Activity Relationship, In vivo, Neoplasms, Humans, Prodrugs, Benzamide, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Water, General Medicine, Prodrug, Cell cycle, Small molecule, In vitro, in vivo, Biochemistry, Cancer cell, Benzamides, cancer cells, prodrug, pharmacology, Lead compound
Abstract

Background: The development of small molecules as cancer treatments is still of both interest and importance. Objective: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments. Method: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity Results: Our results show activities on cancer cell lines ranging from 3-39 μM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo. Conclusion: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.

Published
2021
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5. 2'-Derivatisation of 3'-C-methyl pyrimidine nucleosides

Author

Sarah Couturier, Christian Périgaud, Suzanne Peyrottes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pyrimidine, Nucleoside analogue, 010405 organic chemistry, Stereochemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, 3. Good health, 0104 chemical sciences, chemistry.chemical_compound, chemistry, medicine, Physical and Theoretical Chemistry, medicine.drug
Abstract

International audience; The study of nucleoside and nucleotide analogs has been the subject of extensive development during these last decades. In this field, additions or substitutions on the sugar residue had led to potent drugs in antiviral and anticancer chemotherapies. Herein, we reported the stereoselective synthesis of a new series of pyrimidine nucleosides bearing a double modification in the 2’ and 3’ positions of the sugar scaffold.

Published
2021
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6. 4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies

Author

Suzanne Peyrottes, Jean-Pierre Uttaro, Lars Petter Jordheim, Rayane Ghoteimi, Van Tai Nguyen, Emeline Cros-Perrial, Christophe Mathé, A. Braka, Laurent Chaloin, Christine Ménétrier-Caux, Céline Rodriguez, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stereochemistry, Triazole, Drug Evaluation, Preclinical, enzyme inhibitor, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, GPI-Linked Proteins, 01 natural sciences, Biochemistry, 5'-ectonucleotidase, Nucleobase, immunooncology, chemistry.chemical_compound, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, Ribose, Moiety, Humans, Nucleotide, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 5'-Nucleotidase, chemistry.chemical_classification, bis-phosphonate, Trifluoromethyl, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Nucleotides, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Triazoles, Phosphonate, 0104 chemical sciences, 3. Good health, 010404 medicinal & biomolecular chemistry, Kinetics, chemistry, Enzyme inhibitor, click chemistry, biology.protein, Algorithms
Abstract

International audience; Three series of nucleotide analogues were synthesized and evaluated as potential CD73 inhibitors. Nucleobase replacement consisted in connecting the appropriate aromatic or purine residues through a triazole moiety that is generated from 1,3-dipolar cycloaddition. The first series is related to 4substituted-1,2,3-triazolo--hydroxyphosphonate ribonucleosides. Additional analogues were also obtained, in which the phosphonate group was replaced by a bisphosphonate pattern (P-C-P-C, series 2) or the ribose moiety was removed leading to acyclic derivatives (series 3). The βhydroxyphosphonylphosphonate ribonucleosides (series 2) were found to be potent inhibitors of CD73 using both purified recombinant protein and cell-based assays. Two compounds (2a and 2b) that contained a bis(trifluoromethyl)phenyl or a naphthyl substituents proved to be the most potent inhibitors, with IC50 values of 4.8 ± 0.8 µM and 0.86 ± 0.2 µM, compared to the standard AOPCP (IC50 value of 3.8 ± 0.9 µM), and were able to reverse the adenosine-mediated immune suppression on human T cells. This series of compounds illustrates a new type of CD73 inhibitors.

Published
2020

7. 2-(Substituted amino)-8-azachromones from 4,6-Diaryl-2-pyridones: A Synthetic Strategy toward Compounds of Broad Structural Diversity

Author

Rayane Ghoteimi, Suzanne Peyrottes, Steve Saulnier, Christophe Mathé, Jean-Pierre Uttaro, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
chemistry.chemical_classification, Carbon disulfide, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, Leaving group, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, 3. Good health, Catalysis, Amino acid, chemistry.chemical_compound, Deprotonation, Nucleophile, Group (periodic table), Nucleophilic substitution, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

International audience; 3-Acetoacetyl-4,6-diaryl-2-pyridones are synthesized in three steps from chalcones and then condense with carbon disulfide to afford 8-azachromones containing a methylthio group at C2. This leaving group offers an entry point for the insertion of more complex moieties via nucleophilic substitution. For this purpose, N-nucleophiles are explored according to their positions in the Mayr's nucleophilicity scale (N parameter), and three main classes are distinguished depending on whether the substitution takes place from their neutral forms, from their deprotonated anionic forms, or under nucleophilic catalysis. A broad range of primary and secondary amines may be inserted by this method, including enantiomerically pure amino acids, enabling us to explore structural diversity.

Published
2020
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8. β-Hydroxy- and β-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Plasmodium falciparum Growth

Author

Rachel Cerdan, Thomas Cheviet, Gabriel Bourchenin, Christian Périgaud, Manon Lagacherie, Sharon Wein, Suzanne Peyrottes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Purine, Stereochemistry, Guanine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, In vivo, Aspartic acid, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, IC50, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Drug discovery, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Plasmodium falciparum, biology.organism_classification, Phosphonate, 0104 chemical sciences, 3. Good health, Malaria, 010404 medicinal & biomolecular chemistry, Aminophosphonate, Nucleotide analogue, Molecular Medicine
Abstract

Malaria is an infectious disease caused by a parasite of the genus Plasmodium, and the emergence of parasites resistant to all current antimalarial drugs highlights the urgency of having new classes of molecules. We developed an effective method for the synthesis of a series of β-modified acyclonucleoside phosphonate (ANP) derivatives, using commercially available and inexpensive materials (i.e., aspartic acid and purine heterocycles). Their biological evaluation in cell culture experiments and SAR revealed that the compounds' effectiveness depends on the presence of a hydroxyl group, the chain length (four carbons), and the nature of the nucleobase (guanine). The most active derivative inhibits the growth of Plasmodium falciparum in vitro in the nanomolar range (IC50 = 74 nM) with high selectivity index (SI > 1350). This compound also showed remarkable in vivo activity in P. berghei-infected mice (ED50 ∼ 0.5 mg/kg) when administered by the ip route and is, although less efficient, still active via the oral route. It is the first ANP derivative with such potent antimalarial activity and therefore has considerable potential for development as a new antimalarial drug.

Published
2020
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9. Straightforward Ball‐Milling Access to Dinucleoside 5′,5′‐Polyphosphates via Phosphorimidazolide Intermediates

Author

Suzanne Peyrottes, Xavier Bantreil, Béatrice Roy, Frédéric Lamaty, Anaïs Depaix, Lucie Appy, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Green chemistry, Sodium, chemistry.chemical_element, nucleoside, 010402 general chemistry, 01 natural sciences, Pyrophosphate, Catalysis, chemistry.chemical_compound, Mechanochemistry, [CHIM]Chemical Sciences, Nucleotide, chemistry.chemical_classification, green chemistry, 010405 organic chemistry, Organic Chemistry, General Chemistry, nucleotide, Combinatorial chemistry, ball mill, 0104 chemical sciences, chemistry, sustainable synthesis, CDI, mechanochemistry, Carbonyldiimidazole, Nucleoside, Conjugate
Abstract

International audience; A solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5'-polyphosphates is reported. Under ball-milling conditions, nucleoside 5'-monophosphates are quantitatively activated using N,N'-carbonyldiimidazole into their phosphorimidazolide derivatives. The addition of a nucleoside 5'-mono, di or triphosphate directly leads to the formation of the corresponding dinucleotides. Benefits of the reported one-pot method include the use of unprotected nucleotides in their sodium or acid form, activation by the eco-friendly N,N'-carbonyldiimidazole, non-dry conditions, short reaction time, high conversion rates and easy setup and purification. This work offers new perspectives for the synthesis of nucleotide conjugates and analogues, combining the phosphorimidazolide approach and milling conditions.

Published
2019
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10. Straightforward chemical desymmetrisation of cis-(±)-4-O-protected-cyclopent-2-enol using resolving agents on column chromatography

Author

Suzanne Peyrottes, Bemba Sidi Mohamed, Christophe Mathé, and Jean-Pierre Uttaro

Subjects
On column, chemistry.chemical_compound, Column chromatography, Chemistry, Silica gel, Racemic mixture, Organic chemistry, Enantiomer, Enol
Abstract

A simple and efficient procedure for the separation of cis-(+)- and cis-(−)-4-O-protected-cyclopent-2-enol, from the corresponding racemic mixture as starting material and using resolving agents, is described. The separation of diasteroisomers was accomplished by flash silica gel column chromatography. The enantiomers cis-(+)- and cis-(−)- of 4-O-protected-cyclopent-2-enol were obtained, in enantiomeric pure form, after elimination of the resolving agents.

Published
2019
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11. Synthesis of Substituted 5'-Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73

Author

Jean-Pierre Uttaro, Emeline Cros-Perrial, Rahila Rahimova, Suzanne Peyrottes, Christophe Mathé, Rayane Ghoteimi, Lars Petter Jordheim, Laurent Chaloin, Felix Grosjean, Van Tai Nguyen, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA (UMR_8109)), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Adenosine, Molecular model, Stereochemistry, Cell Survival, Protein Conformation, Organophosphonates, Antineoplastic Agents, GPI-Linked Proteins, 01 natural sciences, Biochemistry, law.invention, chemistry.chemical_compound, Structure-Activity Relationship, Organophosphorus Compounds, law, Cell Line, Tumor, Drug Discovery, medicine, Humans, Nucleotide, Carboxylate, General Pharmacology, Toxicology and Pharmaceutics, Enzyme Inhibitors, 5'-Nucleotidase, Pharmacology, chemistry.chemical_classification, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, 010405 organic chemistry, Organic Chemistry, Phosphonate, Recombinant Proteins, 0104 chemical sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 010404 medicinal & biomolecular chemistry, chemistry, Docking (molecular), Drug Design, Recombinant DNA, Molecular Medicine, Nucleoside, [CHIM.CHEM]Chemical Sciences/Cheminformatics, medicine.drug, Protein Binding
Abstract

Derivatives of 5'-aminoadenosine containing methyl carboxylate, methyl phosphonate, gem-bisphosphonate, bis(methylphosphonate), and α-carboxylmethylphosphonate or phosphonoacetate moieties were synthesized from key intermediate 5'-aminonucleoside. These nucleotide analogues were envisaged as 5'-mono- or diphosphate nucleoside mimics. All compounds were evaluated for CD73 inhibition in a cell-based assay (MDA-MB-231) and toward the purified recombinant protein. Most of them failed to reach significant inhibition of AMP hydrolysis by CD73 at 100 μm. Among the new compounds, the most interesting candidates, 5 (5'-deoxy-5'-N-phosphonomethyladenosine) and 7 (5'-deoxy-5'-N-(ethoxyphosphorylacetate)adenosine), inhibited recombinant CD73 by 36 and 46 % and cellular CD73 by 61 and 45 % at 100 μm, respectively. Molecular modeling partially explains this lack of activity, as the initially predicted docking scores had been encouraging, especially for compound 9.

Published
2019
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12. One-Pot Synthesis of Nucleotides and Conjugates in Aqueous Medium

Author

Béatrice Roy, Anaïs Depaix, and Suzanne Peyrottes

Subjects
chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, One-pot synthesis, 010402 general chemistry, Phosphate, 01 natural sciences, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Hexafluorophosphate, Organic chemistry, Imidazole, Nucleotide, Physical and Theoretical Chemistry, Acetonitrile, Nucleoside, Conjugate
Abstract

Herein, we describe a one-pot synthesis, in a mixture of water/acetonitrile, of nucleoside 5′-polyphosphates and some derivatives starting from their corresponding nucleoside 5′-monophosphates. Phosphorimidazolide intermediates are formed in the presence of imidazole and 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate. Under these mild conditions, nucleoside 5′-di- and 5′-triphosphates, dinucleoside 5′,5′-polyphosphates, as well as some nucleotide analogues modified either on the nucleoside or on the phosphate moieties are obtained in moderate to high yields.

Published
2016
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13. Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

Author

Tai Nguyen Van, Audrey Hospital, Corinne Lionne, Lars P Jordheim, Charles Dumontet, Christian Périgaud, Laurent Chaloin, Suzanne Peyrottes, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche en Infectiologie de Montpellier ( IRIM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Cheval, Christelle, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), 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), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Purine, Stereochemistry, Triazole, [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, Full Research Paper, 5'-nucleotidase, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, lcsh:QD241-441, 03 medical and health sciences, chemistry.chemical_compound, lcsh:Organic chemistry, [SDV.CAN] Life Sciences [q-bio]/Cancer, cancer, Nucleotide, lcsh:Science, 5'-Nucleotidase, chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, cN-II inhibitors, nucleotide, Ribonucleoside, Phosphonate, 0104 chemical sciences, Cytosol, Chemistry, triazole, 030104 developmental biology, Enzyme, chemistry, Biochemistry, lcsh:Q, phosphonate, France
Abstract

International audience; A series of seventeen beta-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 mM

Published
2016
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14. GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors

Author

Vincent Delwail, Jean-Ehrland Ricci, Isabelle Peyrottes, Celine Delpech-Debiais, Sandrine Marchetti, Julie Reverso-Meinietti, Jacqueline Lehmann-Che, Gabriel Brisou, Jozef P. Bossowski, Manuel Grima-Reyes, Christiane Copie-Bergman, Camila Rubio-Patiño, Konstantina Fragaki, Eric de Kerviler, Véronique Paquis-Flucklinger, Thierry Jo Molina, Frederic Peyrade, Annabelle Mouchotte, Tony Petrella, Emma Proïcs, Bertrand Nadel, Els Verhoeyen, Bruno Taillan, Richard Delarue, Catherine Thieblemont, Laetitia Shintu, Agnès Paquet, Rana Mhaidly, Johanna Chiche, Elodie Villa, Georges Garnier, Pascal Barbry, Josette Brière, Damien Ambrosetti, Nicolas Mounier, André Bosly, Jean-François Michiels, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Pasteur [Nice] (CHU), Hôpital Hôtel Dieu, INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), UNICANCER-Université Côte d'Azur (UCA), Hôpital Princesse Grace [Monaco], Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Cliniques universitaires UCL de Mont-Godinne 5530 Yvoir, Centre de pathologie [Dijon], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Service hématologie Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'onco-hématologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de pathologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-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 Nice Sophia Antipolis (... - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, Centre Antoine Lacassagne, Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne

Subjects
0301 basic medicine, Male, Physiology, Phenformin, Cohort Studies, chemistry.chemical_compound, Mice, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Glyceraldehyde 3-phosphate dehydrogenase, Cells, Cultured, Aged, 80 and over, Predictive marker, biology, GAPDH, Glyceraldehyde-3-Phosphate Dehydrogenases, OxPhos, Middle Aged, glycolysis, Prognosis, 3. Good health, Metformin, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Treatment Outcome, Vincristine, R-CHOP, mTOR, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, predictive marker, medicine.drug, Adult, Antimetabolites, Antineoplastic, Mice, Transgenic, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Young Adult, stomatognathic system, medicine, Animals, Humans, Molecular Biology, Cyclophosphamide, PI3K/AKT/mTOR pathway, B cell, Aged, Retrospective Studies, Glutaminolysis, business.industry, Cell Biology, medicine.disease, L-asparaginase, Mice, Inbred C57BL, 030104 developmental biology, HEK293 Cells, chemistry, Doxorubicin, DLBCL, biology.protein, Cancer research, Prednisone, business, Diffuse large B-cell lymphoma, 030217 neurology & neurosurgery
Abstract

International audience; Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH(low) lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism(phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism-using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.

Published
2019
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15. New insights for the preparation of cytidine containing nucleotides using a soluble ether-linked polyethylene glycol support

Author

Béatrice Roy, Suzanne Peyrottes, Anaïs Depaix, Jean-Yves Puy, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
chemistry.chemical_classification, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cytidine, Ether, General Chemistry, Polyethylene glycol, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Cleavage (embryo), 01 natural sciences, Combinatorial chemistry, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Materials Chemistry, Nucleotide, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Linker, ComputingMilieux_MISCELLANEOUS
Abstract

We proposed an improved methodology for soluble PEG-supported synthesis of 5′-nucleotide derivatives from cytidine using a carboxylethoxy linker. Compared to our previous work, no by-product is formed during cleavage from the support and dialysis is not required anymore for purification.

Published
2018
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16. Probing the reactivity of H-phosphonate derivatives for the hydrophosphonylation of various alkenes and alkynes under free-radical conditions

Author

Christian Périgaud, Jean-Pierre Uttaro, Pierre-Yves Geant, Christophe Mathé, Bemba Sidi Mohamed, and Suzanne Peyrottes

Subjects
010405 organic chemistry, Chemistry, General Chemistry, 010402 general chemistry, Photochemistry, 01 natural sciences, Phosphonate, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, Polymer chemistry, Materials Chemistry, Reactivity (chemistry), Photoinitiator
Abstract

Hydrophosphonylation is an efficient process to create carbon–phosphorus bonds from unsaturated C–C bonds and to give rise to alkylphosphonate or vinylphosphonate derivatives. In this work, we report on the reactivity of H-phosphonate derivatives for the hydrophosphonylation of various alkenes and alkynes under photoinduced free-radical conditions. The reaction was carried out on activated, unactivated and/or disubstituted alkenes or alkynes with 2,2-dimethoxy-2-phenylacetophenone as a photoinitiator under UV irradiation.

Published
2016
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17. CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates

Author

Pierre-Yves Geant, Emeline Cros-Perrial, Laurent Chaloin, Suzanne Peyrottes, Charles Dumontet, Lars Petter Jordheim, Céline Rabeson, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut de Recherche en Infectiologie de Montpellier (IRIM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Purine, Models, Molecular, Cell Survival, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, medicine, Humans, Nucleotide, Enzyme Inhibitors, 5'-Nucleotidase, ComputingMilieux_MISCELLANEOUS, Pharmacology, chemistry.chemical_classification, Nucleoside analogue, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Diphosphonates, Dose-Response Relationship, Drug, Molecular Structure, Organic Chemistry, General Medicine, Purine Nucleosides, Adenosine, 3. Good health, 030104 developmental biology, chemistry, Biochemistry, Enzyme inhibitor, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Nucleoside, [CHIM.CHEM]Chemical Sciences/Cheminformatics, medicine.drug
Abstract

The ecto-5′-nucleotidase CD73 has emerged as an important drug target in oncoimmunology as well as in other diseases. We describe new ADP analogues as CD73 inhibitors based on the replacement of the adenosine moiety, in the reference inhibitor APCP, by purine nucleoside analogues. Compounds were assessed for CD73 inhibition both on purified recombinant protein and on CD73-expressing cancer cells. The clofarabine-containing compound (2) was shown to be more potent than APCP with IC50 values of 0.18 μM (vs. 3.8 μM) on purified protein and 0.24 μM (vs. 23.6 μM) on CD73 expressed on cells. This work gives additional insights into structure-activity relationship of substrate-analogues as CD73 inhibitors.

Published
2018
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18. Rapid synthesis of carbonucleoside phophonate analogues as potential antiviral agents via a hydrophosphonylation reaction of ethynyl carbocyclic precursors

Author

Bemba Sidi Mohamed, Christian Périgaud, Christophe Mathé, Suzanne Peyrottes, Jean-Pierre Uttaro, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA (UMR_8109)), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Purine, 010405 organic chemistry, Stereochemistry, Guanine, [CHIM.ORGA]Chemical Sciences/Organic chemistry, General Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Catalysis, Coupling reaction, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Carbocyclic nucleoside, Materials Chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytotoxicity, ComputingMilieux_MISCELLANEOUS
Abstract

A racemic synthesis of new carbocyclic nucleoside ethyl or vinylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using racemic (+/−)-4-O-protected-2-cyclopentanone. All compounds were prepared using a hydrophosphonylation reaction of ethynyl carbocyclic precursors followed by a Mitsunobu coupling reaction between the heterocyclic bases. After deprotection, the compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity.

Published
2018
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19. Vγ9Vδ2 T cell activation by strongly agonistic nucleotidic phosphoantigens

Author

Eric Champagne, Asmaa Mehtougui, Erin J. Adams, Javier Alguacil, Suzanne Peyrottes, Morgane Moulin, Siyi Gu, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Chemistry and Hematology [Utrecht, the Netherlands], University Medical Center [Utrecht], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and 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)

Subjects
0301 basic medicine, T cell, T-Lymphocytes, Phosphatase, Primary Cell Culture, Isopentenyl pyrophosphate, Dose-Response Relationship, Immunologic, Biology, Lymphocyte Activation, Pyrophosphate, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Dimethylallyl pyrophosphate, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Interferon-gamma, 0302 clinical medicine, Adenosine Triphosphate, Hemiterpenes, Organophosphorus Compounds, Antigens, CD, Lysosomal-Associated Membrane Protein 1, medicine, Humans, Nucleotide, Antigens, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Pharmacology, chemistry.chemical_classification, Butyrophilins, Apyrase, Tumor Necrosis Factor-alpha, Receptors, Antigen, T-Cell, gamma-delta, Cell Biology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Organophosphates, 030104 developmental biology, medicine.anatomical_structure, chemistry, Biochemistry, Cell culture, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, K562 Cells, 030215 immunology, HeLa Cells
Abstract

Human Vγ9Vδ2 T cells can sense through their TCR tumor cells producing the weak endogenous phosphorylated antigen isopentenyl pyrophosphate (IPP), or bacterially infected cells producing the strong agonist hydroxyl dimethylallyl pyrophosphate (HDMAPP). The recognition of the phosphoantigen is dependent on its binding to the intracellular B30.2 domain of butyrophilin BTN3A1. Most studies have focused on pyrophosphate phosphoantigens. As triphosphate nucleotide derivatives are naturally co-produced with IPP and HDMAPP, we analyzed their specific properties using synthetic nucleotides derived from HDMAPP. The adenylated, thymidylated and uridylated triphosphate derivatives were found to activate directly Vγ9Vδ2 cell lines as efficiently as HDMAPP in the absence of accessory cells. These antigens were inherently resistant to terminal phosphatases, but apyrase, when added during a direct stimulation of Vγ9Vδ2 cells, abrogated their stimulating activity, indicating that their activity required transformation into strong pyrophosphate agonists by a nucleotide pyrophosphatase activity which is present in serum. Tumor cells can be sensitized with nucleotide phosphoantigens in the presence of apyrase to become stimulatory, showing that this can occur before their hydrolysis into pyrophosphates. Whereas tumors sensitized with HDMAPP rapidly lost their stimulatory activity, sensitization with nucleotide derivatives, in particular with the thymidine derivative, induced long-lasting stimulating ability. Using isothermal titration calorimetry, binding of some nucleotide derivatives to BTN3A1 intracellular domain was found to occur with an affinity similar to that of IPP, but much lower than that of HDMAPP. Thus, nucleotide phosphoantigens are precursors of pyrophosphate antigens which can deliver strong agonists intracellularly resulting in prolonged and strengthened activity.

Published
2017
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20. Water‐Medium Synthesis of Nucleoside 5′‐Polyphosphates

Author

Suzanne Peyrottes, Béatrice Roy, and Anaïs Depaix

Subjects
chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, Imidazoles, Nucleosides, 010402 general chemistry, Ribonucleoside, 01 natural sciences, Biochemistry, Pyrophosphate, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Polyphosphates, Hexafluorophosphate, Reagent, Imidazole, Nucleotide, Acetonitrile, Nucleoside
Abstract

This unit describes a one-pot, two step synthesis of ribonucleoside 5'-di- and 5'-triphosphates, as well as their purification. The first step of the synthesis involves the activation of an unprotected ribonucleoside 5'-monophosphate with 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate and imidazole, in a mixture of water/acetonitrile. The resulting phosphorimidazolate intermediate is then treated with inorganic phosphate or pyrophosphate to afford the corresponding nucleoside 5'-di- or 5'-triphosphates. The attractive features of this strategy include the absence of protecting groups on the starting material and convenient set up (i.e., use of water, non-dry solvents and reagents, commercially available sodium salts). © 2017 by John Wiley & Sons, Inc.

Published
2017
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21. Determination and quantification of intracellular fludarabine triphosphate, cladribine triphosphate and clofarabine triphosphate by LC–MS/MS in human cancer cells

Author

Rabeson, Céline, Géant, Pierre Yves, Chaloin, Laurent, Puy, Jean-Yves, Jordheim, Lars Petter, Cros-Perrial, Emeline, Dumontet, Charles, Peyrottes, Suzanne, Lefebvre-Tournier, Isabelle, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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), Equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Spectrometry, Mass, Electrospray Ionization, Electrospray ionization, Clinical Biochemistry, Antineoplastic Agents, Context (language use), [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, Limit of Detection, Polyphosphates, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, Hexylamine, Cell Line, Tumor, Neoplasms, medicine, Humans, Clofarabine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cladribine, Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, Chromatography, Adenine Nucleotides, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010401 analytical chemistry, Cell Biology, General Medicine, 0104 chemical sciences, 3. Good health, Fludarabine, 030104 developmental biology, chemistry, Arabinonucleosides, Nucleoside, Vidarabine, medicine.drug
Abstract

Purine nucleoside analogues are widely used in the treatment of haematological malignancies, and their biological activity is dependent on the intracellular accumulation of their triphosphorylated metabolites. In this context, we developed and validated a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to study the formation of 5'-triphosphorylated derivatives of cladribine, fludarabine, clofarabine and 2'-deoxyadenosine in human cancer cells. Br-ATP was used as internal standard. Separation was achieved on a hypercarb column. Analytes were eluted with a mixture of hexylamine (5 mM), DEA (0.4%, v/v, pH 10.5) and acetonitrile, in a gradient mode at a flow rate of 0.3mLmin-1. Multiple reactions monitoring (MRM) and electrospray ionization in negative mode (ESI-) were used for detection. The application of this method to the quantification of these phosphorylated cytotoxic compounds in a human follicular lymphoma cell line, showed that it was suitable for the study of relevant biological samples.

Published
2017
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22. New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial

Author

Suzanne Peyrottes, Marjorie Maynadier, Christophe Tran Van Ba, Yann Bordat, Laurent Fraisse, Julie Perez, Sharon Wein, Henri Vial, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), 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), Therapeutic Strategic Unit for Infectious Diseases Unit (TSU), and SANOFI Recherche

Subjects
Erythrocytes, Plasmodium falciparum, Drug Resistance, Babesia, Phosphatidylcholine Biosynthesis, Cell membrane, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, Chloroquine, parasitic diseases, medicine, Food vacuole, Humans, Pharmacology (medical), Antimalarial Agent, Malaria, Falciparum, Mechanisms of Action: Physiological Effects, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 030306 microbiology, Chemiosmosis, Cell Membrane, Proton-Motive Force, biology.organism_classification, 3. Good health, Cell biology, Thiazoles, Infectious Diseases, medicine.anatomical_structure, Biochemistry, chemistry, Pepstatin, medicine.drug
Abstract

Bis-thiazolium salts constitute a new class of antihematozoan drugs that inhibit parasite phosphatidylcholine biosynthesis. They specifically accumulate in Plasmodium - and Babesia -infected red blood cells (IRBC). Here, we provide new insight into the choline analogue albitiazolium, which is currently being clinically tested against severe malaria. Concentration-dependent accumulation in P. falciparum -infected erythrocytes reached steady state after 90 to 120 min and was massive throughout the blood cycle, with cellular accumulation ratios of up to 1,000. This could not occur through a lysosomotropic effect, and the extent did not depend on the food vacuole pH, which was the case for the weak base chloroquine. Analysis of albitiazolium accumulation in P. falciparum IRBC revealed a high-affinity component that was restricted to mature stages and suppressed by pepstatin A treatment, and thus likely related to drug accumulation in the parasite food vacuole. Albitiazolium also accumulated in a second high-capacity component present throughout the blood cycle that was likely not related to the food vacuole and also observed with Babesia divergens -infected erythrocytes. Accumulation was strictly glucose dependent, drastically inhibited by H + /K + and Na + ionophores upon collapse of ionic gradients, and appeared to be energized by the proton-motive force across the erythrocyte plasma membrane, indicating the importance of transport steps for this permanently charged new type of antimalarial agent. This specific, massive, and irreversible accumulation allows albitiazolium to restrict its toxicity to hematozoa-infected erythrocytes. The intraparasitic compartmentation of albitiazolium corroborates a dual mechanism of action, which could make this new type of antimalarial agent resistant to parasite resistance.

Published
2014
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23. Exploring Prodrug Approaches for Albitiazolium and its Analogues

Author

Suzanne Peyrottes, Henri Vial, Sergio A. Caldarelli, Sharon Wein, Christian Périgaud, 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), Dynamique des interactions membranaires normales et pathologiques (DIMNP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)

Subjects
thiazolium salts, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, prodrugs, Drug Discovery, Food vacuole, Choline, Available drugs, choline analogues, phospholipid, See more at: http://www.eurekaselect.com/123861/article#sthash.hInA33kU.dpuf, 030304 developmental biology, 0303 health sciences, Albitiazolium, Resistance development, [CHIM.ORGA]Chemical Sciences/Organic chemistry, General Medicine, Prodrug, 3. Good health, Bioavailability, Thiazoles, plasmodium, Biochemistry, chemistry, Drug Design, 030220 oncology & carcinogenesis, Choline transport
Abstract

International audience; Choline analogues such as bis-thiazolium salts are thought to inhibit choline transport into Plasmodiuminfected erythrocytes, thus preventing parasite PC biosynthesis, and also to interact with plasmodial haemoglobin degradation in the food vacuole. This new and multiple mode of action is a major asset of these new class of antimalarials, as they could help delay resistance development. We synthesized and designed various sets of analogues, notably prodrugs, since the oral bioavailability of bis-thiazolium salts is relatively low. The chemistry underlying this synthesis relies on inexpensive and readily available starting materials and is straightforward. This is essential since the ultimate objective is to obtain affordable and orally available drugs for uncomplicated malaria treatment.

Published
2014
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24. Mo1113 – 3-Oxo-C12:2 N-Acyl Homoserine Lactone, a Quorum Sensing Molecule from the Gut Microbiota: A New Player to Control Gut Inflammation

Author

Sophie Thenet, Céline Osinski, Jean-Maurice Mallet, Cécilia Landman, Elodie Quévrain, Loic Brot, Jean-Pierre Grill, Philippe Seksik, Véronique Carrière, Garance Coquant, Agathe Peyrottes, Doriane Aguanno, and Armelle Leturque

Subjects
Gut inflammation, Quorum sensing, chemistry.chemical_compound, N-Acyl homoserine lactone, Hepatology, biology, chemistry, Biochemistry, Gastroenterology, Gut flora, biology.organism_classification
Published
2019
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25. Evidence that oxidative dephosphorylation by the nonheme Fe(II), α-ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation

Author

Wenlong Cai, Tim S. Bugni, Maïa Meurillon, Xiaodong Liu, Christian Périgaud, Jürgen Rohr, Steven G. Van Lanen, Suzanne Peyrottes, Koichi Nonaka, Anwesha Goswami, Thomas P. Wyche, University of Kentucky, Université de Montpellier (UM), University of Wisconsin-Madison, Daiichi Sankyo Inc., Daiichi Sankyo Co., National Institutes of Health AI087849, and National Center for Advancing Translational Sciences Grant UL1TR000117

Subjects
0301 basic medicine, Oxygenase, [SDV]Life Sciences [q-bio], Iron, Biophysics, Heme, nucleoside, 010402 general chemistry, Hydroxylation, 01 natural sciences, Biochemistry, Article, Substrate Specificity, Dephosphorylation, 03 medical and health sciences, chemistry.chemical_compound, Stereospecificity, Structural Biology, antibiotic, Genetics, nonheme iron, Translocase, Phosphorylation, Molecular Biology, chemistry.chemical_classification, biology, translocase I, Stereoisomerism, Cell Biology, oxygenase, 0104 chemical sciences, 3. Good health, 030104 developmental biology, Enzyme, chemistry, Phosphodiester bond, biology.protein, Biocatalysis, Oxygenases, Ketoglutaric Acids, biosynthesis, Uridine Monophosphate, Nucleoside, Oxidation-Reduction, Hydrogen
Abstract

International audience; LipL and Cpr19 are nonheme, mononuclear Fe(II)-dependent, alpha-ketoglutarate (alpha KG): UMP oxygenases that catalyze the formation of CO2, succinate, phosphate, and uridine-5'-aldehyde, the last of which is a biosynthetic precursor for several nucleoside antibiotics that inhibit bacterial translocase I (MraY). To better understand the chemistry underlying this unusual oxidative dephosphorylation and establish a mechanistic framework for LipL and Cpr19, we report herein the synthesis of two biochemical probes-[1',3',4',5',5'-H-2] UMP and the phosphonate derivative of UMP-and their activity with both enzymes. The results are consistent with a reaction coordinate that proceeds through the loss of one H-2 atom of [1',3',4',5',5'-H-2] UMP and stereospecific hydroxylation geminal to the phosphoester to form a cryptic intermediate, (5'R)-5'-hydroxy-UMP. Thus, these enzyme catalysts can additionally be assigned as UMP hydroxylase-phospholyases.

Published
2016
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26. ChemInform Abstract: Probing the Reactivity of H-Phosphonate Derivatives for the Hydrophosphonylation of Various Alkenes and Alkynes under Free-Radical Conditions

Author

Christophe Mathé, Christian Périgaud, Suzanne Peyrottes, Pierre-Yves Geant, Jean-Pierre Uttaro, and Bemba Sidi Mohamed

Subjects
chemistry.chemical_compound, chemistry, Polymer chemistry, Reactivity (chemistry), General Medicine, Phosphonate, Photoinitiator
Abstract

Efficient hydrophosphonylation of various alkenes and alkynes is achieved under photoinduced free-radical conditions using 2,2-dimethoxy-2-phenylacetophenone as photoinitiator.

Published
2016
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27. 5′,6′-Nucleoside Phosphonate Analogues Architecture: Synthesis and Comparative Evaluation towards Metabolic Enzymes

Author

Julie A. C. Alexandre, Franck Gallier, Suzanne Peyrottes, Dominique Deville-Bonne, Chahrazade El Amri, Christian Périgaud, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Enzymologie Moléculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and 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)

Subjects
Models, Molecular, Cell Survival, Stereochemistry, Organophosphonates, 010402 general chemistry, Antiviral Agents, 01 natural sciences, Biochemistry, Substrate Specificity, Pyrimidine analogue, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Humans, Nucleotide, General Pharmacology, Toxicology and Pharmaceutics, Pharmacology, chemistry.chemical_classification, Nucleoside-phosphate kinase, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Kinase, Organic Chemistry, Ribonucleoside, Phosphonate, 0104 chemical sciences, Nucleic acid, Molecular Medicine, Ribonucleosides, Nucleoside-Phosphate Kinase, Nucleoside, Protein Binding
Abstract

International audience; Nucleoside phosphonates have been designed as stable 5‚ -mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5‚ -mononucleotides, with different degrees of flexibility within the 5‚ ,6 ‚ -CC bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the riboseˆphosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP.

Published
2011
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28. Lipids as Drug Targets for Malaria Therapy

Author

Suzanne Peyrottes, Diana Penarete, Henri Vial, Sergio A. Caldarelli, Sharon Wein, and Laurent Fraisse

Subjects
Drug, chemistry.chemical_classification, media_common.quotation_subject, Phospholipid, Fatty acid, Lipid metabolism, Biology, Glycerophospholipids, Pharmacology, medicine.disease, chemistry.chemical_compound, Biochemistry, chemistry, Drug development, medicine, Potency, Malaria, media_common
Published
2011
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29. Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials

Author

Michel Boisbrun, Henri Vial, Suzanne Peyrottes, Karine Alarcon, Michèle Calas, Xavier J. Salom-Roig, Marjorie Maynadier, Mahama Ouattara, Sergio A. Caldarelli, Sharon Wein, Alain Pellet, and Abdallah Hamze

Subjects
Plasmodium, Plasmodium vinckei, Clinical Biochemistry, Pharmaceutical Science, Pharmacology, Biochemistry, Chemical synthesis, Antimalarials, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Parasitic Sensitivity Tests, Oral administration, parasitic diseases, Drug Discovery, Animals, Structure–activity relationship, Prodrugs, Molecular Biology, 030304 developmental biology, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, biology, Chemistry, Organic Chemistry, Stereoisomerism, Plasmodium falciparum, Prodrug, biology.organism_classification, Malaria, 3. Good health, Thiocarbamate, Thiazoles, 030220 oncology & carcinogenesis, Molecular Medicine, Salts, Thiocarbonate
Abstract

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Published
2010
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30. Development of a sensitive and selective LC/MS/MS method for the simultaneous determination of intracellular 1-beta-d-arabinofuranosylcytosine triphosphate (araCTP), cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP) in a human follicular lymphoma cell line

Author

Charles Dumontet, Christian Périgaud, Suzanne Peyrottes, Isabelle Lefebvre, Jean Yves Puy, Michael Hovaneissian, Sabine Cohen, Béatrice Roy, Céline Crauste, Jérôme Guitton, 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), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Crauste, Céline, Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cytidine triphosphate, Cytidine Triphosphate, viruses, Clinical Biochemistry, Tandem mass spectrometry, Sensitivity and Specificity, 01 natural sciences, Biochemistry, High-performance liquid chromatography, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Tandem Mass Spectrometry, Cell Line, Tumor, Arabinofuranosylcytosine Triphosphate, Humans, heterocyclic compounds, Solid phase extraction, Lymphoma, Follicular, Chromatography, High Pressure Liquid, 030304 developmental biology, 0303 health sciences, Chromatography, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Deoxycytidine triphosphate, 010401 analytical chemistry, Selected reaction monitoring, Cell Biology, General Medicine, Thionucleotides, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, Triple quadrupole mass spectrometer, Deoxycytosine Nucleotides, Arabinofuranosylcytosine triphosphate
Abstract

International audience; Development of a sensitive and selective LC/MS/MS method for the simultaneous determination of intracellular 1-beta-d-arabinofuranosylcytosine triphosphate (araCTP), cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP) in a human follicular lymphoma cell line a b s t r a c t A method was developed for the quantification of araCTP, CTP and dCTP in a human follicular lymphoma cell line. This method involves solid phase extraction (SPE) using a weak anion-exchanger (WAX) cartridge , a porous graphitic carbon high-performance liquid chromatography (HPLC) column separation, and tandem mass spectrometry (MS/MS) detection. By using a triple quadrupole mass spectrometer operating in negative ion multiple reaction monitoring (MRM) mode, the method was able to achieve a lower limit of quantification (LLOQ) of 0.1 g mL −1 for araCTP and of 0.01 g mL −1 for both CTP and dCTP. The method was validated and used to determine the amount of araCTP, CTP and dCTP formed after incubation of araC and an araCMP prodrug in the human follicular lymphoma cell line RL.

Published
2009
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31. Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells

Author

Suzanne Peyrottes, Eric Champagne, Charline Daguzan, Christian Davrinche, Morgane Moulin, Hanna Kulyk-Barbier, Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150) (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 2 - Sciences et Techniques (UM2), Ecole Nationale Supérieure de Chimie de Montpellier, and Grant Number : Fondation pour la Recherche Medicale Grant [DCM20121225761], Comité d'éthique de l'Inserm (CEI), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)

Subjects
Cytotoxicity, Immunologic, 0301 basic medicine, Human cytomegalovirus, lymphocytes, bisphosphonate, [SDV]Life Sciences [q-bio], Isopentenyl pyrophosphate, Cytomegalovirus, hiv-infection, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, Virus Replication, stimulation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, chemistry.chemical_compound, zoledronic acid, T-Lymphocyte Subsets, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, MESH: Cytokines, Diphosphonates, MESH: Dendritic Cells, Receptors, Antigen, T-Cell, gamma-delta, tumor-cells, MESH: Mevalonic Acid, inhibition, 3. Good health, MESH: Leukocytes, Mononuclear, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Cytomegalovirus Infections, Host-Pathogen Interactions, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, receptor-gamma, delta t-cells, MESH: Cells, Cultured, MESH: Cytomegalovirus, replication, MESH: Diphosphonates, T cell, Immunology, Mevalonic Acid, Biology, Cell Line, 03 medical and health sciences, Antigen, MESH: Receptors, Antigen, T-Cell, gamma-delta, medicine, Humans, MESH: Cytotoxicity, Immunologic, MESH: Lymphocyte Activation, MESH: Humans, T-cell receptor, MESH: Virus Replication, MESH: Host-Pathogen Interactions, Lymphokine, Dendritic Cells, MESH: Cytomegalovirus Infections, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Virology, MESH: Cell Line, 030104 developmental biology, chemistry, Cell culture, Leukocytes, Mononuclear, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Human V gamma 9V delta 2 T cells are activated through their TCR by neighboring cells producing phosphoantigens. Zoledronate (ZOL) treatment induces intracellular accumulation of the phosphoantigens isopentenyl pyrophosphate and ApppI. Few attempts have been made to use immunomanipulation of V gamma 9V delta 2 lymphocytes in chronic viral infections. Although V gamma 9V delta 2 T cells seem to ignore human CMV (HCMV)-infected cells, we examined whether they can sense HCMV when a TCR stimulus is provided with ZOL. Fibroblasts treated with ZOL activate V gamma 9V delta 2 T cells to produce IFN-gamma but not TNF. Following the same treatment, HCMV-infected fibroblasts stimulate TNF secretion and an increased production of IFN-g, indicating that V gamma 9V delta 2 cells can sense HCMV infection. Increased lymphokine production was observed with most clinical isolates and laboratory HCMV strains, HCMV-permissive astrocytoma, or dendritic cells, as well as "naive" and activated V gamma 9V delta 2 cells. Quantification of intracellular isopentenyl pyrophosphate/ApppI following ZOL treatment showed that HCMV infection boosts their accumulation. This was explained by an increased capture of ZOL and by upregulation of HMG-CoA synthase and reductase transcription. Using an experimental setting where infected fibroblasts were cocultured with gamma delta cells in submicromolar concentrations of ZOL, we show that V gamma 9V delta 2 cells suppressed substantially the release of infectious particles while preserving uninfected cells. V gamma 9V delta 2 cytotoxicity was decreased by HCMV infection of targets whereas anti-IFN-gamma and anti-TNF Abs significantly blocked the antiviral effect. Our experiments indicate that cytokines produced by V gamma 9V delta 2 T cells have an antiviral potential in HCMVinfection. This should lead to in vivo studies to explore the possible antiviral effect of immunostimulation with ZOL in this context.

Published
2016
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32. Exploring synthetic pathways for nucleosidic derivatives of potent phosphoantigens

Author

Béatrice Roy, Suzanne Peyrottes, Javier Alguacil, Christian Périgaud, David Reyes, Yoann Aubin, Eric Champagne, Centre d'élaboration de matériaux et d'études structurales (CEMES), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mesaconic acid, 010405 organic chemistry, Chemistry, Stereochemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, [SDV]Life Sciences [q-bio], General Chemistry, 010402 general chemistry, 01 natural sciences, Catalysis, 0104 chemical sciences, Coupling (electronics), chemistry.chemical_compound, Materials Chemistry, [CHIM]Chemical Sciences, [SDV.IMM]Life Sciences [q-bio]/Immunology, Nucleoside, ComputingMilieux_MISCELLANEOUS
Abstract

The comparative study of two synthetic pathways for nucleoside phosphoantigens is reported herein. The first using esterification of the γ-phosphate of ATP is leading to low yields whereas the coupling of ADP–imidazolate intermediate with a monophosphate counterpart is more efficient. Using this second approach various analogues of ApppI and ApppH were obtained. We have also investigated the synthesis of (E)-2-methyl-4-(hydroxyl)but-2-en-1-ol from mesaconic acid.

Published
2016
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33. Synthetic Approaches to a Mononucleotide Prodrug of Cytarabine

Author

Suzanne Peyrottes, Gilles Gosselin, R. Bazzanini, Stefano Manfredini, Christian Périgaud, and Marie-Hélène Gouy

Subjects
Antimetabolites, Antineoplastic, Phosphoramidite, Leukemia, Stereochemistry, Deoxyribonucleotides, Cytarabine, Ammonium fluoride, Ara-C, General Medicine, Prodrug, Biochemistry, chemistry.chemical_compound, Phosphotriester, chemistry, Genetics, medicine, Molecular Medicine, Prodrugs, Protecting group, Nucleoside, Ether cleavage, Ara-C, Leukemia, Prodrug, Phosphotriester, medicine.drug
Abstract

Synthetic pathways to a mononucleotide prodrug of cytarabine (Ara-C) bearing S-pivaloyl-2-thioethyl (tBuSATE) groups, as biolabile phosphate protections, are reported. Using a common phosphoramidite approach, two different kinds of nucleoside protecting groups have been investigated. During this study, we observed an intermolecular migration of the Boc protecting group in the course of the tert-butyldimethylsilyl ether cleavage using tetrabutyl ammonium fluoride.

Published
2005
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34. P053 Impact of N- acyl-homoserine lactone 3-oxo-C12:2, a major quorum sensing molecule from gut microbiota, on intestinal epithelial barrier function

Author

Sophie Thenet, Cécilia Landman, A Peyrottes, Jean-Maurice Mallet, Loic Brot, P. Seksik, E. Le Balc'h, Jean-Pierre Grill, Elodie Quévrain, A Leturque, and D Aguanno

Subjects
biology, business.industry, Gastroenterology, General Medicine, Gut flora, biology.organism_classification, chemistry.chemical_compound, Quorum sensing, N-Acyl homoserine lactone, chemistry, Biochemistry, Medicine, Epithelial barrier function, Molecule, business
Published
2018
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35. Synthesis and study of (R)- and (S)-β-hydroxyphosphonate acyclonucleosides as structural analogues of (S)-HPMPC (cidofovir)

Author

Chahrazade El Amri, Mahesh Kasthuri, Christian Périgaud, Valérie Lefort, Suzanne Peyrottes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Enzymologie Moléculaire et Fonctionnelle, Université Pierre et Marie Curie - Paris 6 (UPMC), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), and 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)

Subjects
Kinase, Chemistry, Stereochemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Absolute configuration, RNA, General Chemistry, Catalysis, Nucleobase, chemistry.chemical_compound, Materials Chemistry, Enantiomer, Chirality (chemistry), DNA, Cidofovir
Abstract

International audience; A synthetic pathway to new acyclonucleoside phosphonates, designed as analogues of cidofovir, is described. The reduction of a β-ketophosphonate intermediate, readily available from the nucleobase and benzylacrylate, afforded an enantiomeric mixture of (R)- and (S)-β-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies. The influence of this modification, the presence of the hydroxyl group and chirality on the β-position related to the phosphorus atom, on antiviral activity against a broad variety of DNA and RNA viruses and also on the capacity to be recognized as substrates by human NMP kinases was investigated.

Published
2014
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36. Influence of a Cα-Substitution on the S-Pivaloyl-2-Thioethyl Chain on the Anti-HIV Activity and Stability of the Resulting Zidovudine Mononucleoside Phosphotriester

Author

Suzanne Peyrottes, Gilles Gosselin, Christian Périgaud, A-M Aubertin, and J-L Imbach

Subjects
0301 basic medicine, Stereochemistry, 030106 microbiology, Substituent, 01 natural sciences, Chemical synthesis, Structure-Activity Relationship, 03 medical and health sciences, Zidovudine, chemistry.chemical_compound, Drug Stability, medicine, Nucleotide, chemistry.chemical_classification, Chemistry, Spectrum Analysis, Biological activity, General Medicine, Prodrug, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Reverse Transcriptase Inhibitors, Derivative (chemistry), medicine.drug, Methyl group
Abstract

We report the synthesis, in vitro anti-HIV-1 activity and stability study of a mononucleoside phosphotriester derivative of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a new biolabile phosphate-protection, namely S-pivaloyl-2-thioisopropyl ( tBuSATP). This transient protection was characterized by the presence of a methyl substituent at the Cα-position of the previously described S-pivaloyl-2-thioethyl ( tBuSATE) group. Results demonstrated that the new phosphotriester entity was able to deliver selectively the corresponding 5′-mononucleotide within the infected cells. The introduction of a methyl group at the Cα-position of the tBuSATE chain decreased the rate of this delivery.

Published
2001
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37. An alternative pathway to ribonucleoside β-hydroxyphosphonate analogues and related prodrugs

Author

Audrey Hospital, Maïa Meurillon, Suzanne Peyrottes, Christian Périgaud, 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), CNRS, and région languedoc-roussillon

Subjects
Purine, Pyrimidine, Stereochemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, Antiviral Agents, Nucleobase, related prodrugs, chemistry.chemical_compound, Pyrimidine analogue, Nucleoside β-(S)-hydroxyphosphonate, Nucleotidases, Nucleotidase, Prodrugs, Physical and Theoretical Chemistry, Molecular Structure, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Prodrug, Ribonucleoside, 0104 chemical sciences, Ribonucleosides, Nucleoside
Abstract

International audience; Nucleoside β-(S)-hydroxyphosphonate analogues have recently proven to be interesting bioactive compounds as 5'-nucleotidase inhibitors. These derivatives were obtained in a pyrimidine series through an ex-chiral pool pathway or the stereoselective reduction of a β-ketophosphonate intermediate. Herein, an original synthesis of these compounds using nucleoside epoxide intermediates, containing either a pyrimidine or a purine as nucleobase, was explored and allowed the direct synthesis of the corresponding bis S-acyl-2-thioethyl (SATE) prodrugs.

Published
2013
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38. Identification and characterization of inhibitors of cytoplasmic 5′-nucleotidase cN-II issued from virtual screening

Author

Moez Rhimi, Suzanne Peyrottes, Laurent Chaloin, Zsuzsanna Marton, Corinne Lionne, Lars Petter Jordheim, Nushin Aghajari, Emeline Cros-Perrial, Charles Dumontet, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), French Institut National du Cancer (INCa) 2010-200, Olav Raagholt og Gerd Meidel Raagholts stiftelse for forskning, MR the CNRS, and AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Virtual screening, Identification, Inhibitor, Protein Conformation, Antineoplastic Agents, Pharmacology, Biochemistry, Gene Expression Regulation, Enzymologic, 5'-nucleotidase, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Catalytic Domain, Cell Line, Tumor, High-Throughput Screening Assays, Escherichia coli, medicine, Humans, Clofarabine, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enzyme Inhibitors, Cladribine, 5'-Nucleotidase, 030304 developmental biology, 0303 health sciences, Crystallography, Dose-Response Relationship, Drug, Molecular Structure, Nucleoside analogue, [CHIM.ORGA]Chemical Sciences/Organic chemistry, screening, Enzymatic assay, In vitro, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, 030220 oncology & carcinogenesis, cN-II, Lead compound, Plasmids, medicine.drug
Abstract

International audience; Clinical and preclinical observations have lead to the hypothesis that 50-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se or to increase the activity of cytotoxic nucleoside analogs. To identify potential cN-II inhibitors, we performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant cN-II, soaking experiments with crystals of truncated cN-II as well as biological evaluation of selected compounds, alone or in combination with cytotoxic nucleoside analogs, on cancer cells. The top ranked compounds from virtual screening included an anthraquinone derivative (AdiS) that were shown to block the enzyme activity with a Ki of 2.0 mM. Soaking experiments performed with crystals of truncated cN-II allowed to obtain crystallographic data at a resolution of 2.9 A ̊ and indicating interaction between AdiS and F354/I152 situated in the effector site 1 of cN-II. In addition, this compound exhibited different levels of cytotoxicity in vitro on several cancer cell lines and increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5 mM cladribine, 0.05 mM clofarabine or 30 mM fludarabine. Finally, AdiS showed synergy with cladribine and additivity with clofarabine. This study showed that virtual screening is a useful tool for the identification of potent cN-II inhibitors, and our biological results indicated interesting activity for one lead compound that can be further developed as therapeutics.

Published
2013
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39. SATE (Aryl) Phosphotriester Series. I. Synthesis and Biological Evaluation

Author

Anne-Marie Aubertin, Gilles Gosselin, Christian Périgaud, and Suzanne Peyrottes

Subjects
Anti-HIV Agents, Stereochemistry, viruses, Human immunodeficiency virus (HIV), medicine.disease_cause, Thymidine Kinase, Biochemistry, Cell Line, chemistry.chemical_compound, Genetics, medicine, Humans, Thymine Nucleotides, Biological evaluation, Molecular Structure, Chemistry, Aryl, HIV, virus diseases, Biological Transport, General Medicine, Prodrug, Cell culture, Molecular Medicine, Thymidine, Zidovudine, Dideoxynucleotides
Abstract

Synthesis and biological activities of several phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5'-mononucleotide.

Published
2003
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40. Disulfide prodrugs of albitiazolium (T3/SAR97276): synthesis and biological activities

Author

Mahama Ouattara, Michèle Calas, Marjorie Maynadier, Matthieu Hamel, Christian Périgaud, Jean-Frédéric Duckert, Sergio A. Caldarelli, Sharon Wein, Alain Pellet, Suzanne Peyrottes, Henri Vial, 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), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Sanofi Research & Development, and Sanofi Recherche & Development

Subjects
Stereochemistry, Lysine, Plasmodium falciparum, Stereoisomerism, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Antimalarials, Mice, Structure-Activity Relationship, Valine, Bromide, Oral administration, Drug Discovery, Structure–activity relationship, Animals, Prodrugs, Disulfides, chemistry.chemical_classification, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Prodrug, 0104 chemical sciences, 3. Good health, Malaria, Thiazoles, Enzyme, chemistry, Molecular Medicine
Abstract

International audience; We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

Published
2012
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41. Choline Analogues in Malaria Chemotherapy

Author

Suzanne Peyrottes, Sergio A. Caldarelli, Sharon Wein, Christian Périgaud, Alain Pellet, Henri Vial, 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), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Sanofi Research & Development, and Sanofi Recherche & Development

Subjects
thiazolium salts, pharmacology, medicine.medical_treatment, Pharmacology, Biology, Article, Choline, 03 medical and health sciences, chemistry.chemical_compound, Antimalarials, Plasmodium malariae, Drug Discovery, medicine, Animals, Humans, Phospholipid biosynthesis, choline analogues, phospholipid, 030304 developmental biology, Therapeutic strategy, 0303 health sciences, Chemotherapy, Albitiazolium, 030306 microbiology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Prodrug, medicine.disease, 3. Good health, Malaria, chemistry, plasmodium, quaternary ammonium
Abstract

International audience; Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.

Published
2012
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42. Synthesis of 2',3'-dideoxynucleoside phosphoesters using H-phosphonate chemistry on soluble polymer support

Author

Céline Crauste, Suzanne Peyrottes, Christian Périgaud, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and 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)

Subjects
Polymers, Organophosphonates, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Chemical synthesis, chemistry.chemical_compound, Organophosphorus Compounds, Nucleophilic substitution, Organic chemistry, Molecule, Phosphorylation, Molecular Structure, 010405 organic chemistry, Chemistry, Dideoxynucleosides, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, 2'3' dideoxynucleoside, Phosphonate, Combinatorial chemistry, 0104 chemical sciences, Solubility, Carbonyldiimidazole, Ethylene glycol
Abstract

International audience; Phosphorylation of ddC and 3TC was efficiently performed on soluble poly(ethylene glycol) support. The corresponding 5′-monophosphate derivatives were obtained by oxidation of the support bound 5′-H-phosphonate intermediates. Then, di- and triphosphorylations were carried out using a carbonyldiimidazole activation step followed by nucleophilic substitution with suitable phosphate salts. Trivalent phosphorus chemistry appeared as a good alternative for monophosphate synthesis of acid-sensitive 2′,3′-dideoxynucleosides.

Published
2011
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43. Structural Insights into the Inhibition of Cytosolic 5'-Nucleotidase II (cN-II) by Ribonucleoside 5'-Monophosphate Analogues

Author

Maïa Meurillon, Christian Périgaud, Suzanne Peyrottes, Franck Gallier, Perrine Lallemand, Charles Dumontet, Lars Petter Jordheim, Corinne Lionne, Laurent Chaloin, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Institutional funds from the Centre National de la Recherche Scientifique (CNRS), Association pour la Recherche sur le Cancer (ARC) and the Institut National du Cancer (INCa n°2010-200)., Carles, Brigitte, 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), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, Nucleotidase activity, nucléoside, Biochemistry, 01 natural sciences, Computer Applications, Substrate Specificity, chemistry.chemical_compound, composé chimique, Drug Discovery, Nucleotide, composition enzymatique, 5'-Nucleotidase, lcsh:QH301-705.5, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], chemistry.chemical_classification, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Ecology, Hydrolysis, Phosphonate, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Enzymes, 3. Good health, Computational Theory and Mathematics, protéine, Modeling and Simulation, Computer-Aided Design, Research Article, medicine.drug, Inosine monophosphate, Méthodologie, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Structure-Activity Relationship, 03 medical and health sciences, Cellular and Molecular Neuroscience, Inosine Monophosphate, Genetics, medicine, cancer, Binding site, Inosine, Biology, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Binding Sites, 010405 organic chemistry, Methodology, Ribonucleotides, Ribonucleoside, 0104 chemical sciences, lcsh:Biology (General), chemistry, Enzyme Structure, Computer Science, phosphonate, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Nucleoside
Abstract

Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5′-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues., Author Summary Nucleotidase activity is part of a biological process that allows the cell to regulate the intracellular pools of nucleotides involved in many signaling pathways. During cancer therapy with cytotoxic nucleoside analogues, the role of cN-II is unclear. Therefore, the development of specific inhibitors against this enzyme is of great interest for understanding its implication in cancer biology and drug resistance. Ribonucleoside phosphonates are of major importance because they behave as bioisosteric analogues of the natural cN-II substrates and contain a chemically and enzymatically stable phosphorus-carbon linkage. Taking the advantages of docking methods, we predicted the inhibitory potential of these compounds. Their binding strength was explained by an impressive interaction network involving mainly three residues of the enzyme (acting as hydrophobic tweezers). These new characterized inhibitors will constitute a valuable tool for elucidating the role of cN-II in cancer cells and may be used in combination with cytotoxic nucleosidic drugs in order to increase their antitumor activity. Furthermore, the strategy taking into account the hydrophobic clamp for designing new inhibitors may be applied to other nucleotidases of the HAD family as two of the three identified residues are present in the substrate binding site of cytosolic 5′-nucleotidase III and 5′-deoxynucleotidase-I.

Published
2011
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44. Synthesis of pyrimidine containing nucleoside β-(R/S)-hydroxyphosphonate analogues

Author

Suzanne Peyrottes, Laurent Chaloin, Maïa Meurillon, Christian Périgaud, 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), Institut de Recherche en Infectiologie de Montpellier (IRIM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
pyrimidine, Pyrimidine, Molecular model, Stereochemistry, nucleotide, reduction, mo­lecular modeling, phosphonate, ribo­nucleoside, Molecular modeling, Organic chemistry, 010402 general chemistry, 01 natural sciences, ribonucléoside, Pyrimidine analogue, chemistry.chemical_compound, Nucleotide, Physical and Theoretical Chemistry, Reduction, chemistry.chemical_classification, 010405 organic chemistry, Chemistry, Nucleotides, [CHIM.ORGA]Chemical Sciences/Organic chemistry, nucléotide, 3. Good health, 0104 chemical sciences, dérive, Chimie organique, synthèse asymétrique, aminoacide, Ribonucleosides, Phosphonates, Nucleoside, modèle moléculaire
Abstract

A concise route to nucleoside β-hydroxyphosphonate analogues is described. The use of a nucleoside β-ketophosphonate as the key intermediate allowed both the (R) and (S) isomers of β-hydroxyphosphonate analogues in the pyrimidine series to be accessed. Such derivatives may be considered as stable mimics of 5′-monophosphate nucleosides and, therefore, could be the starting point for the development of potential therapeutic agents.

Published
2011
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45. ChemInform Abstract: Design of New Mononucleotide Prodrugs: Aryl (SATE) Phosphotriester Derivatives

Author

Suzanne Peyrottes, N. Schlienger, Alain Pompon, Thierry Beltran, Christian Périgaud, Isabelle Lefebvre, Jean Louis Imbach, Gilles Gosselin, and Anne-Marie Aubertin

Subjects
chemistry.chemical_compound, Chemistry, Cell culture, Aryl, Kinetics, Nucleic acid, Phosphodiesterase, General Medicine, Prodrug, Esterase, Combinatorial chemistry
Abstract

Synthesis, biological activities and decomposition kinetics of novel phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a S-tButyl-2-thioethyl (tBuSATE) group and L-tyrosinyl residues are reported. All the derivatives appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments. The proposed decomposition process of these mixed phosphotriesters may involve successively an esterase and then a phosphodiesterase activation.

Published
2010
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46. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vgamma9Vdelta2 T cells

Author

Christian Périgaud, Suzanne Peyrottes, Xavier Collet, Eric Champagne, Laurent O. Martinez, Bertrand Perret, Jayati Mookerjee-Basu, Pierre Vantourout, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and 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)

Subjects
T cell, T-Lymphocytes, Immunology, Antigen presentation, Isopentenyl pyrophosphate, Lymphocyte Activation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigen, T-Lymphocyte Subsets, Calcium flux, medicine, Immunology and Allergy, [CHIM]Chemical Sciences, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Adenosine Triphosphatases, 0303 health sciences, Antigen Presentation, Microscopy, Confocal, Chemistry, T-cell receptor, Lymphokine, Receptors, Antigen, T-Cell, gamma-delta, 3. Good health, medicine.anatomical_structure, Biochemistry, Triphosphatase, 030215 immunology
Abstract

Human Vγ9Vδ2 T lymphocytes are activated by phosphoantigens provided exogenously or produced by tumors and infected cells. Activation requires a contact between Vγ9Vδ2 cells and neighboring cells. We previously reported a role for cell surface F1-adenosine triphosphatase (ATPase) in T cell activation by tumors and specific interactions between Vγ9Vδ2 TCRs and purified F1-ATPase. 721.221 cells do not express surface F1-ATPase and do not support phosphoantigen responses unless they are rendered apoptotic by high doses of zoledronate, a treatment that promotes F1-expression as well as endogenous phosphoantigen production. By monitoring calcium flux in single cells, we show in this study that contact of T cells with F1-ATPase on polystyrene beads can partially replace the cell-cell contact stimulus during phosphoantigen responses. Triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester, an adenylated derivative of isopentenyl pyrophosphate, can stably bind to F1-ATPase–coated beads and promotes TCR aggregation, lymphokine secretion, and activation of the cytolytic process provided that nucleotide pyrophosphatase activity is present. It also acts as an allosteric activator of F1-ATPase. In the absence of Vγ9Vδ2 cells, triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester immobilized on F1-ATPase is protected from nucleotide pyrophosphatase activity, as is the antigenic activity of stimulatory target cells. Our experiments support the notion that Vγ9Vδ2 T cells are dedicated to the recognition of phosphoantigens on cell membranes in the form of nucleotide derivatives that can bind to F1-ATPase acting as a presentation molecule.

Published
2010
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47. Synthesis and Evaluation of Bis-Thiazolium Salts as Potential Antimalarial Drug

Author

Sergio A. Caldarelli, Christian Périgaud, Sharon Wein, Jean-Frédéric Duckert, Henri Vial, Michèle Calas, Suzanne Peyrottes, 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), Dynamique des interactions membranaires normales et pathologiques (DIMNP), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stereochemistry, Plasmodium falciparum, Biochemistry, Antimalarials, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Biosynthesis, Microwave chemistry, Phosphatidylcholine, Drug Discovery, Animals, Moiety, Bioorganic chemistry, General Pharmacology, Toxicology and Pharmaceutics, 030304 developmental biology, Pharmacology, 0303 health sciences, 030306 microbiology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Aryl, Organic Chemistry, Biological activity, 3. Good health, Thiazoles, chemistry, Molecular Medicine, Linker
Abstract

International audience; An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability. To characterize the structural requirements of the linker that lead to more rigid analogues with fewer rotatable bonds but which retain antimalarial activity, a new series of compounds incorporating an aryl moiety and eventually oxygen atoms were prepared, and their biological activity was evaluated. Structure-activity relationships suggest that the optimal linker construct is an aromatic group with two n-butyl chains branched at the para position; two new leads (compounds 39 and 40) were selected for further development.

Published
2010
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48. Specific Requirements for V{gamma}9V{delta}2 T Cell Stimulation by a Natural Adenylated Phosphoantigen

Author

Frédéric Pont, Jayati Mookerjee-Basu, Suzanne Peyrottes, Christian Périgaud, Corinne Rolland, Hélène Martin, Christian Davrinche, Eric Champagne, Pierre Vantourout, Laurent O. Martinez, Bertrand Perret, Xavier Collet, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateau Technique de Spectrométrie de Masse, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Departement /u563 : Immunologie et Maladies infectieuses, 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), Association pour la Recherche sur le Cancer (ARC contracts #3711-3913-4847), Ligue Nationale contre le Cancer (#R07002BBA). Inserm (Avenir), FRM, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Eric, Champagne

Subjects
Adenosine monophosphate, Lymphoma, B-Cell, T cell, T-Lymphocytes, Immunology, Antigen presentation, Isopentenyl pyrophosphate, Antigen-Presenting Cells, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adenosine Triphosphate, Hemiterpenes, Organophosphorus Compounds, Antigen, Cell Line, Tumor, nucleotide antigens, medicine, Immunology and Allergy, Humans, Receptor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Diphosphonates, phosphoantigens, Receptors, Antigen, T-Cell, gamma-delta, Adenosine Monophosphate, antigen presentation, medicine.anatomical_structure, chemistry, Biochemistry, Cell culture, Gamma-delta T cells, Cancer cell, 030215 immunology
Abstract

1 pages; International audience; Human Vgamma9Vdelta2 T lymphocytes recognize phosphorylated alkyl Ags. Isopentenyl pyrophosphate (IPP) was previously proposed as the main Ag responsible for Vgamma9Vdelta2 T cell activation by cancer cells. However, triphosphoric acid 1-adenosin-5;-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), a metabolite in which the isopentenyl moiety is linked to ATP, was reported in cells activated with aminobisphosphonates. The contribution of this compound to tumor-stimulatory activity was thus examined. ApppI induces selective expansion of Vgamma9Vdelta2 T cells from PBMCs. In the absence of APCs, however, ApppI has little stimulatory activity on Vgamma9Vdelta2 T cells, and optimal activation with ApppI requires addition of a nucleotide pyrophosphatase releasing IPP plus AMP. Thus, ApppI has no intrinsic stimulatory activity. Nevertheless, stimulation by ApppI is strengthened by the presence of APCs. Moreover, in contrast to IPP, ApppI can be efficiently pulsed on dendritic cells as well as on nonprofessional APCs. Pulsed APCs display stable and phosphatase-resistant stimulatory activity, indicative of Ag modification. HPLC analysis of tumor cell extracts indicates that latent phosphoantigenic activity is stored intracellularly in the Vgamma9Vdelta2 cell-sensitive tumor Daudi and can be activated by a nucleotide pyrophosphatase activity. The presence of ApppI in Daudi cell extracts was demonstrated by mass spectrometry. Nucleotidic Ags such as ApppI are thus a storage form of phosphoantigen which may represent a major source of phosphoantigenic activity in tumor cells. The unique properties of ApppI may be important for the design of Ags used in anticancer immunotherapeutic protocols using Vgamma9Vdelta2 cells.

Published
2009
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49. Insights into the Soluble PEG-Supported Synthesis of Cytosine-Containing Nucleoside 5′-Mono-, Di-, and Triphosphates

Author

Christian Périgaud, Céline Crauste, Suzanne Peyrottes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and 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)

Subjects
chemistry.chemical_classification, Nucleotides, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Polyethylene glycol, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Cytosine Nucleotides, 010402 general chemistry, 01 natural sciences, Chemical synthesis, Polyethylene Glycols, 0104 chemical sciences, chemistry.chemical_compound, Solubility, Nucleic acid biosynthesis, PEG ratio, Methods, Nucleic acid, Organic chemistry, Nucleotide, Phosphorylation, Nucleoside, Cytosine
Abstract

International audience; Nucleoside phosphoesters (nucleotides) have crucial roles in a large variety of biological processes including nucleic acid biosynthesis and their corresponding analogues are extensively used as biological tools. Herein, we describe a new and efficient synthetic procedure involving polyethylene glycol (PEG) as soluble support and regioselective mono-, di-, and triphosphorylation steps. Applied to natural and synthetic cytosine containing nucleosides, this methodology allowed the preparation of various phosphorylated forms in high yields and good purity.

Published
2009
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50. Ex-chiral-pool synthesis of beta-hydroxyphosphonate nucleoside analogues

Author

Suzanne Peyrottes, Christian Périgaud, Franck Gallier, Chimie organique biomoléculaire de synthèse (COBS), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and 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)

Subjects
Physical Chemical and Earth Sciences, chemistry.chemical_classification, Glycosylation, glycosylation, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Stereochemistry, Organic Chemistry, carbohydrates, Diastereomer, 010402 general chemistry, 01 natural sciences, nucleotides, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Chiral pool synthesis, Nucleotide, phosphorus, Physical and Theoretical Chemistry, Nucleoside, Derivative (chemistry), ComputingMilieux_MISCELLANEOUS
Abstract

1434 193x English; International audience; A new series of mononucleotide analogues bearing a nonhydrolysable P-C bond instead of the P-O phosphate linkage is presented. We intend to set up an approach that allows the synthesis of beta-hydroxyphosphonate nucleoside analogues as a single diastereoisomer. In this respect, the key "sugar-phosphonate" intermediate was obtained through an Arbusov reaction from an iodosugar derivative in which the stereochemistry of the beta-hydroxy group is determined by the choice of the starting material and remains in the resulting nucleotide analogues. ((C) Wiley-VCH Verlag GmbH and Co. KGaA, 69451 Weinheim, Germany, 2007).

Published
2007
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