121 results on '"Peyrottes S"'
Search Results
2. Meeting report Montpellier Infectious Diseases (MID), 2nd Annual Meeting (2012)
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Bastien, P, Braun-Breton, C, Chazal, N, Devaux, C, Foulongne, V, Frank, M, Hernandez, Jean-François, Kremer, L, Lebrun, M, Le Moing, V, Leonetti, J.-P, Lionne, C, Peyrottes, S, Biologie, Génétique et Pathologie des Pathogènes Eucaryotes (MIVEGEC-BioGEPPE), Pathogènes, Environnement, Santé Humaine (EPATH), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), 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), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en Biologie Cellulaire (CRBM), 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), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), 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)
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Drug-resistant pathogens ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Mechanisms of virulence ,Infectious diseases ,Novel drug developments - Abstract
International audience; For the second consecutive year, teams of the network “Montpellier Infectious Diseases” held their annual meeting. Whereas the 2011 meeting was focused on host-pathogen interaction and pathophysiology, the 2012 meeting was focused on the cooperation between medical and chemical sciences interdisciplinary approaches to fight against virus, bacteria and parasites. Several approaches aimed at designing new bioactive compounds were described during this meeting.
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- 2013
3. A step further in th SATE mononucleotide prodrug approach
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Peyrottes, S., Villard, A.-L., Coussot, G., Augustijns, P., Lefebvre, Isabelle, Aubertin, A.-M., Gosselin, G., Perigaud, C., 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), Laboratory for Pharmaceutical Technology and Biopharmacy, Laboratory for Pharmaceutical, Laboratoire de Virologie, I.N.S.E.R.M., and Carles, Brigitte
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[CHIM.ORGA]Chemical Sciences/Organic chemistry ,[CHIM.ORGA] Chemical Sciences/Organic chemistry ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
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- 2008
4. 201Tl+-labelled Prussian blue nanoparticles as contrast agents for SPECT scintigraphy
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Perrier, M., primary, Busson, M., additional, Massasso, G., additional, Long, J., additional, Boudousq, V., additional, Pouget, J.-P., additional, Peyrottes, S., additional, Perigaud, Ch., additional, Porredon-Guarch, C., additional, de Lapuente, J., additional, Borras, M., additional, Larionova, J., additional, and Guari, Y., additional
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- 2014
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5. Choline Analogues in Malaria Chemotherapy
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Peyrottes, s, primary
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- 2012
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6. A step further in the SATE mononucleotide prodrug approach
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Peyrottes, S., primary, Villard, A.-L., additional, Coussot, G., additional, Augustijns, P., additional, Lefebvre, I., additional, Aubertin, A.-M., additional, Gosselin, G., additional, and Perigaud, C., additional
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- 2008
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7. Exploring synthetic routes to nucleoside alkynylphosphonates
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Meurillon, M., primary, Peyrottes, S., additional, and Perigaud, C., additional
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- 2008
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8. 588 IN VITRO ANTIVIRAL ACTIVITY AND PHARMACOLOGY OF IDX184, A NOVEL AND POTENT INHIBITOR OF HCV REPLICATION
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Cretton-Scott, E., primary, Perigaud, C., additional, Peyrottes, S., additional, Licklider, L., additional, Camire, M., additional, Larsson, M., additional, La Colla, M., additional, Hildebrand, E., additional, Lallos, L., additional, Bilello, J., additional, McCarville, J., additional, Seifer, M., additional, Liuzzi, M., additional, Pierra, C., additional, Badaroux, E., additional, Gosselin, G., additional, Surleraux, D., additional, and Standring, D.N., additional
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- 2008
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9. Synthetic Approaches to a Mononucleotide Prodrug of Cytarabine
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Bazzanini, R., primary, Gouy, M. -H., additional, Peyrottes, S., additional, Gosselin, G., additional, Périgaud, C., additional, and Manfredini, S., additional
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- 2005
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10. SATE (Aryl) Phosphotriester Series. Part 2. Stability Studies and Physicochemical Parameters
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Coussot, G., primary, Lefebvre, I., additional, Dimalta, D., additional, Peyrottes, S., additional, Pompon, A., additional, Gosselin, G., additional, and Perigaud, C., additional
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- 2004
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11. SATE (Aryl) Phosphotriester Series. Part 1. Synthesis and Biological Evaluation
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Peyrottes, S., primary, Gosselin, G., additional, Aubertin, A.‐M., additional, and Perigaud, C., additional
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- 2004
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12. SATE Pronucleotide Approaches: An Overview
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Peyrottes, S., primary
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- 2004
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13. SATE (Aryl) Phosphotriester Series. II. Stability Studies and Physicochemical Parameters
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Coussot, G., primary, Lefebvre, I., additional, Dimalta, D., additional, Peyrottes, S., additional, Pompon, A., additional, Gosselin, G., additional, and Périgaud, C., additional
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- 2003
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14. SATE (Aryl) Phosphotriester Series. I. Synthesis and Biological Evaluation
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Peyrottes, S., primary, Gosselin, G., additional, Aubertin, A.-M., additional, and Périgaud, C., additional
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- 2003
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15. ChemInform Abstract: Design of New Mononucleotide Prodrugs: Aryl (SATE) Phosphotriester Derivatives
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Peyrottes, S., primary, Schlienger, N., additional, Beltran, T., additional, Lefebvre, I., additional, Pompon, A., additional, Gosselin, G., additional, Aubertin, A.‐M., additional, Imbach, J.‐L., additional, and Perigaud, C., additional
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- 2001
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16. 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
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Peyrottes, S, primary, Périgaud, C, additional, Aubertin, A-M, additional, Gosselin, G, additional, and Imbach, J-L, additional
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- 2001
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17. DESIGN OF NEW MONONUCLEOTIDE PRODRUGS: ARYL (SATE) PHOSPHOTRIESTER DERIVATIVES
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Peyrottes, S., primary, Schlienger, N., additional, Beltran, T., additional, Lefebvre, I., additional, Pompon, A., additional, Gosselin, G., additional, Aubertin, A.-M., additional, Imbach, J.-L., additional, and Périgaud, C., additional
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- 2001
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18. New Series of Mixed Pronucleotides. Synthesis and Anti-HIV Activities of Mononucleoside Phenyl SATE Phosphotriesters
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Schlienger, N., primary, Peyrottes, S., additional, Aubertin, A-M., additional, Gosselin, G., additional, Imbach, J-L., additional, and Périgaud, C., additional
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- 1999
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19. Replacement of the Phosphodiester Backbone of Oligodeoxynucleotide Analogues by Non-Ionic Phosphoramidate (P-NH2)
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Peyrottes, S., primary, Vasseur, J.-J., additional, Imbach, J.-L., additional, and Rayner, B., additional
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- 1997
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20. Oligodeoxynucleoside phosphoramidates (P-NH2): synthesis and thermal stability of duplexes with DNA and RNA targets
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Peyrottes, S, primary
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- 1996
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21. Synthesis, Base Pairing Properties and Nuclease Resistance of Oligothymidylate Analogs Containing Methoxyphosphoramidate Internucleoside Linkages
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Peyrottes, S., primary, Vasseur, J. J., additional, Imbach, J. L., additional, and Rayner, B., additional
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- 1994
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22. S-Acyl-2-Thioethyl Aryl Phosphotriester Derivatives of AZT: Synthesis, Antiviral Activity, and Stability Study
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Peyrottes, S., Coussot, G., Lefebvre, I., Imbach, J.-L., Gosselin, G., Aubertin, A.-M., and Perigaud, C.
- Abstract
The synthesis, antiviral activity, and stability study of phosphotriester derivatives of 3-azido-2,3-dideoxythymidine (AZT) bearing modified
l -tyrosinyl residues are reported. These compounds were obtained via phosphoramidite (PIII) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC50 values between the micro- and nanomolar range, especially in thymidine kinase deficient (TK-) cells, showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters successively involves an esterase and a phosphodiesterase hydrolysis.- Published
- 2003
23. S-Acyl-2-thioethyl Aryl Phosphotriester Derivatives as Mononucleotide Prodrugs
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Schlienger, N., Peyrottes, S., Kassem, T., Imbach, J.-L., Gosselin, G., Aubertin, A.-M., and Perigaud, C.
- Abstract
The synthesis and biological activities of phosphotriester derivatives of 3-azido-2,3-dideoxythymidine (AZT) bearing a phenyl group or
l -tyrosinyl residues are reported. The target compounds were obtained via either PV or PIII chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC50 values between the micro- and nanomolar range. Furthermore, compounds incorporating an amino- and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine kinase-deficient (TK-) cells showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may involve esterase activation followed by phosphodiesterase hydrolysis.- Published
- 2000
24. The Hydrazine Moiety in the Synthesis of Modified Nucleosides and Nucleotides.
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Guillou A, Peyrottes S, Vasseur JJ, Mathé C, and Smietana M
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- Humans, Molecular Structure, Hydrazines chemistry, Hydrazines chemical synthesis, Hydrazines pharmacology, Nucleosides chemistry, Nucleosides chemical synthesis, Nucleosides pharmacology, Nucleotides chemistry, Nucleotides chemical synthesis, Nucleotides pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Antiviral Agents chemistry
- Abstract
Synthetic nucleoside mimics are re-emerging as crucial contenders for antiviral and anticancer medications. While, Ribavirin stands out for its unique antiviral properties, predominantly associated with its distinctive triazole heterocycle as a nucleobase, the exploration of alternative nitrogen-based aromatic heterocycles hold great promises for the discovery of novel bioactive nucleoside mimics. Although nucleoside derivatives synthesized from hydrazine-ribose units have been in development for many decades, they have been little evaluated biologically and even less for their antiviral properties. With the aim of taking a closer look at these under-explored derivatives and investigating their synthetic pathways, this review provides an overview of the molecular design, the chemical synthesis, and the biological activity, when available, of these nucleoside analogues. Overall, the entire body of work already done motivates further exploration of these analogues and encourages us of formulating structurally novel nucleoside drug candidates featuring innovative mode of action., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)
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- 2024
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25. Probing the Use of Triphenyl Phosphonium Cation for Mitochondrial Nucleoside Delivery.
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Guiraud M, Ali LMA, Gabrieli-Magot E, Lichon L, Daurat M, Egron D, Gary-Bobo M, and Peyrottes S
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Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)
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- 2024
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26. Purine containing carbonucleoside phosphonate analogues as novel chemotype for Plasmodium falciparum Inhibition.
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Mohamed BS, Nguyen MC, Wein S, Uttaro JP, Robert X, Violot S, Ballut L, Jugnarain V, Mathé C, Cerdan R, Aghajari N, and Peyrottes S
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- Plasmodium falciparum metabolism, Nucleosides, Purines metabolism, Organophosphonates pharmacology, Antimalarials pharmacology, Antimalarials metabolism
- Abstract
The nucleotidase ISN1 is a potential therapeutic target of the purine salvage pathway of the malaria parasite Plasmodium falciparum. We identified PfISN1 ligands by in silico screening of a small library of nucleos(t)ide analogues and by thermal shift assays. Starting from a racemic cyclopentyl carbocyclic phosphonate scaffold, we explored the diversity on the nucleobase moiety and also proposed a convenient synthetic pathway to access the pure enantiomers of our initial hit (compound (±)-2). 2,6-Disubstituted purine containing derivatives such as compounds 1, (±)-7e and β-L-(+)-2 showed the most potent inhibition of the parasite in vitro, with low micromolar IC
50 values. These results are remarkable considering the anionic nature of nucleotide analogues, which are known to lack activity in cell culture experiments due to their scarce capacity to cross cell membranes. For the first time, we report the antimalarial activity of a carbocyclic methylphosphonate nucleoside with an L-like configuration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nushin Aghajari reports financial support was provided by French National Research Agency., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)- Published
- 2023
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27. Second-Generation CD73 Inhibitors Based on a 4,6-Biaryl-2-thiopyridine Scaffold.
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Ghoteimi R, Braka A, Rodriguez C, Cros-Perrial E, Duvauchelle V, Uttaro JP, Mathé C, Ménétrier-Caux C, Jordheim LP, Chaloin L, and Peyrottes S
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- Humans, Pyridines pharmacology, Recombinant Proteins chemistry, 5'-Nucleotidase, Adenosine pharmacology
- Abstract
Various series of 4,6-biaryl-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6-disubstituted 3-cyano-2-chloro-pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell-based assays, highlighting the difficulty to target protein-protein interface on proteins existing as soluble and membrane-bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6-biaryl-2-thiopyridine core were shown to be able to reverse the adenosine-mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)-N-(isoxazol-3-yl)acetamide (with total reversion at 100 μM) and methyl 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)acetate (with partial reversion at 10 μM). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
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- 2023
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28. Prodrugs of Nucleoside 5'-Monophosphate Analogues: Overview of the Recent Literature Concerning their Synthesis and Applications.
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Roy B, Navarro V, and Peyrottes S
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- Humans, Antiviral Agents pharmacology, Nucleotides chemistry, Nucleotides metabolism, Nucleotides pharmacology, Phosphorylation, Nucleosides chemistry, Nucleosides metabolism, Nucleosides pharmacology, Prodrugs chemistry
- Abstract
Nucleoside analogues are widely used as anti-infectious and antitumoral agents. However, their clinical use may face limitations associated with their physicochemical properties, pharmacokinetic parameters, and/or their peculiar mechanisms of action. Indeed, once inside the cells, nucleoside analogues require to be metabolized into their corresponding (poly-)phosphorylated derivatives, mediated by cellular and/or viral kinases, in order to interfere with nucleic acid biosynthesis. Within this activation process, the first-phosphorylation step is often the limiting one and to overcome this limitation, numerous prodrug approaches have been proposed. Herein, we will focus on recent literature data (from 2015 and onwards) related to new prodrug strategies, the development of original synthetic approaches and novel applications of nucleotide prodrugs (namely pronucleotides) leading to the intracellular delivery of 5'-monophosphate nucleoside analogues., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
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29. Mononucleoside phosphorodithiolates as mononucleotide prodrugs.
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Schlienger N, Lefebvre I, Aubertin AM, Peyrottes S, and Périgaud C
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Structure-Activity Relationship, Sulfhydryl Compounds chemical synthesis, Sulfhydryl Compounds chemistry, Virus Replication drug effects, Anti-HIV Agents pharmacology, HIV-1 drug effects, Nucleosides pharmacology, Prodrugs pharmacology, Sulfhydryl Compounds pharmacology
- 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 (EC
50 ) 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
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30. Cytotoxic and Antitumoral Activity of N-(9H-purin-6-yl) Benzamide Derivatives and Related Water-soluble Prodrugs.
- Author
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Cros-Perrial E, Saulnier S, Raza MZ, Charmelot R, Egron D, Dumontet C, Chaloin L, Peyrottes S, and Jordheim LP
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- Benzamides pharmacology, Humans, Structure-Activity Relationship, Water, Antineoplastic Agents pharmacology, Neoplasms, Prodrugs pharmacology
- 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2022
- Full Text
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31. An original pronucleotide strategy for the simultaneous delivery of two bioactive drugs.
- Author
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Villard AL, Aubertin AM, Peyrottes S, and Périgaud C
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- Anti-HIV Agents chemistry, Anti-HIV Agents metabolism, Anti-HIV Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents metabolism, Antiviral Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Drug Carriers chemistry, HIV-1 drug effects, Humans, Nucleotides metabolism, Nucleotides pharmacology, Prodrugs chemistry, Prodrugs metabolism, Prodrugs pharmacology, Nucleotides chemistry
- Abstract
The synthesis and in vitro anti-HIV activity of a novel series of phosphoramidate pronucleotides including a S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protecting group are reported. Such constructs, obtained through different phosphorus chemistries, are characterized by the association of two different anti-HIV nucleoside analogues linked to the phosphorus atom respectively by the sugar residue and the exocyclic amino function of the nucleobase. In vitro, comparative anti-HIV evaluation demonstrates that such original prodrugs are able to allow the efficient intracellular combination release of a 5'-mononucleotide as well as another nucleoside analogue. In human T4-lymphoblastoid cells, the pronucleotide 1 shows remarkable antiviral activity with an EC
50 in the nanomolar range (0.6 ηM) and without additional cytotoxicity. In addition, these two pronucleotide models exhibit higher selectivity index than the equimolar mixture of their constitutive nucleoside analogues opening the way to further studies with regard to the current use of drug combinations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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32. Synthesis of Aminomethylene- gem -bisphosphonates Containing an Aziridine Motif: Studies of the Reaction Scope and Insight into the Mechanism.
- Author
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Cheviet T and Peyrottes S
- Subjects
- Diphosphonates, Aziridines, Organophosphonates
- Abstract
A broad range of N -carbamoylaziridines were obtained and then treated by the diethyl phosphonate anion to afford α-methylene- gem -bisphosphonate aziridines. Study of the reaction's scope and additional experiments indicates that the transformation proceeds via a new mechanism involving the chelation of lithium ion. This last step is crucial for the reaction to occur and disfavors the aziridine ring-opening. A phosphonate-phosphate rearrangement from a α-hydroxybisphosphonate aziridine intermediate is also proposed for the first time. This reaction provides a simple and convenient method for the synthesis of a highly functionalized phosphonylated aziridine motif.
- Published
- 2021
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33. 4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies.
- Author
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Ghoteimi R, Braka A, Rodriguez C, Cros-Perrial E, Tai Nguyen V, Uttaro JP, Mathé C, Chaloin L, Ménétrier-Caux C, Jordheim LP, and Peyrottes S
- Subjects
- 5'-Nucleotidase metabolism, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins metabolism, Humans, Kinetics, Molecular Structure, Nucleotides chemical synthesis, Nucleotides chemistry, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, 5'-Nucleotidase antagonists & inhibitors, Algorithms, Nucleotides pharmacology, Triazoles pharmacology
- Abstract
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 4-substituted-1,2,3-triazolo-β-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 β-hydroxyphosphonylphosphonate 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 IC
50 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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34. 2-(Substituted amino)-8-azachromones from 4,6-Diaryl-2-pyridones: A Synthetic Strategy toward Compounds of Broad Structural Diversity.
- Author
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Saulnier S, Ghoteimi R, Mathé C, Peyrottes S, and Uttaro JP
- Abstract
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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35. β-Hydroxy- and β-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Plasmodium falciparum Growth.
- Author
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Cheviet T, Wein S, Bourchenin G, Lagacherie M, Périgaud C, Cerdan R, and Peyrottes S
- Subjects
- Animals, Antimalarials therapeutic use, Female, Humans, K562 Cells, Mice, Nucleosides chemistry, Nucleosides pharmacology, Nucleosides therapeutic use, Organophosphonates chemistry, Organophosphonates pharmacology, Organophosphonates therapeutic use, Plasmodium falciparum physiology, Antimalarials chemistry, Antimalarials pharmacology, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects
- 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 (IC
50 = 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
- Full Text
- View/download PDF
36. Synthetic Strategies for Dinucleotides Synthesis.
- Author
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Appy L, Chardet C, Peyrottes S, and Roy B
- Subjects
- Deoxycytosine Nucleotides agonists, Deoxycytosine Nucleotides chemistry, Deoxycytosine Nucleotides pharmacology, Dinucleoside Phosphates chemistry, Dinucleoside Phosphates isolation & purification, Dry Eye Syndromes drug therapy, Green Chemistry Technology, Humans, Ophthalmic Solutions, Phosphorylation, Polyphosphates chemical synthesis, Polyphosphates chemistry, Purinergic P2Y Receptor Agonists chemistry, Purinergic P2Y Receptor Agonists isolation & purification, Receptors, Purinergic metabolism, Uracil Nucleotides chemistry, Uridine agonists, Uridine analogs & derivatives, Uridine chemistry, Uridine pharmacology, Dinucleoside Phosphates chemical synthesis, Purinergic P2Y Receptor Agonists chemical synthesis
- Abstract
Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell proliferation, regulation of enzymes, neurotransmission, platelet disaggregation and modulation of vascular tone. Various methodologies have been developed over the past fifty years to access these compounds, involving enzymatic processes or chemical procedures based either on P(III) or P(V) chemistry. Both solution-phase and solid-support strategies have been developed and are reported here. Recently, green chemistry approaches have emerged, offering attracting alternatives. This review outlines the main synthetic pathways for the preparation of dinucleoside 5',5'-polyphosphates, focusing on pharmacologically relevant compounds, and highlighting recent advances.
- Published
- 2019
- Full Text
- View/download PDF
37. Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues.
- Author
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Cheviet T, Lefebvre-Tournier I, Wein S, and Peyrottes S
- Subjects
- Biological Transport, Drug Design, Erythrocytes parasitology, Humans, Inhibitory Concentration 50, Malaria drug therapy, Malaria parasitology, Plasmodium falciparum metabolism, Pyrimidines metabolism, Antimalarials pharmacology, Nucleosides metabolism, Nucleotides metabolism, Plasmodium falciparum drug effects, Purines metabolism
- Abstract
Malaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the Plasmodium genus. Only a few WHO-recommended treatments are available to prevent or cure plasmodial infections, but genetic mutations in the causal parasites have led to onset of resistance against all commercial antimalarial drugs. New drugs and targets are being investigated to cope with this emerging problem, including enzymes belonging to the main metabolic pathways, while nucleoside and nucleotide analogues are also a promising class of potential drugs. This review highlights the main metabolic pathways targeted for the development of potential antiplasmodial therapies based on nucleos(t)ide analogues, as well as the different series of purine-containing nucleoside and nucleotide derivatives designed to inhibit Plasmodium falciparum purine metabolism.
- Published
- 2019
- Full Text
- View/download PDF
38. Synthesis of Substituted 5'-Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73.
- Author
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Ghoteimi R, Nguyen VT, Rahimova R, Grosjean F, Cros-Perrial E, Uttaro JP, Mathé C, Chaloin L, Jordheim LP, and Peyrottes S
- Subjects
- Adenosine pharmacology, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Drug Design, Enzyme Inhibitors pharmacology, GPI-Linked Proteins antagonists & inhibitors, Humans, Models, Molecular, Molecular Structure, Organophosphonates chemistry, Organophosphorus Compounds chemistry, Protein Binding, Protein Conformation, Recombinant Proteins chemistry, Structure-Activity Relationship, 5'-Nucleotidase antagonists & inhibitors, Adenosine analogs & derivatives, Adenosine chemical synthesis, Antineoplastic Agents chemical synthesis, Enzyme Inhibitors chemical synthesis
- 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2019
- Full Text
- View/download PDF
39. Lead optimization and biological evaluation of fragment-based cN-II inhibitors.
- Author
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Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, and Peyrottes S
- Subjects
- 5'-Nucleotidase metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HL-60 Cells, Humans, Models, Molecular, Molecular Structure, Purines chemical synthesis, Purines chemistry, Structure-Activity Relationship, 5'-Nucleotidase antagonists & inhibitors, Antineoplastic Agents pharmacology, Purines pharmacology
- 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 K
i 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
40. Straightforward Ball-Milling Access to Dinucleoside 5',5'-Polyphosphates via Phosphorimidazolide Intermediates.
- Author
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Appy L, Depaix A, Bantreil X, Lamaty F, Peyrottes S, and Roy B
- Abstract
A solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5'-polyphosphates is reported. Under ball-milling conditions, nucleoside 5'-monophosphates were quantitatively activated using 1,1'-carbonyldiimidazole, forming their phosphorimidazolide derivatives. The addition of a nucleoside 5'-mono-, di- or triphosphate directly led 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 1,1'-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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2019
- Full Text
- View/download PDF
41. CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates.
- Author
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Dumontet C, Peyrottes S, Rabeson C, Cros-Perrial E, Géant PY, Chaloin L, and Jordheim LP
- Subjects
- 5'-Nucleotidase biosynthesis, 5'-Nucleotidase metabolism, Cell Line, Tumor, Cell Survival drug effects, Diphosphonates chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Purine Nucleosides chemistry, Structure-Activity Relationship, 5'-Nucleotidase antagonists & inhibitors, Diphosphonates pharmacology, Enzyme Inhibitors pharmacology, Purine Nucleosides pharmacology
- 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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
42. Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface.
- Author
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Rahimova R, Fontanel S, Lionne C, Jordheim LP, Peyrottes S, and Chaloin L
- Subjects
- Adenosine metabolism, Allosteric Site, Antibodies, Monoclonal chemistry, Antineoplastic Agents chemistry, Cell Proliferation, Computational Biology, Crystallography, X-Ray, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins genetics, Humans, Immune System, Inflammation, Kinetics, Magnetic Resonance Spectroscopy, Models, Statistical, Molecular Dynamics Simulation, Phenotype, Protein Binding, Protein Conformation, Protein Multimerization, Recombinant Proteins chemistry, Software, 5'-Nucleotidase antagonists & inhibitors, 5'-Nucleotidase genetics
- Abstract
The ecto-5'-nucleotidase CD73 plays an important role in the production of immune-suppressive adenosine in tumor micro-environment, and has become a validated drug target in oncology. Indeed, the anticancer immune response involves extracellular ATP to block cell proliferation through T-cell activation. However, in the tumor micro-environment, two extracellular membrane-bound enzymes (CD39 and CD73) are overexpressed and hydrolyze efficiently ATP into AMP then further into immune-suppressive adenosine. To circumvent the impact of CD73-generated adenosine, we applied an original bioinformatics approach to identify new allosteric inhibitors targeting the dimerization interface of CD73, which should impair the large dynamic motions required for its enzymatic function. Several hit compounds issued from virtual screening campaigns showed a potent inhibition of recombinant CD73 with inhibition constants in the low micromolar range and exhibited a non-competitive inhibition mode. The structure-activity relationships studies indicated that several amino acid residues (D366, H456, K471, Y484 and E543 for polar interactions and G453-454, I455, H456, L475, V542 and G544 for hydrophobic contacts) located at the dimerization interface are involved in the tight binding of hit compounds and likely contributed for their inhibitory activity. Overall, the gathered information will guide the upcoming lead optimization phase that may lead to potent and selective CD73 inhibitors, able to restore the anticancer immune response.
- Published
- 2018
- Full Text
- View/download PDF
43. Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine.
- Author
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Laux WH, Priet S, Alvarez K, Peyrottes S, and Périgaud C
- Subjects
- Adenine chemical synthesis, Adenine chemistry, Adenine pharmacology, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Humans, Microbial Sensitivity Tests, Molecular Structure, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Adenine analogs & derivatives, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, HIV-1 enzymology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Background The replacement of β,γ-pyrophosphate by β,γ-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5'-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir). Methods Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp). Results Searching for nucleoside 5'-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC
50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM). Conclusion PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.- Published
- 2018
- Full Text
- View/download PDF
44. Vγ9Vδ2 T cell activation by strongly agonistic nucleotidic phosphoantigens.
- Author
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Moulin M, Alguacil J, Gu S, Mehtougui A, Adams EJ, Peyrottes S, and Champagne E
- Subjects
- Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Antigens pharmacology, Antigens, CD immunology, Butyrophilins immunology, Dose-Response Relationship, Immunologic, HeLa Cells, Humans, Interferon-gamma biosynthesis, Interferon-gamma immunology, K562 Cells, Lysosomal-Associated Membrane Protein 1 biosynthesis, Lysosomal-Associated Membrane Protein 1 immunology, Primary Cell Culture, Receptors, Antigen, T-Cell, gamma-delta classification, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes cytology, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha biosynthesis, Tumor Necrosis Factor-alpha immunology, Antigens, CD genetics, Butyrophilins genetics, Hemiterpenes pharmacology, Lymphocyte Activation drug effects, Organophosphates pharmacology, Organophosphorus Compounds pharmacology, Receptors, Antigen, T-Cell, gamma-delta genetics, T-Lymphocytes drug effects
- 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
- Full Text
- View/download PDF
45. Water-Medium Synthesis of Nucleoside 5'-Polyphosphates.
- Author
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Depaix A, Peyrottes S, and Roy B
- Subjects
- Imidazoles chemistry, Nucleosides chemistry, Nucleosides chemical synthesis, Polyphosphates chemistry
- 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., (Copyright © 2017 John Wiley & Sons, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
46. Determination and quantification of intracellular fludarabine triphosphate, cladribine triphosphate and clofarabine triphosphate by LC-MS/MS in human cancer cells.
- Author
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Puy JY, Jordheim LP, Cros-Perrial E, Dumontet C, Peyrottes S, and Lefebvre-Tournier I
- Subjects
- Adenine Nucleotides analysis, Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate analysis, Adenosine Triphosphate metabolism, Antineoplastic Agents analysis, Arabinonucleosides analysis, Cell Line, Tumor, Chromatography, High Pressure Liquid methods, Cladribine analogs & derivatives, Cladribine analysis, Clofarabine, Humans, Limit of Detection, Neoplasms drug therapy, Neoplasms metabolism, Polyphosphates metabolism, Spectrometry, Mass, Electrospray Ionization methods, Vidarabine analysis, Vidarabine metabolism, Adenine Nucleotides metabolism, Antineoplastic Agents metabolism, Arabinonucleosides metabolism, Cladribine metabolism, Polyphosphates analysis, Tandem Mass Spectrometry methods, Vidarabine analogs & derivatives
- 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., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
47. Evidence that oxidative dephosphorylation by the nonheme Fe(II), α-ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation.
- Author
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Goswami A, Liu X, Cai W, Wyche TP, Bugni TS, Meurillon M, Peyrottes S, Perigaud C, Nonaka K, Rohr J, and Van Lanen SG
- Subjects
- Biocatalysis, Hydrogen metabolism, Hydroxylation, Oxidation-Reduction, Phosphorylation, Stereoisomerism, Substrate Specificity, Uridine Monophosphate chemistry, Heme metabolism, Iron metabolism, Ketoglutaric Acids metabolism, Oxygenases metabolism, Uridine Monophosphate metabolism
- Abstract
LipL and Cpr19 are nonheme, mononuclear Fe(II)-dependent, α-ketoglutarate (αKG):UMP oxygenases that catalyze the formation of CO
2 , 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'-2 H]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 one2 H atom of [1',3',4',5',5'-2 H]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., (© 2017 Federation of European Biochemical Societies.)- Published
- 2017
- Full Text
- View/download PDF
48. Recent Trends in Nucleotide Synthesis.
- Author
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Roy B, Depaix A, Périgaud C, and Peyrottes S
- Subjects
- Chemistry Techniques, Synthetic, Molecular Conformation, Nucleotides chemistry, Nucleotides isolation & purification, Nucleotides chemical synthesis
- Abstract
Focusing on the recent literature (since 2000), this review outlines the main synthetic approaches for the preparation of 5'-mono-, 5'-di-, and 5'-triphosphorylated nucleosides, also known as nucleotides, as well as several derivatives, namely, cyclic nucleotides and dinucleotides, dinucleoside 5',5'-polyphosphates, sugar nucleotides, and nucleolipids. Endogenous nucleotides and their analogues can be obtained enzymatically, which is often restricted to natural substrates, or chemically. In chemical synthesis, protected or unprotected nucleosides can be used as the starting material, depending on the nature of the reagents selected from P(III) or P(V) species. Both solution-phase and solid-support syntheses have been developed and are reported here. Although a considerable amount of research has been conducted in this field, further work is required because chemists are still faced with the challenge of developing a universal methodology that is compatible with a large variety of nucleoside analogues.
- Published
- 2016
- Full Text
- View/download PDF
49. Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation.
- Author
-
Nguyen Van T, Hospital A, Lionne C, Jordheim LP, Dumontet C, Périgaud C, Chaloin L, and Peyrottes S
- Abstract
A series of seventeen β-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
- Full Text
- View/download PDF
50. Aminobisphosphonates Synergize with Human Cytomegalovirus To Activate the Antiviral Activity of Vγ9Vδ2 Cells.
- Author
-
Daguzan C, Moulin M, Kulyk-Barbier H, Davrinche C, Peyrottes S, and Champagne E
- Subjects
- Cell Line, Cells, Cultured, Cytokines metabolism, Cytomegalovirus classification, Cytomegalovirus Infections immunology, Cytomegalovirus Infections metabolism, Cytomegalovirus Infections virology, Cytotoxicity, Immunologic, Dendritic Cells immunology, Dendritic Cells metabolism, Diphosphonates metabolism, Host-Pathogen Interactions immunology, Humans, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Activation, Mevalonic Acid metabolism, Receptors, Antigen, T-Cell, gamma-delta metabolism, Virus Replication, Cytomegalovirus immunology, Diphosphonates immunology, Receptors, Antigen, T-Cell, gamma-delta genetics, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
Human Vγ9Vδ2 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 Vγ9Vδ2 lymphocytes in chronic viral infections. Although Vγ9Vδ2 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 Vγ9Vδ2 T cells to produce IFN-γ but not TNF. Following the same treatment, HCMV-infected fibroblasts stimulate TNF secretion and an increased production of IFN-γ, indicating that Vγ9Vδ2 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 Vγ9Vδ2 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 γδ cells in submicromolar concentrations of ZOL, we show that Vγ9Vδ2 cells suppressed substantially the release of infectious particles while preserving uninfected cells. Vγ9Vδ2 cytotoxicity was decreased by HCMV infection of targets whereas anti-IFN-γ and anti-TNF Abs significantly blocked the antiviral effect. Our experiments indicate that cytokines produced by Vγ9Vδ2 T cells have an antiviral potential in HCMV infection. This should lead to in vivo studies to explore the possible antiviral effect of immunostimulation with ZOL in this context., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
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