Synthesis and Evaluation of Analogues of N-Phthaloyl-L-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1
| Autor: | Alexandre Ceccaldi, Philippe Schambel, Catherine Senamaud-Beaufort, Thierry Drujon, Christine Champion, Philippe Karoyan, Paola B. Arimondo, Gaël Marloie, Dominique Guianvarc'h, Saâdia Asgatay, Arumugam Rajavelu, Alexandre Erdmann, Olivier Lequin, Albert Jeltsch |
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| Přispěvatelé: | Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA), 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 du CNRS (INC)-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), Université Pierre et Marie Curie - Paris 6 (UPMC), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie de la Matière Condensée de Paris (site Paris VI) (LCMCP (site Paris VI)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Methyltransferase Stereochemistry Phthalic Acids Phthalimides Stereoisomerism DNA methyltransferase Phthalimide Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Catalytic Domain Cell Line Tumor Drug Discovery Humans Structure–activity relationship DNA (Cytosine-5-)-Methyltransferases 030304 developmental biology Indole test 0303 health sciences [CHIM.ORGA]Chemical Sciences/Organic chemistry Tryptophan 3. Good health Molecular Docking Simulation chemistry Docking (molecular) 030220 oncology & carcinogenesis Molecular Medicine DNA |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2013, 57 (2), pp.421-434. ⟨10.1021/jm401419p⟩ Journal of Medicinal Chemistry, 2013, 57 (2), pp.421-434. ⟨10.1021/jm401419p⟩ |
| ISSN: | 0022-2623 1520-4804 |
| DOI: | 10.1021/jm401419p⟩ |
| Popis: | International audience; : DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-Phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogs were synthesized to understand its interaction with DNMT. The indole, carboxylate and phthalimide moieties were modified. Homologated and conformationally constrained analogs were prepared. The latter were synthesized from prolino-homotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors. |
| Databáze: | OpenAIRE |
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