دورية أكاديمية
6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: synthesis, structural studies and cytotoxic activities.
| العنوان: | 6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: synthesis, structural studies and cytotoxic activities. |
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| المؤلفون: | Amiable, Claire, Paoletti, Julie, Haouz, Ahmed, Padilla, André, Labesse, Gilles, Kaminski, Pierre-Alexandre, Pochet, Sylvie |
| المساهمون: | Université Paris Descartes - Paris 5 (UPD5), Chimie et Biocatalyse, Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Cristallographie (Plateforme) - Crystallography (Platform), Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale Montpellier (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Fondation pour la Recherche Médicale (DCM20111223063 to S. Pochet), Institut Pasteur, CNRS, INSERM and the French Infrastructure for Integrated Structural Biology (FRISBI, ANR-10-INSB-05-01)., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010) |
| المصدر: | ISSN: 0223-5234. |
| بيانات النشر: | HAL CCSD Elsevier |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Cancer, Cross-coupling reaction, Crystal structure, DNPH1, Inhibitor, Nucleoside analogues, MESH: Animals, MESH: Antineoplastic Agents/chemical synthesis, MESH: Enzyme Inhibitors/chemistry, MESH: Enzyme Inhibitors/metabolism, MESH: Enzyme Inhibitors/pharmacology, MESH: Humans, MESH: Molecular Docking Simulation, MESH: Molecular Targeted Therapy, MESH: N-Glycosyl Hydrolases/antagonists & inhibitors, MESH: N-Glycosyl Hydrolases/chemistry, MESH: N-Glycosyl Hydrolases/metabolism, MESH: Nuclear Proteins/antagonists & inhibitors, MESH: Antineoplastic Agents/chemistry, MESH: Nuclear Proteins/chemistry, MESH: Nuclear Proteins/metabolism, MESH: Protein Conformation, MESH: Proto-Oncogene Proteins/antagonists & inhibitors, MESH: Proto-Oncogene Proteins/chemistry, MESH: Proto-Oncogene Proteins/metabolism, MESH: Purine Nucleotides/chemical synthesis, MESH: Purine Nucleotides/chemistry, MESH: Purine Nucleotides/metabolism, MESH: Purine Nucleotides/pharmacology, MESH: Antineoplastic Agents/metabolism |
| الوصف: | International audience ; The 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 (DNPH1) has been proposed as a new molecular target for cancer treatment. Here, we describe the synthesis of a series of novel 6-aryl- and 6-heteroarylpurine riboside 5'-monophosphates via Suzuki-Miyaura cross-coupling reactions, and their ability to inhibit recombinant rat and human DNPH1. Enzymatic inhibition studies revealed competitive inhibitors in the low micromolar range. Crystal structures of human and rat DNPH1 in complex with one nucleotide from this series, the 6-naphthylpurine derivative, provided detailed structural information, in particular regarding the possible conformations of a long and flexible loop wrapping around the large hydrophobic substituent. Taking advantage of these high-resolution structures, we performed virtual docking studies in order to evaluate enzyme-inhibitor interactions for the whole compound series. Among the synthesized compounds, several molecules exhibited significant in vitro cytotoxicity against human colon cancer (HCT15, HCT116) and human promyelocytic leukemia (HL60) cell lines with IC50 values in the low micromolar range, which correlated with in vitro DNPH1 inhibitory potency. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/25108359; pasteur-01483767; https://pasteur.hal.science/pasteur-01483767Test; PUBMED: 25108359 |
| DOI: | 10.1016/j.ejmech.2014.07.110 |
| الإتاحة: | https://doi.org/10.1016/j.ejmech.2014.07.110Test https://pasteur.hal.science/pasteur-01483767Test |
| رقم الانضمام: | edsbas.7FC36582 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ejmech.2014.07.110 |
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