期刊
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
卷 373, 期 1748, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rstb.2017.0364
关键词
zinc metalloenzymes; epigenetics; histone deacetylases; enzyme inhibitors; peptidomimetics
类别
资金
- INTERREG ISCE:-Chem selected under the European Cross-border Cooperation Programme INTERREG IV A France (Channel)-England [1917/4061]
- ERDF
- Centre Universitaire Normand de Chimie Organique 'Crunch' network
- European Union's Seventh Framework Programme for Research, Technological Development and Demonstration [602080, 241865]
- University of East Anglia
- La Ligue Contre le Cancer
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Deutsche Forschungsgemeinschaft (DFG) [Ju295/13-1, Si868/13-1]
- Centre National de la Recherche Scientifique (CNRS)
- Universite de Strasbourg
- COST Action [CM1406]
A series of hvdroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 ca vb on atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hvdroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition. This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据