Normandie University, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.
School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK.
Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748). doi: 10.1098/rstb.2017.0364.
A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon 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 hydroxamic 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'.
合成了一系列通过不同长度的羟肟酸连接到手性咪唑并酮哌嗪支架上的化合物。具有 6 个和 7 个碳原子连接体长度的化合物在组蛋白去乙酰化酶（HDAC）抑制中最为有效，并且是 HDAC1、HDAC6 和 HDAC8 同工型的特异性亚微摩尔抑制剂。对接模型预测了结合模式，即羟肟酸与活性位点锌离子的结合，以及咪唑并酮哌嗪与酶边缘之间的额外相互作用。这些化合物对 MV4-11、THP-1 和 U937 癌细胞系的抑制作用为微摩尔级。组蛋白 H3 和微管蛋白乙酰化水平的增加支持通过 HDAC 抑制的细胞作用机制。本文是“表观遗传化学生物学前沿”讨论专题的一部分。
