Chen Danqi, Shen Aijun, Fang Guanghua, Liu Hongchun, Zhang Minmin, Tang Shuai, Xiong Bing, Ma Lanping, Geng Meiyu, Shen Jingkang
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharm Sin B. 2016 Jan;6(1):93-9. doi: 10.1016/j.apsb.2015.11.002. Epub 2016 Jan 7.
Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs.
组蛋白乙酰化是染色质结构和基因表达调控中的一个关键过程。组蛋白去乙酰化酶（HDACs）去除乙酰基团，导致染色质浓缩和转录抑制。HDAC抑制剂被认为是一类新型抗癌药物，已被证明可改变基因转录并发挥抗肿瘤作用。本文描述了我们关于四氢异喹啉化合物作为HDAC抑制剂的结构测定和构效关系（SAR）优化的工作。测试了这些化合物抑制HDAC 1、3、6的能力以及它们抑制一组癌细胞系增殖的能力。其中，化合物82对HDAC 1、3、6表现出最大的抑制活性，并强烈抑制癌细胞系的生长，结果明显优于参考化合物伏立诺他（SAHA）。化合物82以浓度依赖性方式增加组蛋白H3、H4和微管蛋白的乙酰化，表明它是一种广泛的HDAC抑制剂。
