Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
Bioorg Chem. 2021 May;110:104801. doi: 10.1016/j.bioorg.2021.104801. Epub 2021 Mar 5.
The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.
由于组蛋白去乙酰化酶（HDAC）酶之间的序列同源性，因此发现和开发同工型选择性的 HDAC 抑制剂是一项具有挑战性的任务。在本工作中，设计、合成了新型四氢苯并[b]噻吩-3-甲腈基苯甲酰胺，并将其作为 HDAC 抑制剂进行了评价。药效团建模是我们的主要设计策略，确定了两个具有哌啶连接基（系列 1）和哌嗪连接基（系列 2）的新型四氢苯并[b]噻吩-3-甲腈基衍生物系列作为 HDAC 抑制剂。在所合成的化合物中，具有 4-（氨甲基）哌啶连接基的 9h 和具有哌嗪连接基的 14n 对人源 HDAC1 和 HDAC6 均表现出良好的活性。这两种化合物对几种人癌细胞系也表现出良好的抗增殖活性。这两种化合物（9h 和 14n）还诱导 U937 和 MDA-MB-231 癌细胞的细胞周期停滞和凋亡。总的来说，这是首次使用环状连接基而非脂肪链和芳环系统发现具有潜在同工型选择性的 HDAC 抑制剂，这在已知的 HDAC 抑制剂中是没有报道过的。
