College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
Department of Pharmacology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea.
Arch Pharm Res. 2018 Oct;41(10):967-976. doi: 10.1007/s12272-018-1045-z. Epub 2018 Jun 20.
Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin's acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively. In silico docking simulation also indicates that compound 4c tightly binds to the deep substrate-binding pocket of HDAC6 by coordinating the active zinc ion in a bidentate manner and forming hydrogen bond interactions with Ser531 and His573 amino acid residues. In particular, compound 4c (GI = 147 μM) affords the significant enhancement of anti-proliferative effect on MDA-MB-231 cells, compared with its parent compound 2c (GI > 1000 μM) and acetyl-donating group deficient compound 6 (GI = 554 μM). Overall, compound 4c presents a novel strategy for developing acetyl-donating HDAC inhibitors.
阿司匹林是治疗炎症、发热和疼痛的最古老药物之一。据报道，它通过乙酰化丝氨酸残基来共价修饰 COX-2 酶。凭借阿司匹林的乙酰化潜力，我们首次开发了新型乙酰供体 HDAC 抑制剂。在这项研究中，我们报告了乙酰供体 HDAC 抑制剂的设计、合成、计算机对接研究和生物学评价。化合物 4c 使 MDA-MB-231 细胞暴露，显著促进了 HDAC6 和 HDAC1 的底物 α-微管蛋白和组蛋白 H3 的乙酰化。计算机对接模拟还表明，化合物 4c 通过双齿配位方式与活性锌离子配位，并与 Ser531 和 His573 氨基酸残基形成氢键相互作用，紧密结合到 HDAC6 的深底物结合口袋中。特别是，与母体化合物 2c（GI > 1000 μM）和乙酰供体缺失的化合物 6（GI = 554 μM）相比，化合物 4c（GI = 147 μM）对 MDA-MB-231 细胞的增殖抑制作用显著增强。总的来说，化合物 4c 为开发乙酰供体 HDAC 抑制剂提供了一种新策略。
