School of Biological Science and Technology, University of Jinan, Jinan, Shandong Province 250022, China.
Institute for Translation Medicine, Qingdao University, Qingdao, Shandong Province 266071, China.
Bioorg Med Chem Lett. 2019 Jan 1;29(1):15-21. doi: 10.1016/j.bmcl.2018.11.027. Epub 2018 Nov 14.
Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.
组蛋白去乙酰化酶（HDACs）已被证明是开发抗肿瘤药物的有前途的靶标。在这项研究中，我们报告了一类新型基于羟肟酸的双取代芳香酰胺 HDAC 抑制剂的设计和合成，其核心为 1,2,4-噁二唑。大多数新合成的化合物对 HDAC1 表现出优异的抑制作用和显著的抗增殖活性。其中，化合物 11a 和 11c 以剂量依赖性方式增加组蛋白 H3 和 H4 的乙酰化。此外，11a 和 11c 显著诱导 HepG2 癌细胞凋亡。最后，通过分子对接研究合理说明了化合物 11a 的高效能。
