Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho 900000, Vietnam.
Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon 22212, Korea.
Molecules. 2022 Mar 28;27(7):2204. doi: 10.3390/molecules27072204.
Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC values of 3.4-37.8 µM. Compound with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound displayed an IC value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (-7.92 kcal/mol) of compound toward HDAC6. In addition, dock pose analysis also proved that compound might serve as a potent inhibitor of HDAC11.
在所有人类癌症中都发现了表观遗传改变，它们是癌症治疗的有希望的靶点。在这个意义上，组蛋白去乙酰化酶抑制剂（HDACIs）是一种有趣的抗癌药物，在癌细胞的表观遗传调控中发挥着重要作用。在这里，我们报告了 15 种具有喹唑啉酮核心结构的新型羟肟酸基组蛋白去乙酰化酶抑制剂。五种化合物表现出抗增殖活性，IC 值为 3.4-37.8 μM。带有 2-巯基喹唑啉酮帽部分的化合物 对 MCF-7 细胞表现出最高的抗增殖功效。对于 HDAC6 靶选择性研究，化合物 显示出 2.3 μM 的 IC 值，是 HDAC3、HDAC4、HDAC8 和 HDAC11 的 29.3 倍。Western blot 分析证明化合物 强烈抑制 HDAC6 的靶蛋白微管蛋白乙酰化。化合物 对 HDAC11 的抑制活性也强于对照药物 Belinostat。然后使用分子对接研究探索了化合物 对 HDAC 酶的作用机制。数据显示化合物 对 HDAC6 具有高结合亲和力（-7.92 kcal/mol）。此外，对接构象分析还证明化合物 可能是 HDAC11 的有效抑制剂。
