Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China.
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1918-1927. doi: 10.1080/14756366.2022.2097446.
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound exhibited class I selectivity with IC values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC value of >1000 µM), respectively. In the antiproliferative assay, compound showed both hematological and solid cancer inhibitory activities. In the flow cytometry, promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells.
组蛋白去乙酰化酶（HDACs）是表观遗传学中抗癌药物开发的有效靶点。在发现具有抗癌活性的新型 HDAC 抑制剂的过程中，5-氯-4-((取代苯基)氨基)嘧啶片段被组装成 HDAC 抑制剂的结构中的帽基团。SAR 表明，小基团（如甲氧基取代）的存在有利于 HDAC 抑制活性。在酶抑制选择性测试中，化合物 对 HDAC1、HDAC2 和 HDAC3 的抑制活性的 IC 值分别为 0.684 μM（选择性指数 >1462）、2.548 μM（选择性指数 >392）和 0.217 μM（选择性指数 >4608），而对 HDAC6 的抑制活性（IC 值>1000 μM）。在增殖抑制测定中，化合物 表现出血液学和实体癌抑制活性。在流式细胞术分析中， 促进 K562 细胞的 G0/G1 期细胞周期停滞和凋亡。
