Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents
Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents
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psammaplin A 及其类似物作为有效组蛋白脱乙酰酶抑制剂和细胞毒剂的合成、生物学评价和分子模型研究
DOI：
10.1016/j.bmcl.2015.12.094
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Liu Dan
中科院分区：
文献类型：
--
作者：
Wen Jiachen;Bao Yu;Niu Qun;Liu Jiang;Yang Jinyu;Wang Wanqiao;Jiang Tao;Fan Yinbo;Li Kun;Wang Jian;Zhao Linxiang;Liu Dan
以3-溴-4-羟基苯甲醛和海因为原料，经Knoevenagel缩合、水解、肟化和酰胺化四步反应合成了沙马普利A，总收率37%。合成了一系列新的Psammaplin A类似物，重点是苯环上取代基的变化和肟部分的修饰。在所有合成的化合物中，化合物5d和5显示出比psammaplin A更好的HDAC抑制作用，并且对四种癌细胞系（PC-3，MCF-7，A549和HL-60）具有相当的细胞毒性。分子对接和动力学模拟结果表明：（i）肟基上的氢原子通过水桥氢键与HDAC 1的Asp 99相互作用;（ii）羟基最佳连接在苯的对位，与活性中心隧道入口处的Glu 203相互作用。
In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds,5dand5eshowed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on thepara-position of benzene, interacting with Glu203 at the entrance to the active site tunnel.