Wen Jiachen, Bao Yu, Niu Qun, Liu Jiang, Yang Jinyu, Wang Wanqiao, Jiang Tao, Fan Yinbo, Li Kun, Wang Jian, Zhao Linxiang, Liu Dan
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Bioorg Med Chem Lett. 2016 Sep 1;26(17):4372-6. doi: 10.1016/j.bmcl.2015.12.094. Epub 2015 Dec 29.
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, 5d and 5e showed 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 the para-position of benzene, interacting with Glu203 at the entrance to the active site tunnel.
在本研究中，以3-溴-4-羟基苯甲醛和乙内酰脲为原料，通过Knoevenagel缩合、水解、肟化和酰胺化四步反应，实现了沙马普林A的简洁合成方法，总收率为37%。合成了一系列以苯环上取代基变化和肟部分修饰为重点的新型沙马普林A类似物。在所有合成的化合物中，5d和5e对HDAC的抑制作用优于沙马普林A，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表明：（i）肟基的氢原子通过水桥氢键与HDAC1的Asp99相互作用；（ii）苯环对位上最佳连接一个羟基，与活性位点通道入口处的Glu203相互作用。
