Structure-based optimization of click-based histone deacetylase inhibitors

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• 作者：Jingli Hou ; Congran Feng ; Zhonghua Li ; Qinghong Fang ; Huihui Wang ; Guoxian Gu ; YikangShi ; Pi Liu ; Feng Xu ; Zheng Yin ; Jie Shen ; Peng Wang
• 关键词：Histone deacetylase inhibitor ; Click chemistry ; Hydroxamic acid ; Structure-based optimization
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：46
• 期：8
• 页码：3190-3200
• 全文大小：1385 K

文摘

Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC₅₀ value of 22 nM and 18 nM, respectively.