Design, synthesis, and preliminary bioactivity evaluation of N¹-hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors

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• 作者：Xue Wang ; Xiaoyang Li ; Jingyao Li ; Jinning Hou ; Ying Qu ; Chenggong Yu ; Feng He ; Wenfang Xu and Jingde Wu
• 刊名：Chemical Biology & Drug Design
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：89
• 期：1
• 页码：38-46
• 全文大小：1716K
• ISSN：1747-0285

文摘

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N¹-hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC₅₀ = 0.074 μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC₅₀ = 0.131 μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.