Design, synthesis, and preliminary bioactivity evaluation of N1‐hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors. (26th October 2016)

• Record Type: Journal Article
• Authors: Wang, Xue; Li, Xiaoyang; Li, Jingyao; Hou, Jinning; Qu, Ying; Yu, Chenggong; He, Feng; Xu, Wenfang; Wu, Jingde
• Is Part Of: Chemical biology & drug design. Volume 89:Number 1(2017)
• Page Start: 38
• Page End: 46
• Publication Date: 2016-10-26
• Subjects: antiproliferative activity -- HDACIs -- molecular docking -- selectivity; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12819
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : 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 N 1 ‐hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound12m was identified to be the most potent one (IC50 = 0.074 μ m against HeLa nuclear extract) and showed higher inhibitory activity than the positive controlSAHA (IC50 = 0.131 μ m ), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited12m 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 toSAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs. Abstract : A series of N 1 ‐hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized as novel histone deacetylase inhibitors. Among them, compound12m was identified to be the most potent one (IC50 = 0.074 μ m against Hela nuclear extract) superior to the positive controlSAHA, while presented less potent in vitro antiproliferative assay.