Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

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外文摘要：A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1 (HDACl) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT 116 xenograft model (TGI =75.2％,150 mg/kg,p.o.) without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC 1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

外文关键词：

EvodiamineHistone deacetylaseTopoisomeraseDual inhibitorsAntitumor activity

作者：

Yahui Huang、Shuqiang Chen、Shanchao Wu、Guoqiang Dong、Chunquan Sheng

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作者单位：

Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433,China

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key R&D Program of Chinaand the Innovation Program of Shanghai Municipal Education Commis

项目编号：

grants 81872742 to Guoqiang Dong81725020 to Chunquan Shenggrant 2017YFA0506000 to Chunquan Sheng

出版年：

2020

药学学报(英文版)

CSTPCDCSCDSCI

ISSN：

年,卷(期)：2020.10(7)

被引量4
参考文献量1