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

• 作 者: Yahui Huang Shuqiang Chen Shanchao Wu Guoqiang Dong Chunquan Sheng
• 机 构: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai
• 出 处: 药学学报（英文版）
• 发表日期: 2020年7期
• 关键词: Evodiamine Histone deacetylase Topoisomerase Dual inhibitors Antitumor activity

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.