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 (HDAC1) 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 HCT116 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 HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

多目标药物发现中的一大挑战是要鉴定出比单一目标抑制剂和药物组合具有治疗优势的类药物先导化合物。受我们先前设计抗肿瘤依维他命衍生物的启发，本文成功鉴定了选择性组蛋白脱乙酰基酶1（HDAC1）和拓扑异构酶2（TOP2）双重抑制剂，显示出有效的体外和体内抗肿瘤潜能。特别是，化合物30a具有口服活性，并且在HCT116异种移植模型中具有出色的体内抗肿瘤活性（TGI = 75.2％，150 mg / kg，口服））没有明显的毒性，它比HDAC抑制剂伏立诺他，TOP抑制剂依维他明及其组合更有效。综上所述，这项研究突出了基于依夫二胺的HDAC1 / TOP2双重抑制剂的治疗优势，并为开发新型多靶点抗肿瘤药物提供了有价值的线索。