Zhu Fugui, Meng Xiangguo, Liang Huixin, Sheng Chunquan, Dong Guoqiang, Liu Dan, Wu Shanchao
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People's Republic of China; Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
College of Pharmacy, Shanghai University of Medicine and Health Sciences, 279 Zhouzhugong Road, Shanghai 201318, People's Republic of China.
Bioorg Chem. 2022 May;122:105702. doi: 10.1016/j.bioorg.2022.105702. Epub 2022 Mar 6.
On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.
基于拓扑异构酶（Top）和组蛋白去乙酰化酶（HDAC）抑制剂之间的协同作用，设计并合成了一系列新型的基于吴茱萸碱的Top/HDAC双重抑制剂。系统的构效关系（SAR）研究发现了化合物29b和45b，它们同时抑制Top和HDAC，并对HCT116细胞系表现出强大的抗肿瘤活性。化合物29b和45b能有效诱导细胞凋亡并使细胞周期停滞于G2期，显著抑制HCT116细胞中的细胞HDAC，且具有良好的体外代谢稳定性。总的来说，这项工作为基于吴茱萸碱的Top/HDAC双重抑制剂提供了有价值的SAR信息和先导化合物。
