Fu Dong-Jun, Zhang Li, Song Jian, Mao Ruo-Wang, Zhao Ruo-Han, Liu Ying-Chao, Hou Yu-Hui, Li Jia-Huan, Yang Jia-Jia, Jin Cheng-Yun, Li Ping, Zi Xiao-Lin, Liu Hong-Min, Zhang Sai-Yang, Zhang Yan-Bing
School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA 92868, USA.
Eur J Med Chem. 2017 Feb 15;127:87-99. doi: 10.1016/j.ejmech.2016.12.027. Epub 2016 Dec 14.
A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.
设计、合成了一系列新型的芒柄花素 - 二硫代氨基甲酸盐衍生物,并对其针对三种选定癌细胞系(MGC - 803、EC - 109、PC - 3)的抗增殖活性进行了评估。本报告探讨了这种芒柄花素 - 二硫代氨基甲酸盐支架的首个构效关系(SAR),并评估了该结构类别的14种变体。在这些类似物中,4 - [((3 - [(3 - (4 - 甲氧基苯基)-4 - 氧代 - 4H - 色烯 - 7 - 基)氧基]丙基)硫代] - 碳硫酰基] - 哌嗪 - 1 - 羧酸叔丁酯(8i)对PC - 3细胞表现出最佳抑制活性(IC = 1.97 μM)。细胞机制研究表明,8i使细胞周期停滞在G1期,并以浓度依赖的方式调节G1检查点相关蛋白的表达。此外,8i可通过MAPK信号通路抑制PC - 3细胞的生长,并通过Wnt通路抑制其迁移。