Design and synthesis of formononetin-dithiocarbamate hybrids that inhibit growth and migration of PC-3 cells via MAPK/Wnt signaling pathways

• DOI: 10.1016/j.ejmech.2016.12.027
• Publication Date: 2016-12-14T13:01:45Z
• Authors: Dong-Jun Fu; Li Zhang; Jian Song; Ruo-Wang Mao; Ruo-Han Zhao; Ying-Chao Liu; Yu-Hui Hou; Jia-Huan Li; Jia-Jia Yang; Cheng-Yun Jin; Ping Li; Xiao-Lin Zi; Hong-Min Liu; Sai-Yang Zhang; Yan-Bing Zhang
• Keywords: Dithiocarbamate

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 (IC50 = 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.