Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers

• DOI: 10.1016/j.ejmech.2017.07.011
• Publication Date: 2017-07-08T20:47:41Z
• Authors: Dong-Jun Fu; Jian Song; Yu-Hui Hou; Ruo-Han Zhao; Jia-Huan Li; Ruo-Wang Mao; Jia-Jia Yang; Ping Li; Xiao-Lin Zi; Zhong-Hua Li; Qing-Qing Zhang; Fei-Yan Wang; Sai-Yang Zhang; Yan-Bing Zhang; Hong-Min Liu
• Keywords: Linker; Triazine; Structure–activity relationship; Triazole

A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine (11E) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers.