Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents

作者：Wang, Linxiao; Xu, Shan; Liu, Xiaobo; Chen, Xiuying; Xiong, Hehua; Hou, Shanshan; Zou, Wensheng; Tang, Qidong; Zheng, Pengwu^*; Zhu, Wufu^*

来源：Bioorganic Chemistry, 2018, 77: 370-380.

DOI：10.1016/j.bioorg.2018.01.037

• N-methylpicolinamide
• Thienopyrimidine
• Triazole
• c-Met
• Antitumor activity
• Docking study
• Apoptosis

Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21-26, 27-34, 35-41, 42-47 and 48-54) were designed and synthesized. And all the target compounds were evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno[3,2-d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7-5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC50 values of 0.9 +/- 0. 1 mu M, 0.5 +/- 0.1 mu M and 1.1 +/- 0.2 mu M, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM). What's more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner.

• 出版日期2018-4
• 单位江西科技师范大学; 郑州大学