Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors

Abstract

Six series of pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety were designed and synthesized, and some bio-evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC₅₀ values in single-digit μm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF-7 cell lines, with the IC₅₀ values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μm, respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3-d]pyrimidine derivatives bearing 1,2,3-triazole moiety was superior to the pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety. Thirdly, three selected compounds (16d, 18d, and 20d) were further evaluated for inhibitory activity against the c-Met kinase, and the 16d could inhibit the c-Met kinase selectively by experiments of enzyme-based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.

Keywords: 1,2,3-triazole; antitumor activity; apoptosis and cell cycle; c-Met; docking study; pyrrolopyrimidine/pyrazolopyrimidine.