Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1, 2, 3‐triazole moiety as c‐Met kinase inhibitors. (6th May 2018)

• Record Type: Journal Article
• Authors: Wang, Linxiao; Liu, Xiaobo; Duan, Yongli; Li, Xiaojing; Zhao, Bingbing; Wang, Caolin; Xiao, Zhen; Zheng, Pengwu; Tang, Qidong; Zhu, Wufu
• Is Part Of: Chemical biology & drug design. Volume 92:Number 1(2018)
• Page Start: 1301
• Page End: 1314
• Publication Date: 2018-05-06
• Subjects: 1, 2, 3‐triazole -- antitumor activity -- apoptosis and cell cycle -- c‐Met -- docking study -- pyrrolopyrimidine/pyrazolopyrimidine; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13192
• Languages: English
• ISSNs: 1747-0277

Abstract

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 compound16d 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, and20d ) were further evaluated for inhibitory activity against the c‐Met kinase, and the16d 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. Abstract : Six series of pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1, 2, 3‐triazole moiety were designed and synthesized. Most of compounds showed moderate to significant antitumor activity.16d can inhibit c‐Met kinase selectively and induce apoptosis of HepG2 cells and arrested the cell cycle in G2/M phase. Docking study was investigated to explore the binding modes of compounds with c‐Met.