期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 141, 期 -, 页码 538-551出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.027
关键词
Pyrrolo[2,3-b]pyridines; Pyrrolo[2,3-d]pyrimidines; Pyridazinone; c -Met; Antitumor activity; Docking study
资金
- National Natural Science Funds of China [21662014, 81460527]
- Outstanding Youth Foundation of Jiangxi
- Natural Science Foundation of Jiangxi, China [20171BCB23078, 20171ACB21052, 20171BAB215073, 20161BAB215216]
- Science and Technology Project [GJJ160787]
- Graduate Students' Science and Technology Innovation Project of Jiangxi Science & Technology Normal University [YC2016-X16]
In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 +/- 0.45 mu M,132 +/- 0.26 mu M, 6.27 +/- 1.04 mu M and 4.63 +/- 0.83 mu M. The structure activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3-b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF(3) on the aryl group show the best activity. (C) 2017 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据