期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 123, 期 -, 页码 80-89出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.06.056
关键词
4-Arylaminopyrimidine derivatives; Hydrazone moiety; Dual inhibitor; L1196M ALK; ROS1
资金
- Program for Liaoning Excellent Talents in University [LR2014030, 2013921042]
- National Natural Science Foundation of China [21002065]
A series of 4-arylaminopyrimidine derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against ALK-addicted KARPAS299 and ROS1-addicted HCC78, while also showing much less potent activity against A549, H460 and HT-29, whose growth were not dependent on ALK and/or ROS1, as compared with crizotinib and ceritinib. The most promising compound, 7b, showed high antiproliferative effects on ALK-addicted KARPAS299 and ROS1-addicted HCC78 cell lines with IC50 of 20 nM and 28 nM, respectively, but showed no inhibitory activity against A549, H460 and HT-29. The enzymatic assay identified 7b as a potent and selective ALK and ROS1 dual inhibitor with IC50 of 2.5 nM and 2.7 nM, respectively. It also exhibited good inhibitory activity against the L1196M ALK with an IC50 value of 67 nM. (C) 2016 Elsevier Masson SAS. All rights reserved.
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