期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 3, 页码 886-896出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.12.002
关键词
c-Met; Antitumor activity; Synthesis; Molecular docking; 6,7-Disubstituted-4-(2-fluorophenoxy); quinolines
资金
- National Natural Science Foundation of China [81573295]
- Program for Liaoning Excellent Talents in University [LR2014030]
- Project of Education Department of Liaoning [L2013382]
- Development Project of Ministry of Education Innovation Team [IRT1073]
Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC50 = 1.1 nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC50 values of 0.08, 0.22 and 0.07 M, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole4-carboxamido as a linker was of great importance for the antitumor activity. (C) 2016 Elsevier Ltd. All rights reserved.
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