Abstract
A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Anilides / chemical synthesis*
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Anilides / chemistry
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Anilides / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Inhibitory Concentration 50
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / chemistry
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Spectrometry, Fluorescence
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Structure-Activity Relationship
Substances
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Anilides
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Antineoplastic Agents
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N-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
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Protein Kinase Inhibitors
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Quinolines
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Proto-Oncogene Proteins c-met