Abstract
A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
Keywords:
Anti-tumor; Kinase inhibitor; Quinoline; Semicarbazone; c-Met.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / toxicity
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Binding Sites
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Evaluation, Preclinical
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Drug Screening Assays, Antitumor
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HT29 Cells
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Humans
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Molecular Docking Simulation
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Phosphorylation / drug effects
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / toxicity
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / toxicity
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Semicarbazides / chemical synthesis*
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Semicarbazides / chemistry
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Semicarbazides / toxicity
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Semicarbazones / chemical synthesis
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Semicarbazones / chemistry*
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Semicarbazones / toxicity
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(2,4-difluorobenzylidene)semicarbazide
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Protein Kinase Inhibitors
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Quinolines
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Semicarbazides
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Semicarbazones
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Proto-Oncogene Proteins c-met