Abstract
A novel series of 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives targeting VEGFR-2, PDGFR-β and c-Kit kinases were designed and synthesized. The molecular design was based on the SAR features of indolin-2-ones as kinase inhibitors. SAR study of the series allowed us to identify compounds possessing more potent inhibitory activities against the three kinases than sunitinb with IC50 values in the low nanomolar range in vitro. Additionally, some compounds also showed favorable antiproliferative activities against a panel of cancer cell lines (BXPC-3, T24, BGC, HEPG2 and HT29).
Keywords:
2-Dihydroindolinone derivatives; Antiproliferative; Inhibitor; Molecular docking; Receptor tyrosine kinase.
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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Apoptosis / drug effects
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Design*
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Drug Screening Assays, Antitumor
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HT29 Cells
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry*
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Indoles / toxicity
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Molecular Conformation
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Molecular Dynamics 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 / toxicity
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Proto-Oncogene Proteins c-kit / metabolism
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Indoles
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N-(2-(diethylamino)ethyl)-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene)-4,5,6,7-tetrahydro-1H-indole-3-carboxamide
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Protein Kinase Inhibitors
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indoline
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Proto-Oncogene Proteins c-kit
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-2