Abstract
Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11 and 12 had the highest potency and, compared to sunitinib, showed: (1) significant increase in anti-proliferation of various cancer cells with a favorable selective index (SI); (2) higher inhibitory potency against both VEGFR-2 and PDGFRβ. The molecular modeling results showed that, in terms of VEGFR-2 binding, the synthesized products had a similar binding mode to sunitinib but with tighter interaction.
Keywords:
(2-oxoindolin-3-ylidene)methylpyrrole; PDGFRβ inhibitor angiogenesis; VEGFR-2 inhibitor; multi-target kinase inhibitor.
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis*
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Angiogenesis Inhibitors / pharmacology
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Gene Expression
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HCT116 Cells
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Molecular Docking Simulation
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Secondary
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Pyrrolidinones / chemical synthesis*
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Pyrrolidinones / pharmacology
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Sunitinib
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Angiogenesis Inhibitors
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Indoles
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Protein Kinase Inhibitors
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Pyrroles
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Pyrrolidinones
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PDGFRB protein, human
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-2
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Sunitinib