Abstract
The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC(50) 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
MeSH terms
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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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Binding Sites
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cyclin A / antagonists & inhibitors
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Cyclin A / metabolism
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Cyclin D / antagonists & inhibitors
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Cyclin D / metabolism
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 2 / chemistry
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / metabolism
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Models, Molecular
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Neoplasms / drug therapy
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
Substances
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Antineoplastic Agents
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Cyclin A
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Cyclin D
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Enzyme Inhibitors
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Pyrimidines
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4