Abstract
The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / chemistry
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Adenine / 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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Apoptosis
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CDC2 Protein Kinase / antagonists & inhibitors
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Cell Line, Tumor
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Computer Simulation
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacology
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Drug Screening Assays, Antitumor
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Humans
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Methylamines / chemical synthesis*
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Methylamines / chemistry
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Methylamines / pharmacology
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Models, Molecular
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Phosphorylation
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Purines / chemical synthesis*
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Purines / chemistry
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Purines / pharmacology
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Retinoblastoma Protein / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Cyclopentanes
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Methylamines
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N2-(4-aminocyclohexyl)-9-cyclopentyl-N6-(6-(2-hydroxyphenyl)pyridin-3-ylmethyl)-9H-purine-2,6-diamine
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Purines
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Retinoblastoma Protein
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CDC2 Protein Kinase
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Adenine