Abstract
A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1-cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC(50) of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.
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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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2-CDC28 Kinases*
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Crystallography, X-Ray
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Cyclin B / antagonists & inhibitors
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / chemistry
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Humans
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Models, Molecular
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Molecular Structure
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Purines / chemical synthesis
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Purines / chemistry*
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Roscovitine
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Structure-Activity Relationship
Substances
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1-(6-(3-chlorophenylamino)-9-isopropyl-9H-purin-2-yl)-3-methylpent-1-yn-3-ol
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1-(6-(4-chlorobenzylamino)-9-isopropyl-9H-purin-2-yl)-3-methylpent-1-yn-3-ol
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Cyclin B
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Enzyme Inhibitors
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Purines
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Roscovitine
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Adenine