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Cyclin-Dependent Kinase Inhibition by New C-2 Alkynylated Purine Derivatives and Molecular Structure of a CDK2−Inhibitor Complex
Ist Teil von
Journal of medicinal chemistry, 2000-04, Vol.43 (7), p.1282-1292
Ort / Verlag
Washington, DC: American Chemical Society
Erscheinungsjahr
2000
Quelle
MEDLINE
Beschreibungen/Notizen
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 IC50 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.