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.

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The synthesis of new purine derivatives designed to inhibit cell cycle regulating cyclin-dependent kinases (CDKs), is reported. These compounds, related to olomoucine and roscovitine, are characterised by the presence of a pyrrolidine methanol substituent at C-2 and a variety of ortho, meta and/or para substituents on the C-6 arylamino group.

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