CYTOKININ-DERIVED CYCLIN-DEPENDENT KINASE INHIBITORS - SYNTHESIS AND CDC2 INHIBITORY ACTIVITY OF OLOMOUCINE AND RELATED-COMPOUNDS

Cyclin-dependent kinases (cdk) have recently raised considerable inter est in view of their essential role in the regulation of the cell divi sion cycle. The structure-activity relationships of cdk inhibition sho wed that the 1, 3, and 7 positions of the purine ring must remain free , probably for a direct interaction, in which it behaves as a hydrogen bond acceptor. Olomoucine ylamino)-2-[(2-hydroxyethyl)amino]-9-methyl purine, OC), roscovitine 1-(hydroxymethyl)propyl]amino]-9-isopropylpur ine), and other N-6,2,9-trisubstituted adenines were found to exert a strong inhibitory effect on the p34(cdc2)/cyclin B kinase. Removal or change of the side chain at position 2 or the hydrophobic group at pos ition 9 dramatically decreased the inhibitory activity of olomoucine o r roscovitine. Inhibition of cdk with OC and related compounds clearly arrests cell proliferation of many tumor cell lines at G(1)/S and G(2 )/M transitions and also triggers apoptosis in the target tumor cells in vitro and in vivo. Thus, from a pharmacological point of view, OC m ay represent a model compound for a new class of antimitotic and antit umor drugs.