Synthesis and Biological Properties of C-2, C-8, N-9 Substituted 6-(3-Chloroanilino)-purine Derivatives as Cyclin-Dependent Kinase Inhibitors, Part 2

Abstract

In this study, C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives were syn-thesized and their inhibitory effects on cyclin-dependent kinases (CDK2, 4) as well astheir cytotoxicities were evaluated. The effects of substituents at the C-2, C-8, and N-9positions of the substituted purine were investigated. Among the compounds tested,[6-(3-chloroanilino)-2-(2-hydroxymethyl-4-hydroxypyrrolidyl)-9-isopropylpurine] (4h)was the most active inhibitor of CDK2 with IC50 of 0.3µM, i.e. a two-fold increasedinhibitory activity as compared to roscovitine. Results from structure-activity relationshipstudies should allow the design of more potent and selective CDK2 inhibitors, which mayprovide an effective therapy for cancer or other CDK-dependent diseases.