Synthesis and biological properties of C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives as cyclin-dependent kinase inhibitors. Part II.
In this study, C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives were synthesized and their inhibitory effects on cyclin-dependent kinases (CDK2, 4) as well as their cytotoxicities were evaluated. The effects of substituents at the C-2, C-8, and N-9 positions 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 0.3 microM, i.e. a two-fold increased inhibitory activity as compared to roscovitine. Results from structure-activity relationship studies should allow the design of more potent and selective CDK2 inhibitors, which may provide an effective therapy for cancer or other CDK-dependant diseases.
Oh
C H
CH
Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, Korea.
Kim
H K
HK
Lee
S C
SC
Oh
C
C
Yang
B S
BS
Rhee
H J
HJ
Cho
J H
JH
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011687:Purines; D018844:Cyclin-Dependent Kinases