Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors.
A series of 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines 15-19, 30-38 capable of selectively inhibiting CDK2 activity were synthesized by derivatization at C-4, C-6 and N-1 with various amines and lower alkyl groups. For above synthetic compounds, biological evaluation was carried out and structure-activity relationship was examined. In our series, 4-anilino compounds exhibited better CDK2 inhibitory activity and antitumor activity compared to 4-benzyl compounds. The compounds 33a,b having a 3-fluoroaniline group at C-4 showed comparable or superior CDK2 inhibitory activity to those of olomoucine and roscovitine as reference compounds. In general, the unsubstituted compounds (30a,b, 33a,b, 36a,b) at N-1 possessed higher potency than the substituted compounds (32a,b, 34a,b) for the CDK2 inhibitory activity. As for EGFR inhibitory activity, most compounds didnot have a significant activity. The compounds 32a,b exhibited potent cell growth inhibitory activity against human cancer cell lines, but their CDK2 inhibitory activities were slightly poorer than olomoucine.
Kim
Dong Chan
DC
Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
Lee
Yeo Ran
YR
Yang
Beom-Seok
BS
Shin
Kye Jung
KJ
Kim
Dong Jin
DJ
Chung
Bong Young
BY
Yoo
Kyung Ho
KH
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D007701:Kinetin; D009682:Magnetic Resonance Spectroscopy; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077546:Roscovitine; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D000077546:Roscovitine; C090046:olomoucine; D066246:ErbB Receptors; D018844:Cyclin-Dependent Kinases; D007701:Kinetin