title: Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Dong Chan
authors.initials: DC
authors.lastname: Kim
authors.forename: Yeo Ran
authors.initials: YR
authors.lastname: Lee
authors.forename: Beom-Seok
authors.initials: BS
authors.lastname: Yang
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Bong Young
authors.initials: BY
authors.lastname: Chung
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
mesh_terms: 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
chemical_list: 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