8-Azapurines as new inhibitors of cyclin-dependent kinases.
Purine inhibitors of cyclin-dependent kinases (CDK) seem to be a potential anticancer drug candidate as one of the first representatives, roscovitine, is passing Phase II clinical trials for cancer and glomerulonephritis. In this article, we describe a novel modification of the purine scaffold influencing CDK2 inhibitory activities as well as anticancer properties in cell lines of different histopathological origin. The introduced N at position 8 of the purine ring generally lowered CDK2 inhibitory activity of new 8-azapurines (1,2,3-triazolo[4,5-d]pyrimidines) in comparison to the model trisubstituted purines, whereas the antiproliferative potential of some derivatives remained very high, reflecting their ability to activate p53 tumor suppressor.
Isotope Laboratory, Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic.
Libor
L
Havlicek
Kveta
K
Fuksova
Vladimir
V
Krystof
Martin
M
Orsag
Borivoj
B
Vojtesek
Miroslav
M
Strnad
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011687:Purines; D016159:Tumor Suppressor Protein p53; C015008:triazolopyrimidinone; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases