Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue.
Pharmacological inhibitors of cyclin-dependent kinases (CDKs) have a wide therapeutic potential. Among the CDK inhibitors currently under clinical trials, the 2,6,9-trisubstituted purine (R)-roscovitine displays rather high selectivity, low toxicity, and promising antitumor activity. In an effort to improve this structure, we synthesized several bioisosteres of roscovitine. Surprisingly, one of them, pyrazolo[1,5-a]-1,3,5-triazine 7a (N-&-N1, GP0210), displayed significantly higher potency, compared to (R)-roscovitine and imidazo[2,1-f]-1,2,4-triazine 13 (N-&-N2, GP0212), at inhibiting various CDKs and at inducing cell death in a wide variety of human tumor cell lines. This approach may thus provide second generation analogues with enhanced biomedical potential.
Popowycz
Florence
F
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, UMR-CNRS 5246, Laboratoire de Chimie Organique 1, Universite de Lyon, Universite Claude Bernard-Lyon 1, Batiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
Fournet
Guy
G
Schneider
Cédric
C
Bettayeb
Karima
K
Ferandin
Yoan
Y
Lamigeon
Cyrile
C
Tirado
Oscar M
OM
Mateo-Lozano
Silvia
S
Notario
Vicente
V
Colas
Pierre
P
Bernard
Philippe
P
Meijer
Laurent
L
Joseph
Benoît
B
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D000077546:Roscovitine; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology
D011687:Purines; D011720:Pyrazoles; D014227:Triazines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases