title: Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue.
abstract: 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.
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Popowycz
authors.forename: Guy
authors.initials: G
authors.lastname: Fournet
authors.forename: Cédric
authors.initials: C
authors.lastname: Schneider
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Cyrile
authors.initials: C
authors.lastname: Lamigeon
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
authors.forename: Silvia
authors.initials: S
authors.lastname: Mateo-Lozano
authors.forename: Vicente
authors.initials: V
authors.lastname: Notario
authors.forename: Pierre
authors.initials: P
authors.lastname: Colas
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
mesh_terms: 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
chemical_list: D011687:Purines; D011720:Pyrazoles; D014227:Triazines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases