2. Academic Validation
  3. Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue

Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue

  • J Med Chem. 2009 Feb 12;52(3):655-63. doi: 10.1021/jm801340z.
Florence Popowycz 1,  Guy Fournet,  Cédric Schneider,  Karima Bettayeb,  Yoan Ferandin,  Cyrile Lamigeon,  Oscar M Tirado,  Silvia Mateo-Lozano,  Vicente Notario,  Pierre Colas,  Philippe Bernard,  Laurent Meijer,  Benoît Joseph
Affiliations

Affiliation

  • 1 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.
PMID: 19128055 DOI: 10.1021/jm801340z
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.

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