Details

Autor(en) / Beteiligte

• Legraverend, Michel
• Tunnah, Paul
• Noble, Martin
• Ducrot, Pierre
• Ludwig, Odile
• Grierson, David S
• Leost, Maryse
• Meijer, Laurent
• Endicott, Jane

Titel

Cyclin-Dependent Kinase Inhibition by New C-2 Alkynylated Purine Derivatives and Molecular Structure of a CDK2−Inhibitor Complex

Ist Teil von

• Journal of medicinal chemistry, 2000-04, Vol.43 (7), p.1282-1292

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2000

Quelle

MEDLINE

Beschreibungen/Notizen

• A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1−cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC50 of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.