| Abstract
| - Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinaseshave a promising potential for applications against several neurodegenerative diseases suchas Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources,are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures ofvarious indirubins with GSK-3β, CDK2 and CDK5/p25, we have modeled the binding ofindirubins within the ATP-binding pocket of these kinases. This modeling approach providedsome insight into the molecular basis of indirubins' action and selectivity and allowed us toforecast some improvements of this family of bis-indoles as kinase inhibitors. Predictedmolecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized andevaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained byintroduction of a methyl substitution on N1.
|
