- Practical synthesis of roscovitine and CR8
-
Roscovitine and CR8 are potent inhibitors of cyclin-dependent kinases. A scalable synthesis of both inhibitors is described. In the case of CR8, the biarylmethylamine moiety was obtained as a stable and high-purity salt.
- Oumata, Nassima,Ferandin, Yoan,Meijer, Laurent,Galons, Herve
-
experimental part
p. 641 - 644
(2010/04/22)
-
- Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1
-
Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-β peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1δ provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-β in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.
- Oumata, Nassima,Bettayeb, Karima,Ferandin, Yoan,Demange, Luc,Lopez-Giral, Angela,Goddard, Marie-Lorène,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Flajolet, Marc,Greengard, Paul,Meijer, Laurent,Galons, Hervé
-
experimental part
p. 5229 - 5242
(2009/07/01)
-
