Abstract EN:

Cyclin-dependent kinases (CDKs) are involved in key molecular features of numerous diseases such as cancer, diabete, polycystic-kidneys desease, Alzheimer’s desease. . . In the first part of this thesis, new series of 2,6,9-trisubstitued purines, structurally related to the CDK inhibitor roscovitine, have been prepared. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Two series of compounds could be distinguished. Biarylamines derivatives (arylanilines) displayed potent inhibition of both CDKs and CK1. Several derivatives were inhibitors of CDK1/cyclin B (IC50: 200-300 nM), CDK5/p25 (IC50 < 100 nM) and CK1 (IC50: < 50 nM). The most active product was able to prevent the CK1-dependent production of amyloid-ß in a cell model. The second series of compounds are biarylmethylamines (arylbenzylamines). These derivatives displayed high antiproliferative activity on various cancer cells. In particular against HT-116 cell line and leukaemia cells. The mechanism of the apoptotic activity was elucidated: they activated caspases in a dose-dependent manner. In the second part of this thesis tools useful for the elucidation of the molecular targets of CDKs inhibitors have been prepared. A new chemical approach has been proposed for the preparation of purine conjugates suitable for affinity chromatography or labeled with a fluorescent dansyl group. In an affinity chromatography experiment, the over-expression of CDK5 could be observed in polycystic kidney cells