9 Summary

The thesis presented here is introduced by an overview on the available data concerning cyclin-dependent kinases (cdks) and their functions in cell cycle regulation. In this context the relevance of disorders in the cdk-system for pathogenesis is discussed, and the various cdk-inhibitor classes known to date are summarised.

Preparative studies were performed to investigate structure activity relationships of the paullone class of cdk-inhibitors, yielding derivatives with modified heterocyclic scaffolds. The new compounds are characterised by a thienoazepine substructure (109) or a pyridoazepine substructure (110 und 111).

Furthermore derivatives of the most interesting paullone, Alsterpaullone (3), were synthesised. The variations include modifications of the lactam structure (154, 156) and of the substitution pattern (160). The new compound 184 was synthesised as a result of preparative studies with trifluoromethyl substituted paullones with side chains in position 2.

None of the new derivatives showed an increased inhibitory activity on cdk or on the growth of tumor cells compared to Alsterpaullone.* Compound 111a represents a new paullone with a remarkable selectivity for the inhibition of glycogen synthase kinase 3β.
Molecular modelling studies indicate that differences in the electron density of the heterocyclic systems are responsible for the decreased cdk inhibitory activity of the pyrido derivatives 110 and 111 compared to the benzo- and the thienoanellated derivatives.

* The results of the biological testing for compound 160 are not available, yet.