With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition data of 52 paullone entities, which were aligned by a docking routine into the ATP-binding cleft of a CDK1/cyclin B homology model. Variation of grid spacing and column filtering were used during the optimization of the models. The predictive ability of the models was shown by a leave-one-out cross-validation and the prediction of an independent set of test compounds, which were synthesized especially for this purpose. Besides paullones with the basic indolo[3,2-d][1]benzazepine core, the test set comprised novel thieno[3',2':2,3]azepino[4,5-b]indoles, pyrido[2',3':2,3]azepino[4,5-b]indoles, and a pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepine. The best statistical values for the CoMSIA were obtained for the CDK1-models (r(2)() = 0.929 and q(2)() = 0.699), which were clearly superior to the models for CDK5 (r(2)() = 0.874 and q(2)() = 0.652) and GSK-3 (r(2)() = 0.871 and q(2)() = 0.554).

Epoxide moieties are incorporated into the scaffold of kenpaullone and 9-trifluoromethylpaullone by Stille coupling to introduce the unsaturated side chains, followed by epoxidation of the C,C-double bonds using a peroxide/nitrile mixture. The growth-inhibitory properties of paullones (IV), (VI), (IX) and (XV) are compared with the results for kenpaullone. All novel derivatives reveal a stronger general antiproliferative activity. -(XIE, X.; LEMCKE, T.; GUSSIO, R.; ZAHAREVITZ, D. W.; LEOST, M.; MEIJER, L.; KUNICK*, C.; Eur. J. Med. Chem. 40 (2005) 7, 655-661; Inst. Pharm.

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