Here, we describe new 4-arylazo-3,5-diamino-1H-pyrazole derivatives developed from CAN508, one of the first inhibitors to show preference for transcriptional regulator cyclin-dependent kinase 9. By substituting nitrogen in the pyrazole ring and employing a heteroatom in the 4-aryl ring, we obtained more potent derivatives differing in their CDK-selectivity profiles. The antiproliferative and anti-CDK kinase activities of the novel arylazopyrazoles were examined. The cellular effect of compound IVc was studied on MCF-7 cells synchronized by various methods and compared with other selective CDK inhibitors. The results demonstrated that IVc shows a preference for CDK4 and CDK1. In contrast to cytostatic effects induced by IVc in MCF-7 and K562 cells, we observed apoptotic activities in the RPMI-8226 cell line, which were confirmed by detecting active caspases by different biochemical assays.

Department of Organic Chemistry Faculty of Science Palacký University 17 listopadu 12 771 46 Olomouc Czech Republic

Laboratory of Growth Regulators and Department of Chemical Biology and Genetics Centre of the Region Haná for Biotechnological and Agricultural Research Palacký University and Institute of Experimental Botany AS CR Šlechtitelů 27 783 71 Olomouc Czech Republic

Laboratory of Growth Regulators and Department of Chemical Biology and Genetics Centre of the Region Haná for Biotechnological and Agricultural Research Palacký University and Institute of Experimental Botany AS CR Šlechtitelů 27 783 71 Olomouc Czech Republic; Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Žlutý kopec 7 656 53 Brno Czech Republic

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Modification of Boc-Protected CAN508 via Acylation and Suzuki-Miyaura Coupling