title: Novel arylazopyrazole inhibitors of cyclin-dependent kinases.
abstract: 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.
authors.affiliation: Laboratory of Growth Regulators & 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.
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Schütznerová
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Cankař
authors.affiliation: Laboratory of Growth Regulators & 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.
authors.forename: Veronika
authors.initials: V
authors.lastname: Brychtová
authors.affiliation: Laboratory of Growth Regulators & 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.
authors.forename: Jana
authors.initials: J
authors.lastname: Navrátilová
authors.affiliation: Laboratory of Growth Regulators & 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. Electronic address: vladimir.krystof@upol.cz.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D018844:Cyclin-Dependent Kinases
keywords: Cell cycle; Cyclin-dependent kinases; Inhibitor; Selectivity