Novel arylazopyrazole inhibitors of cyclin-dependent kinases. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Jorda, Radek; Schütznerová, Eva; Cankař, Petr; Brychtová, Veronika; Navrátilová, Jana; Kryštof, Vladimír
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 9(2015)
• Page Start: 1975
• Page End: 1981
• Publication Date: 2015-05-01
• Subjects: HUHDSOITAVSODF-BUHFOSPRSA-N -- SIRSCBHJSFPOKE-BUHFOSPRSA-N -- ZUYBNBWNFRTAHF-VAWYXSNFSA-N -- RZLCSJZALMLKCU-OUKQBFOZSA-N -- FYUJZFIJRVUPND-VAWYXSNFSA-N -- PCXUEKLZJHRQPT-UHFFFAOYSA-N -- IYZXPGINIXJBBP-UHFFFAOYSA-N -- HUJNIHKUVFHKLH-UHFFFAOYSA-N; CDK cyclin-dependent kinase; Cyclin-dependent kinases -- Inhibitor -- Cell cycle -- Selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.025
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Here, we describe new 4-arylazo-3, 5-diamino-1 H -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 compoundIVc was studied on MCF-7 cells synchronized by various methods and compared with other selective CDK inhibitors. The results demonstrated thatIVc shows a preference for CDK4 and CDK1. In contrast to cytostatic effects induced byIVc 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.