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Novel arylazopyrazole inhibitors of cyclin-dependent kinases

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    0454915 - ÚEB 2016 RIV GB eng J - Journal Article
    Jorda, Radek - Schütznerová, E. - Cankař, P. - Brychtová, Veronika - Navrátilová, Jana - Kryštof, Vladimír
    Novel arylazopyrazole inhibitors of cyclin-dependent kinases.
    Bioorganic & Medicinal Chemistry. Roč. 23, č. 9 (2015), s. 1975-1981. ISSN 0968-0896
    R&D Projects: GA ČR GAP305/12/0783; GA ČR GA14-19590S; GA MŠk(CZ) LO1204
    Institutional support: RVO:61389030
    Keywords : Cyclin-dependent kinases * Inhibitor * Cell cycle
    Subject RIV: CE - Biochemistry
    Impact factor: 2.923, year: 2015

    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.
    Permanent Link: http://hdl.handle.net/11104/0255588
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