Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

D. Mariano A. Vera¹  E. Laura Moyano²  Ivana Malvacio³  Mattia Sturlese⁴  Alberto Cuzzolin⁴  Stefano Moro⁴ 

[1] Department of Chemistry, QUIAMM-INBIOTEC, School of Exact and Natural Sciences, National University of Mar del Plata, Mar del Plata, Buenos Aires, Argentin;Department of Organic Chemistry, INFIQC, School of Chemical Sciences, National University of Cordoba, Cordoba, Argentina;Department of Organic Chemistry, INFIQC, School of Chemical Sciences, National University of Cordoba, Cordoba, Argentina;Molecular Modeling Section (MMS), Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, via Marzolo, Padova, Italy;Molecular Modeling Section (MMS), Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, via Marzolo, Padova, Italy;

关键词: H;    serine-threonine checkpoint kinase 1 (Chk1);    molecular docking;    molecular dynamics (MD);    supervised molecular dynamics (SuMD);   

DOI  :  10.1080/14756366.2017.1404592

来源: publisher

【 摘 要 】

The serine-threonine checkpoint kinase 1 (Chk1) plays a critical role in the cell cycle arrest in response to DNA damage. In the last decade, Chk1 inhibitors have emerged as a novel therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic agents. In the search for new Chk1 inhibitors, a congeneric series of 2-aryl-2 H-pyrazolo[4,3-c]quinolin-3-one (PQ) was evaluated by in-vitro and in-silico approaches for the first time. A total of 30 PQ structures were synthesised in good to excellent yields using conventional or microwave heating, highlighting that 14 of them are new chemical entities. Noteworthy, in this preliminary study two compounds 4e2 and 4h2 have shown a modest but significant reduction in the basal activity of the Chk1 kinase. Starting from these preliminary results, we have designed the second generation of analogous in this class and further studies are in progress in our laboratories.

【 授权许可】

CC BY