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. (1st January 2018)

• Record Type: Journal Article
• Authors: Malvacio, Ivana; Cuzzolin, Alberto; Sturlese, Mattia; Vera, D. Mariano A.; Moyano, E. Laura; Moro, Stefano
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 33:Number 1(2018)
• Page Start: 171
• Page End: 183
• Publication Date: 2018-01-01
• Subjects: 2-Aryl-2H-pyrazolo[4, 3-c]quinolin-3-one (PQ) -- serine-threonine checkpoint kinase 1 (Chk1) -- molecular docking -- molecular dynamics (MD) -- supervised molecular dynamics (SuMD); Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2017.1404592
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 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 compounds4e2 and4h2 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.