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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.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2017 Dec; Vol. 33 (1), pp. 171-183. - Publication Year :
- 2017
-
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 compounds 4e <subscript>2</subscript> and 4h <subscript>2</subscript> 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.
- Subjects :
- Checkpoint Kinase 1 metabolism
Dose-Response Relationship, Drug
Humans
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyrazoles chemical synthesis
Pyrazoles chemistry
Quinolines chemical synthesis
Quinolines chemistry
Structure-Activity Relationship
Checkpoint Kinase 1 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Quinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 33
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29210298
- Full Text :
- https://doi.org/10.1080/14756366.2017.1404592