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Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2022 Dec; Vol. 37 (1), pp. 531-541. - Publication Year :
- 2022
-
Abstract
- Different 2,4-thiazolidinedione-tethered coumarins 5a-b , 10a-n and 11a-d were synthesised and evaluated for their inhibitory action against the cancer-associated h CAs IX and XII, as well as the physiologically dominant h CAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins 10a , 10 h , and 2-thienyl/furyl-bearing coumarins 11a-c exhibited the best h CA IX (K <subscript>I</subscript> s between 0.48 and 0.93 µM) and h CA XII (K <subscript>I</subscript> s between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target h CA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins 10a , 10 h and 11a-c , were assessed in an in vitro antiproliferative assay, and then the most potent antiproliferative agent 11a was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.
- Subjects :
- Antigens, Neoplasm metabolism
Apoptosis drug effects
Carbonic Anhydrase IX metabolism
Carbonic Anhydrase Inhibitors chemical synthesis
Carbonic Anhydrase Inhibitors chemistry
Cell Cycle drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Coumarins chemical synthesis
Coumarins chemistry
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship
Thiazolidinediones chemical synthesis
Thiazolidinediones chemistry
Carbonic Anhydrase IX antagonists & inhibitors
Carbonic Anhydrase Inhibitors pharmacology
Carbonic Anhydrases metabolism
Coumarins pharmacology
Drug Discovery
Thiazolidinediones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 37
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34991416
- Full Text :
- https://doi.org/10.1080/14756366.2021.2024528