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Discovery of new 6-ureido/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII.

Ashraf K El-DamasyHyun Ji KimAlessio NocentiniSeon Hee SeoWagdy M EldehnaEun-Kyoung BangClaudiu T SupuranGyochang Keum
Published in: Journal of enzyme inhibition and medicinal chemistry (2023)
A series of 6-ureido/amidocoumarins ( 5a-p and 7a-c ) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase h CA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against h CA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms h CA IX ( K I s: 14.7-82.4 nM) and h CA XII ( K I s: 5.9-95.1 nM), whereas the cytosolic off-target h CA I and II isoforms have not inhibited by all tested coumarins up to 100 μM. These findings granted the target coumarins an excellent selectivity profile towards both h CA IX and h CA XII isoforms, supporting their development as promising anticancer candidates. Moreover, all target molecules were evaluated for their anticancer activities against HCT-116 and MCF-7 cancer cells. The 3,5-bis-trifluoromethylphenyl ureidocoumarin 5i , exerted the best anticancer activity. Overall, ureidocoumarins, particularly compound 5i, could serve as a promising prototype for the development of potent anticancer CAIs.
Keyphrases
  • protein kinase
  • photodynamic therapy
  • cell death
  • breast cancer cells