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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.

ABSTRACT: A series of 6-ureido/amidocoumarins (5a-p and 7a-c) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase hCA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against hCA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms hCA IX (KIs: 14.7-82.4 nM) and hCA XII (KIs: 5.9-95.1 nM), whereas the cytosolic off-target hCA 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 hCA IX and hCA 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.

SUBMITTER: El-Damasy AK 

PROVIDER: S-EPMC9897768 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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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.

El-Damasy Ashraf K AK   Kim Hyun Ji HJ   Nocentini Alessio A   Seo Seon Hee SH   Eldehna Wagdy M WM   Bang Eun-Kyoung EK   Supuran Claudiu T CT   Keum Gyochang G  

Journal of enzyme inhibition and medicinal chemistry 20231201 1

A series of 6-ureido/amidocoumarins (<b>5a-p</b> and <b>7a-c</b>) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase <i>h</i>CA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against <i>h</i>CA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms <i>h</i>CA IX (<i>K</i><sub>I</sub>s: 14.7-82.4 nM) and <i>h</i>CA XII (<i>K</i><sub>I</sub>s: 5.9-95.1 nM), wher  ...[more]

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