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 (K_Is: 14.7–82.4 nM) and hCA XII (K_Is: 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.

GRAPHICAL ABSTRACT

Keywords:

• Ureidocoumarins
• carbonic anhydrase IX
• carbonic anhydrase XII
• SLC-0111
• anticancer activity

Additional information

Funding

This research was supported by the National Research Council of Science & Technology (NST) grant by the Korean Government (MSIT) (No. CAP-20-01-KRIBB), the Korea Research Fellowship Program grant through NRF funded by the Ministry of Science and ICT (2019H1D3A1A0107088214, A. K. El-Damasy), and the Institutional Program grant by the Korea Institute of Science and Technology (2E31512).