Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

Automated summary

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for targeting cancer. CA isoforms IX and XII are overexpressed in human solid tumors and play a critical role in regulating tumor acidification, proliferation, and progression. Novel sulfonamides based on the coumarin scaffold were designed and synthesized as potent and selective CA inhibitors, with some compounds showing high inhibition activity against tumor-associated CA IX and CA XII.