Selective Inhibition of Carbonic Anhydrase IX and XII by Natural Coumarin Coladonin and Its Derivatives: Promising Antimelanoma and Antiglioblastoma Agents.

Coladonin, a natural sesquiterpene coumarin ether isolated from , along with seven ester derivatives were investigated as inhibitors of human carbonic anhydrases IX and XII (hCA IX/XII). A series of coladonin-derived analogues () was synthesized and tested against five CA isoforms (hCA I, II, IV, IX, XII). Coladonin and its trifluoracetyl derivative strongly and selectively inhibited hCA IX ( = 90 and 70 nM, respectively) and hCA XII ( = 210 and 110 nM, respectively). Compound exhibited better selectivity on hCA IX than acetazolamide (). The antimelanoma and antiglioblastoma efficacy of coladonin and was evaluated under hypoxic conditions. Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor currently in clinical phase IIb. These results highlight coladonin as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors.