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 Ferula tunetana, 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 (7a-g) was synthesized and tested against five CA isoforms (hCA I, II, IV, IX, XII). Coladonin 6 and its trifluoracetyl derivative 7e strongly and selectively inhibited hCA IX (Ki = 90 and 70 nM, respectively) and hCA XII (Ki = 210 and 110 nM, respectively). Compound 7e exhibited better selectivity on hCA IX than acetazolamide (AAZ). The antimelanoma and antiglioblastoma efficacy of coladonin 6 and 7e was evaluated in vitro under hypoxic conditions. Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor SLC-0111 currently in clinical phase IIb. These results highlight coladonin 6 as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors.