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