Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IX with triazole-linked O-glycosides of benzene sulfonamides

Abstract

We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8–53 nM and 9.7–107 nM, respectively was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM), this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.