Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides—a new target for the design of antitumor and antiglaucoma drugs?

The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme XII (hCA XII), has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and sulpiride, or indisulam, a compound in clinical development as antitumor drug), as well as the sulfamate antiepileptic drug topiramate. Some simple amino-/hydrazine-/hydroxy-substituted aromatic/heterocyclic sulfonamides have also been included in the study. All types of activity have been detected, with several medium potency inhibitors (KIs in the range of 34–220 nM), whereas ethoxzolamide and several halogenated sulfanilamides showed stronger potency, with KIs in the range of 11–22 nM. The antiglaucoma sulfonamides used clinically, except dichlorophenamide, which is a moderate inhibitor (KI of 50 nM), as well as topiramate, indisulam, and sulpiride behave as very potent hCA XII inhibitors, with KIs in the range of 3.0–5.7 nM. Several subnanomolar inhibitors (KIs in the range of 0.30–0.85 nM) have also been detected. Compounds with excellent selectivity against hCA XII over hCA II have been found, showing selectivity ratios in the range of 177.7–566.7. Apparently, hCA XII is a target of the antiglaucoma sulfonamides, and potent hCA XII inhibitors may be developed/used for the management of hypoxic tumors, together with inhibitors of the other tumor-associated isozyme, CA IX.