Carbonic anhydrase inhibitors. Inhibition of transmembrane isozymes XII (cancer-associated) and XIV with anions

Metal complexing anions represent an important class of inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The first inhibition study of the transmembrane isozymes CA XII (tumor-associated) and XIV with anions is reported. These isozymes showed inhibition profiles with physiologic/non-physiologic anions quite distinct from any other cytosolic (CA I and II) or transmembrane isoforms (e.g., CA IX) investigated earlier. hCA XII has a good affinity for fluoride and bicarbonate but is not inhibited by heavier halides, perchlorate, nitrate, and nitrite. The best hCA XII inhibitors were cyanide (K(I) of 1 microM) and azide (K(I) of 80 microM). hCA XIV was on the other hand weakly inhibited by fluoride and not at all inhibited by perchlorate, but showed good affinity for most other anions investigated here. Chloride and bicarbonate showed K(I)s in the range of 0.75-0.77 mM for this isoform. The best hCA XIV anion inhibitors were sulfate, phenylarsonic, and phenylboronic acid (K(I) in the range of 10-92 microM).