Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with organic phosphates and phosphonates

The interaction of five human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, that is, hCA I, II, IV, V, and IX with a small library of phosphonic acids/organic phosphates, including methylphosphonic acid, MPA; phenylphosphonic acid, PPA; N-(phosphonoacetyl)-l-aspartic acid, PALA, methylene diphosphonic acid MDPA, the O-phosphates of serine (Ser-OP) and threonine (Thr-OP) as well as the antiviral phosphonate foscarnet has been studied. hCA I was activated by all these compounds, with the best activators being MPA and PPA (KAs of 0.10–1.20 μM). MPA and PPA were on the other hand nanomolar inhibitors of hCA II (KIs of 98–99 nM). PALA showed an affinity of 7.8 μM, whereas the other compounds were weak, millimolar inhibitors of this isozyme. The best hCA IV inhibitors were PALA (79 nM) and PPA (5.4 μM), whereas the other compounds showed KIs in the range of 0.31–5.34 mM. The mitochondrial isozyme was weakly inhibited by all these compounds (KIs in the range of 0.09–41.7 mM), similarly to the transmembrane, tumor-associated isozyme (KIs in the range of 0.86–2.25 mM). Thus, phosphonates may lead to CA inhibitors with selectivity against two physiologically relevant isozymes, the cytosolic hCA II or the membrane-bound hCA IV.