Carbonic anhydrase inhibitors. Identification of selective inhibitors of the human mitochondrial isozymes VA and VB over the cytosolic isozymes I and II from a natural product-based phenolic library

We have investigated the enzyme inhibition characteristics of a natural product (NP)-based phenolic library against a panel of human carbonic anhydrases (hCAs, EC 4.2.1.1) which included hCAs I and II (cytosolic) and hCA VA/VB (mitochondrial isoforms). Most of these compounds were weak, micromolar inhibitors of the two cytosolic hCAs (K(I)s > 10 mu M) but showed good hCA VA/VB inhibitory activity with inhibition constants in the range of 70-125 nM. The selectivity ratios for inhibiting the mitochondrial over the cytosolic isoforms for these phenol derivatives were in the range of 120-3800, making them the most isoform-selective compounds for inhibiting hCA VA/VB known to date. The CA VA/VB enzymes are involved in biosynthetic processes such as gluconeogenesis, lipogenesis and ureagenesis, and no pharmacological inhibitors with good selectivity are currently available. Thus the NP inhibitors identified during these studies are excellent leads for obtaining even more effective compounds that selectively target mitochondrial hCAs, and also have the potential to be used as tools for understanding the physiological processes that are regulated by the two mitochondrial CA isoforms. (C) 2009 Elsevier Ltd. All rights reserved.