Design, synthesis, and biological evaluation of selective hCA IX inhibitors

Carbonic Anhydrases (CAs; EC 4.2.1.1) are well-known zinc metalloproteins involved in the catalysis of a very simple but essential physiological reaction: carbon dioxide hydration to bicarbonate and proton. These enzymes are of clinical relevance in cancer therapy and among the 15 isoforms known in humans, CA IX, almost exclusively overexpressed in hypoxic tumors, is involved with CA XII in tumorigenesis. Inhibition of the tumor associated isoform IX is now considered as a pertinent approach for the development of new therapies against hypoxic tumors. Different efforts and new families of pharmacological agents were developed that specifically target CA IX over the ubiquitous cytosolic off-target isoforms CA I and CA II. The aim of this chapter is to give a comprehensive update on the reported discoveries in the field of CA IX inhibitors with an emphasis on the new families of compounds, which reach in vivo/preclinical studies for their potential in cancer therapy.