Development of a novel class of selective human carbonic anhydrase IX inhibitors containing a trifluorohydroxy propanone pharmacophore

Carbonic anhydrases (CAs) are emerging as potential biological targets for cancer therapy. In particular, hCA IX isoform has been found to be expressed in a wide variety of malignancies and appear to be tightly regulated by micro-environmental hypoxia. Primary sulfonamides, the most clinically used CAs inhibitors (CAIs), have been shown to reverse the effect of the extracellular CAs and inhibit the growth of cancer cell. However, one main drawback of these classical CAIs is the lack of selectivity for inhibiting transmembrane CAs over the other cytoplasmic CA isoforms. In this scenario, efforts are being initiated to find novel and selective CAIs, in order to explore molecular diversities and discover original pharmacophores and chemotypes. In this work, we report the synthesis, biological evaluation, x-ray structural and computational studies of a series of aromatic substituted trifluorohydroxypropanone derivatives on different CA isoforms. Almost all the tested compounds selectively inhibited hCA IX, with Ki values ranging in submicromolar / high nanomolar range. Moreover, both x-ray crystallography data (from CAII and CAIX mimic structures in complex with an inhibitor) and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. These insights provide structural determinants for the development of novel anticancer agents with original mechanism of action.