Di-meta-Substituted Fluorinated Benzenesulfonamides as Potent and Selective Anticancer Inhibitors of Carbonic Anhydrase IX and XII.

The development of selective drug candidate molecules for cancer-related carbonic anhydrase isozymes IX and XII is challenging due to high homology binding sites among 12 catalytically active isozymes. Starting from the trifluorinated benzenesulfonamide with cyclooctylamino substituent at the meta position, we designed and synthesized di-meta-substituted fluorinated benzenesulfonamides with up to 10-fold affinity improvement for CAIX, resulting in low picomolar binders. The resulting CAIX-targeting compounds showed up to 1000-fold selectivity over off-target CA isozymes. The crystal structures of CAIX and CAXII complexes with synthesized compounds revealed detailed insights into protein-ligand interactions and adopted complex conformation. The potential of compounds with reduced off-target effects as possible anticancer drugs is supported by this study.