Ricerc@Sapienza

So far, the design of human carbonic anhydrase (CA) inhibitors has been easily driven by the introduction of specific Zinc Binding Groups (ZBGs) (primary and secondary sulfonamides and their bioisosteres, dithiocarbamates, phosphonates, hydroxamic acids, and so on), which directly or indirectly block the enzyme-mediated catalytic CO2 hydration. All these inhibitors have been elegantly characterized by X-ray diffraction studies of hCA II-inhibitor adducts. The results led to the discovery of several drug candidates potent and selective for clinical purposes.

Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers.