Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors

Abstract

The synthesis of selective inhibitors of human carbonic anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targeted pathology, and this was partially addressed with the introduction of a sugar moiety (the so-called "sugar approach"). Since glycomimetics are considered more selective than the parent sugars in inhibiting carbohydrate-processing enzyme, we explored the possibility of further tuning the selectivity of hCAs inhibitors by combining the sulfonamide moiety with a sugar analogue residue. In particular, we report the synthesis of two novel hCAs inhibitors 2 and 3 which feature the presence of a piperidine iminosugar and an additional carbohydrate moiety derived from levoglucosenone (1), a key intermediate derived from cellulose pyrolysis. Biological assays revealed that iminosugar 2 is a very strong inhibitor of the central nervous system (CNS) abundantly expressed hCA VII (KI of 7.4 nM) and showed a remarkable selectivity profile toward this isoform. Interestingly, the presence of levoglucosenone in glycomimetic 3 imparted a strong inhibitory activity toward the tumor associated hCA IX (KI of 35.9 nM).