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 (K I 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 (K I of 35.9 nM).
Highlights
The synthesis of selective inhibitors of human carbonic anhydrases 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 human (h) expressed carbonic anhydrases (CAs, EC 4.2.1.1) are zinc(II) metalloenzymes that catalyze the reversible hydration of carbon dioxide (CO2) to hydrogen carbonate (HCO3−) and protons (H+).[1]
One promising strategy that has emerged in recent years to differentiate transmembrane from the physiologically dominant cytosolic isozymes human carbonic anhydrases (hCAs) I and II is to design inhibitors with polar or charged tails, impairing their ability to diffuse through lipid membranes.[8]
Summary
AAcetazolamide (AAZ) was used as reference inhibitor. bMean from three different assays, by a stopped flow technique (errors were in the range of ±5−10% of the reported values). BMean from three different assays, by a stopped flow technique (errors were in the range of ±5−10% of the reported values) Such a low inhibition value for the central nervous system (CNS) abundantly expressed hCA VII makes compound 2 highly valuable for further explorations within the Medicinal Chemistry field such as for neuropathic pain.[27,28] the iminosugar derivative 2 resulted in being a very high nanomolar inhibitor of the tumor associated hCAs IX and XII, it is worth noting that a good isoform selectivity was obtained. The kinetic inhibition profile of compound 3 for the tumor associated hCAs IX and XII was shown to be inverted when compared to 2.
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