Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibition
• Carbohydrate Chemistry

Background:

• Selective inhibition of human carbonic anhydrases (hCAs) is crucial for minimizing side effects.
• The
• sugar approach
• using sugar moieties has improved hCA inhibitor selectivity.
• Glycomimetics offer enhanced selectivity over parent sugars for enzyme inhibition.

Purpose of the Study:

• To synthesize novel hCA inhibitors by combining sulfonamide moieties with sugar analogues.
• To investigate the potential of piperidine iminosugars and levoglucosenone derivatives for selective hCA inhibition.

Main Methods:

• Synthesis of novel hCA inhibitors 2 and 3, incorporating piperidine iminosugar and levoglucosenone-derived moieties.
• Biological assays to evaluate inhibitory activity and selectivity against various hCA isoforms.

Main Results:

• Iminosugar 2 demonstrated potent inhibition of hCA VII (K_I = 7.4 nM), a highly expressed isoform in the central nervous system, with remarkable selectivity.
• Levoglucosenone-containing glycomimetic 3 exhibited strong inhibitory activity against tumor-associated hCA IX (K_I = 35.9 nM).

Conclusions:

• Combining sulfonamides with sugar analogues, specifically iminosugars and levoglucosenone derivatives, can yield highly selective hCA inhibitors.
• These novel inhibitors show promise for therapeutic applications targeting specific hCA isoforms involved in CNS disorders and cancer.