Design and synthesis of polyhydroxypyrrolidines as enzyme inhibitors

MARIANA VARDÉ; OSCAR VARELA; EVANGELINA REPETTO

Simposio; Exploring the Frontiers of Chemistry: Challenges for the 21st Century; 2019

Exactas UBA-Ben Gurion University

The increasing interest in polyhydroxypyrrolidines (PHP) relies on their potential as therapeutics for the treatment of varied diseases. The biological activity of these compounds is related to their ability to inhibit glycosidases, enzymes involved in numerous events, such as bacterial and viral infections, tumor metastasis, etc. In fact, PHP are mimetics of common sugars (iminosugars) that result from the replacement of ring oxygen atom by a nitrogen atom.In the search of new PHP as enzyme inhibitors, we have employed the 1,3-dipolar cycloaddition of azomethine ylides and sugar enones derived from pentoses, as a key step in the synthesis of optically pure PHP, that contained an aryl substituent. These compounds were evaluated as inhibitors of the β-galactofuranosidase from Penicillium fellutanum. This enzyme, which is not commercially available, is very interesting since many pathogenic microorganisms, including mycobacteria, fungus (Aspergillus and Penicillium), and protozoa (Trypanosoma and Leishmania) display β-galactofuranosidase activity. The inhibition of enzymes involved in the metabolism of galactofuranose, which is absent in higher eukaryotes, is expected to prevent the proliferation of pathogens. Unfortunately, none of the PHP evaluated revealed a noticeable inhibitory activity of the enzyme, which is highly sensitive to steric factors. We attributed the lack of activity to the steric hindrance of the aryl group in the PHP that hampers their accommodation within the active site. Therefore, we have designed and synthesized PHP lacking of aromatic substituents attached to pyrrolidine ring. Thus, we are studying the 1,3-dipolar cycloaddition of imines, derived from 2,2-dimethoxyacetaldehyde and common amino acids, or synthetic ones derived from carbohydrates to obtain cycloadducts, even this last one entirely based on carbohydrate precursors. The products of further transformations (analogues of compounds previously synthetized) will be evaluated as inhibitors of the β-galactofuranosidase.