Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi

Abstract

Trypanosoma cruzi trans-sialidase (TcTS) is a surface enzyme that catalyses the transfer of residues of the monosaccharide sialic acid from host sialoglycoconjugates to the mucins, abundant proteins expressed on the parasite surface. Physiologically TcTs actively participates of the mechanisms of evasion from the immune system, cell invasion and blood cell apoptosis. This enzyme is, therefore, essential for the development of Chagas Disease, and is considered a promising molecular target for drug design. Thus, the aim of the present work was the design and synthesis of D-galactose-derived potential inhibitors of TcTS using strategies of molecular modification, in special molecular simplification. Ten aryl galactosides modified at carbon-3 were synthesized and characterized for evaluation against TcTS by spectrofluorimetry. By using classical carbohydrate chemistry 4-methoxycarbonylphenyl -D-galactopyranoside and 4-methoxycarbonyl-2-nitrophenyl -D-galactopyranoside were prepared. The regioselective 3-O-alkylation of both compounds was then carried out using methyl iodide, tert-butyl bromoacetate and bromoacetonitrile as electrophylic reagents. The regioselectivity was achieved by employing the dibutyltin oxide method, in which cyclic tin complexes are formed and, upon reaction with an alkyl halide, furnish 3-O-alkylated products, in general high yields and selectivity. The alkylated products bearing tert-butoxycarbonylmethyl or cyanomethyl groups were modified in order to obtain derivatives bearing at C-3 a carboxymethyl or a 5-tetrazolylmethyl group.