Síntese de N-glicosilssulfonamidas, de aza-açúcares derivados de N-Acetilglicosamina e D-Glicose e tentativa de síntese de inibidores potenciais de quitinases

Abstract

In Medicinal Chemistry the enzymes of pathogens like fungi or bacteria are considered good molecular targets for the development of new drugs and the inhibition of these enzymes can result in pharmacological action trough the perturbation of metabolic processes of these organisms, eventually leading to their death. In the case of genetic diseases, the enzyme inhibitors can be used to restore metabolic equilibrium. Several enzymes like exoglycosidases, endoglycosidases and glycosyltransferases use carbohydrates as substrate. This thesis is composed of two chapters and the main objective is the synthesis of potential glycosidase inhibitors. In the first chapter the synthesis of twenty D-glucose and N-acetylglucosamine-based N-glycosylsulfonamides was described. These compounds are considered a new class of bioactive compounds. Four of the designed derivatives are naphthalene sulfonamides, which were obtained initially as anomeric mixtures : (1:3), from which the pure anomer was isoled by crystallization, although in low yields. After some studies a new method for the synthesis of N-glycosylsulfonamides was developed, allowing the preparation of the naphthalene derivatives in good yields. In this chapter the oxidation at C-1 of the N-glycosylsulfonamides was studied in order to obtain the corresponding N-sulfonylglycosylimines, analogues of PUGNAC, a well known enzymatic inhibitor. In the second chapter, are described the studies aiming at the synthesis of an aza-sugar-derived pseudo-disaccharide. Initially, the synthesis of an aza-sugar from D-glucosamine hydrochloride, in twelve steps, was attempted. However, due to difficulties encountered in the inversion of the configuration at C-5 of a key intermediate, this approach was abandoned. Thus the synthesis of another aza-sugar from D-mannitol was undertaken. The intermediates were also used in a study aimed at the obtention of diastereoisomers of the synthesized aza-sugar. In connection with the synthesis of the pseudo-disaccharide, a model glycosylation reaction of cyclohexanol with four glucosamine-derived glycosyl halides, using the Koenigs-Knorr conditions, was performed. Three glycosylation promoters were evaluated, namely, silver triflate, silver carbonate and mercuric bromide/mercuric oxide. Finally, a few unsuccessful attempts were made to synthesize an aza-sugar-derived pseudo-disaccharide.