Síntese e avaliação biológica de derivados de carboidratos e nucleosídeos

Abstract

In the last few years, the carbohydrate chemistry has been growing surprisingly, especially because of the diversity of biological applications of this class of compounds. This present work aimed to synthesize and evaluate a series of carbohydrates and nucleosides, in order to contribute for the study of their structure-activity relationship. A series of sugar esters from glucose, mannose, galactose and fructose with stearic and palmitic acids was synthesized with the respective acid chlorides in aqueous basic medium in the presence of DMAP with 30 - 40% yield. Mannofuranose, galactofuranose and fructose derivatives were prepared for the synthesis of β-L-mannofuranosyl(6→2)-fructosyl(2→6)-β-L-galactofuranose, however the coupling reactions were not successful and the synthesis was interrupted. Purinic nucleosides and analogs were synthesized under Mitsunobu conditions, using the appropriated purine and the respective alcohols, as for example, menthol, dodecanol, benzyl alcohol, oleic alcohol and glucose and mannose derivatives, with 37 - 86% yield. Synthesis of the carbocyclic nucleoside, 4-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl] cyclopentanol, was carried out until intermediate 6-chloro-9-(6-oxabicyclo[3.1.0]hex-3-yl)-9H-purine. After several attempts in order to open the epoxide with cyanides, the synthesis was discontinued. All synthetic compounds and a series of 22 commercial carbohydrates were biologically evaluated against T. cruzi gGAPDH and L. tarentolae APRT enzymes, several microorganisms and the leaf-cutting ant Atta sexdens. The evaluated carbohydrates were inactive or showed moderate inhibition against gGAPDH enzyme at 200 μM. D-isoascorbic acid showed an inhibition of 67% (100 μM) against the APRT enzyme. The evaluated nucleosides and analogs were inactive or showed low inhibition against the gGAPDH enzyme at 200 μM. 6-Chloro-9-dodecyl-9H-purine showed an inhibition of 63% (100 μM) against the APRT enzyme. The sugar esters of fatty acids presented no toxic effect to the ants. In the case of 6-O-estearoyl-D-glucopiranose, 6-O-palmitoyl-D-mannopiranose e 6-O-palmitoyl-D-galactopiranose, it was observed a small growth of the survival of the worker ants. They showed no inhibition or low inhibition (20%) of the symbiotic fungus Leucoagaricus gongylophorus. 6-Chloro-9-dodecyl-9H-purine showed a moderate inhibition against Escherichia coli. The compounds analyzed will be employed as models for the design and synthesis of more active compounds.