Síntese de tetrazóis e oxadiazóis a partir da glicosamina e trealose e avaliação da citotoxidade e modo de ação de derivados da glicosamina

Abstract

In this work two synthesis routes of tetrazoles and oxadiazoles analogs from carbohydrates were studied. One starting from the D-glucosamine sulfate and other starting from the trealose. For the first route five synthesis alternatives were tested. Just in the fifth synthesis sequence four new tetrazoles derivatives and two new oxadiazoles derivativeswere obtained by N- and S-alkylations in moderate overall yield (12-14%) after five steps. For the second route two synthesis alternatives were tested. And just in the second synthesis sequence five new tetrazoles derivatives and two new oxadiazoles derivatives were obtained by N- and S-alkylations in good overall yield (28-33%) after five steps. Cytotoxic evaluation of tetrazolic and oxadiazolic derivatives of Dglucosamine in ovarian, breast, colon and leukemia tumor lines was realized. Substantial activities were detected for all compounds in all tested strains. The lowervalues of cytotoxicity were detected in thio-tetrazolic compounds (IC 50 = 18.6 M) and oxadiazolium thiols (IC50 = 15.4 M) in THP-1-type leukemic lines. In order to study the mode of action of compounds of higher cytotoxicity, an investigation of the metabolite expression associated with programmed cell death was conducted. Throughout the tests, significant increases of the expressions of Caspase-3, BAK, p21 and TP53 were observed, suggesting a mechanism of action of cell death by apoptosis.