Synthesis and Molecular Modeling of Carbohydrate with Potential Anti-glucosidase Activity / Síntese e modelagem molecular de carboidratos com potencial atividade anti-glucosidase

AUTOR(ES)

Adriane da Silveira Gomes

DATA DE PUBLICAÇÃO

2008

RESUMO

Carbohydrates of glycoconjugates display high degree of complexity and structural diversity, playing a central role in biological processes. Glucosidases are enzymes that catalyze the cleavage of glycosidic bonds in oligosaccharides or glycoconjugates, being essentials in several metabolic pathways and in the biosynthesis of glycoproteins and glycosfingolipids. Several glucosidase inhibitors from natural and synthetic sources have been described, such as: acarbose (1), miglitol (2), voglibose (3) and N-butyl-desoxy-nojirimycin (4). Compounds 1, 2 and 3 are used in the treatment of type II diabetes mellitus and 4 for patients with Gauchers disease. Concerning to the importance of the design and synthesis of new glucosidase inhibitors, as well as the need of 3D models for glucosidases, the aims of this work were: i) the synthesis of potentially anti-glucosidase carba-sugars and pseudodisaccharides, ii) the evaluation of its inhibitory activities by using ?-D-glucosidase from Saccharomyces cerevisiae and iii) the use of bioinformatics and molecular modeling techniques for creation of a 3D structural homology model of rat intestinal sucrase to accomplish the structure-activity relationships studies concerning to the pharmacophoric pattern of the reported inhibitors. Thus, starting with the key precursor 12, prepared in six steps, different carba-sugars were synthesized. Additionally, reductive amination reactions, allylic rearrangement and "click chemistry" were applied on the synthesis of novel pseudosaccharides 81, 89 and 99, respectively. Compound 46 was assayed for enzymatic inhibition and demonstrated reasonable activity for the inhibition of ?-D-glucosidase. Docking simulations by using the rat sucrase model and the determination of pharmacophoric pattern provided significant information concerning to the enzymes active site and the inhibitors binding pattern. Therefore, the synthetic strategies, enzymatic kinetic assays and molecular modeling studies performed in this work resulted in relevant contributions to the carbohydrate chemistry, making possible for our research group to evaluate potential ?-glucosidase inhibitors in silico, which can be synthesized and assayed for enzymatic activity in the future.

ASSUNTO(S)

glucosidase inhibitors inibidores de glucosidase molecular modeling pseudodissaccharides carba-açúcares carba-sugars modelagem molecular pseudodissacarídeos

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