In humans, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are the small intestinal glucosidases responsible for catalyzing the last glucose-releasing step in starch digestion. MGAM and SI are each composed of duplicated catalytic domains, N-terminal membrane domains (ntMGAM and ntSI) and C-terminal luminal domains (ctMGAM and ctSI). They display complementary substrate specificities for the mixture of short, linear and branched oligosaccharide substrates that typically make up terminal starch-digestion products. As they are involved in the breakdown of dietary starch and sugars into glucose, regulating their activities with α-glucosidase inhibitors is an attractive approach to control blood glucose levels for the prevention and treatment of type-2 diabetes.This thesis work deals with mapping (determination of selectivity and specificity) of MGAM and SI with synthetic inhibitors. The syntheses and enzymatic evaluation of sulfonium-ion glucosidase inhibitors, with potent inhibitory activities against intestinal glucosidases are the main topics of this thesis. First, an alternative route for the synthesis of kotalanol, a naturally-occurring sulfonium-ion glucosidase inhibitor isolated from Salacia reticulata, and its 6'-epimer are described, and the inhibitory activities of these compounds against ntMGAM are reported. Second, the total syntheses of de-O-sulfonated ponkoranol, another naturally-occurring sulfonium-ion glucosidase inhibitor isolated from the same species, its 5'-epimer, and their selenium analogues are described. The synthetic route is also extended to obtain 3'-O-methylponkoranol. The inhibitory activities of these latter compounds against the four human intestinal glucosidase enzymes, ntMGAM, ctMGAM, ntSI, and ctSI are examined. Finally, from the structural studies of ntMGAM, it was postulated that ctMGAM might have an extended binding site compared to ntMGAM, which favours binding of longer inhibitors such as acarbose (an antidiabetic drug that is currently in use for the treatment of type-2 diabetes). Based on this difference, the syntheses of candidate inhibitors containing maltose extensions at 3'- and 5'- of de-O-sulfonated ponkoranol are described. The inhibition of maltose hydrolysis suggests that selective inhibition of one enzyme unite over the others is possible despite relatively small structural changes in the inhibitor. This panel of inhibitors can now be used to turn off certain enzymes while probing the action of others with respect to starch digestion.
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Thesis advisor: Pinto, B. Mario
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