A novel class of glycosidase inhibitors: structures related to australine, lentiginosine, salacinol and swainsonine

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(Thesis) Ph.D.
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This thesis focuses on the design and syntheses of the sulfonium-ion analogues of australine, lentiginosine, swainsonine, and other analogues of salacinol as potential glycosidase inhibitors, together with the investigation of their enzyme inhibitory activities. The syntheses of several bicyclic sulfonium-ion analogues of a naturally occurring glycosidase inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, are described. These compounds were designed to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor. We postulated that a permanent positive charge on the sulfur atom will mimic the highly unstable oxacarbenium ion transition state in a glycosidase-catalyzed hydrolysis reaction. Screening of these compounds against Drosophila melanogaster Golgi-alpa-mannosidase II (dGMII), an important mannosidase that is involved in the N-glycosylation pathway, showed that the configuration of the sulfonium-ion center is critical for activity and the design of new agents should incorporate this feature. The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, are also described. The conformational preferences of these compounds, based on analysis of 1H-1H vicinal coupling constants and 1D-NOESY data, are attributed to both steric and electrostatic interactions. These compounds will be used in the study of structure-activity relationships with glycosidase enzymes. Finally, synthesis of analogues of the naturally occurring glycosidase inhibitor, salacinol, in which the D-arabinitol ring has been replaced by D-lyxitol or D-ribitol, along with polyhydroxylated imino- and thio-alditols, containing a phosphate group instead of the usual sulfate group in the side chain are described. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides into glucose, shows that they are not effective inhibitors of MGA and demonstrates the importance of the D-arabinitol configuration of the heterocyclic ring and the side chain substituents of salacinol for effective inhibition. The compounds were also screened against dGMII and were found not to be effective inhibitors of this enzyme.
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