Design and synthesis of novel inihibitors of the Golgi [alpha]-mannosidase II
Stanton, Charles John
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In recent years, considerable effort has been devoted to unraveling the biological roles of oligosaccharides and the mechanism-of-action of the enzymes implicated in their biosynthesis. Cells that have undergone oncogenic transformation often display abnormal cell surface oligosacharides and these changes in gycosylation are important determinants of the stage, direction and fate of tumor progression. Inhibition of the mannose trimming enzyme human Golgi ?–mannosidase II (HGMII), which acts late in the N-glycan processing pathway, provides one route to blocking the oncogene-induced changes in cell surface oligosaccharide structures. Potent inhibitors of glycosidases are thought to mimic oxocarbenium ion-like transition states. For example, the inhibitory activity of the natural product swainsonine has long been attributed to its five-membered ring resembling a flattened six-membered ring, and thus attaining an oxocarbenium-like structure. In an effort to identify more effective inhibitors of Class 2 mannosidases, we have initiated a program to design novel synthetic inhibitors, which are selective for the Golgi ?- mannosidase II enzyme. Amongst the new analogs that have been synthesized are various bicyclic sulfonuim salt- and azasugar analogs of swainsonine. This Thesis describes two novel classes of unnatural glycosidase inhibitors.