| Interest in C-glycosides as glycomimetics has led to the development of several methodologies for their synthesis. The Mootoo's group has shown that 1-thio-1,2-O-isopropylidene acetals (TIAs) are precursors to beta-C-galactodisaccharides. In this thesis, application of the TIA methodology to five C-glycoside analogs of the Gal1beta->1alphaMan O-disaccharide mimetic of sialyl Lewis X is described: two conformationally restrained analogs which have different conformational properties with respect to the intersaccharide linkages and three unrestrained structures with one or two fluorines on the intersaccharide carbon. These C-glycoside analogs are important because they are more hydrolytically stable than O-glycosides and could be more practical for drug development. The restrained C-glycosides are designed to restrict the conformational mobility around the Gal pseudoglycosidic linkage and only allow free rotation around the Man linkage. The fluorine substituent in the mono- and difluoro C-glycosides are also expected to effect conformational bias about the intersaccharide bond. Therefore these compounds could be useful as probes for interrogation of the conformational requirements for binding.; Conformational analysis of these C-glycosides was performed by a combination of NMR spectroscopy and molecular mechanics (MM) and molecular dynamics (MD) calculations. The P-selectin binding of these mimetics in a Biacore assay was also determined. At 12 mM, the O-glycoside showed 48% inhibition of binding, while the C-glycoside analogs exhibited between 25-39% inhibition. The conformational and selectin binding data is discussed within the context of the crystal structure of sLex-P-selectin.; The application of the TIA methodology to the preparation of the C-glycoside of methyl alpha-D-altropyranosyl-(1→4)-alpha-D-glucopyranoside is also presented. This synthesis illustrates the suitability of the C-glycoside methodology to C-disaccharides with unusual glycone segments, and is also pertinent to the altromycins, a naturally occurring class of aryl-alpha-C-altrosides. |
