Abstract
The cell surface heparan sulfate (HS) and its structurally related heparin (HP) are members of the glycosaminoglycan (GAG) family. They are linear polyanionic polysaccharides containing a 1沦4-linked disaccharide repeating unit composed of an uronic acid and 脉-D-glucosamine. HS and HP play important roles in regulating the biological activity of several proteins in the coagulation cascade along with many other processes of biomedical importance including growth factor interactions, viral entry, and angiogenesis. Due to the difficulty in obtaining homogeneous heparin oligosaccharides from natural sources, chemical synthesis may offer a good solution. This dissertation is concerned with the development of methodologies for the synthesis of heparin oligosaccharides and studies their interaction with various proteins. Chapter 1 begins with a description of glycoconjugates on the cell surface and an introduction to the structural characteristics of HP/HS molecules. The biological properties of HS and HP are briefly summarized to provide more information between HS/HP with proteins. The synthesis of HS/HP oligosaccharides documented in the literature reports are summarized in Chapter 2. Chapter 3 describes our specific aims and retro-synthetic plan. The studies on the synthesis of monosaccharide building blocks are described in Chapters 4 and 5. Chapter 4 discusses our new strategies to synthesize D-glucosamine-derived glycosyl donors via our new developed regioselective one-pot protection methodology. The reducing end sugar unit can be prepared from a common intermediate. Chapter 5 reveals the shortest route to synthesize the 1,6-anhydro-刍-L-idopyranose, starting from commercially available and cheap diacetone 脉-D-glucose up to 300-gram scale. Chapter 6 illustrates the synthesis, isolation, purification and structural identification of HP/HS tri-, penta-, and heptasaccharides in detail. The final products were subjected to different bioassays, as specified in Chapter 7. Chapter 8 describes the chemoenzymatic method to prepare HS oligomers with anticoagulant properties. The conclusion of this work is summarized in Chapter 9. Finally, Chapter 10 provides the detailed experimental section and physical data of new compounds.