Synthetic and structural studies on carbohydrate-derived cardioprotective and anticancer agents

This dissertation describes synthetic and analytical studies in two areas of carbohydrate chemistry and biochemistry: (1) the use of carbohydrate synthons in the synthesis of the natural product hongconin, and (2) the development of hyaluronic acid oligosaccharides as probes for cancer metastasis.

The natural product hongconin is an isochromanquinoid with demonstrated cardioprotective properties. Described here is a concise methodology for the first enantioselective synthesis of this compound (and analogs) starting from a simple carbohydrate derivative. The novel synthetic strategy represents a significant simplification in synthesizing optically pure isochromanquinoids, and would allow numerous other natural products with similar chemical structures to be conveniently synthesized in an analogous fashion.

A recently discovered process which appears to play a critical role in the metastasis of melanoma cells to the lungs is the binding of the cancer cell's CD44 receptor to hyaluronic acid, a polysaccharide that is synthesized in the plasma membrane and is associated with the host cell's extracellular matrix. The central hypothesis of this study is that metastasis might be prevented by introducing relatively small HA- oligosaccharides that would function as CD44 "metastasis receptor" antagonists. Support for this hypothesis was found in first-generation experiments using enzyme digestion-derived HA oligosaccharides: these compounds were found to virtually prevent the metastasis of B16F10 melanoma cells to the lungs in a murine model. Also described here is the development of two analytical protocols to characterize these oligosaccharides, namely high-performance anion-exchange chromatography with pulsed amperometric detection and electrospray-ionization mass spectrometry. The utility of the developed methods was highlighted in the discernment of previously unobserved odd-numbered oligosaccharides in the digestion mixtures. Finally, S- and C-linked oligosaccharide intermediates were synthesized with the aim of developing HA mimics with improved in vivo stability.