Synthetic and structural studies on anticancer agents : C-/O-linked and S-/O-linked hyaluronic acid oligosaccharide mimetics

Hyaluronic acid (HA) is a polysaccharide synthesized in the plasma membrane of cells and is associated with the host cell's extracellular matrix. Recent studies have established that HA plays an important role in cancer metastasis by interacting with cancer cell's CD44 receptor and serving as a chemoattractant for establishing metastatic foci. In first generation studies, HA oligosaccharides were found to show profound antimetastatic activity in a B 16F10 mouse melanoma model. Our goal was to develop mimetic compounds for the natural HA oligosaccharides that would be resistant to enzymatic degradation and serve as candidates for antimetastatic drugs in the treatment of cancer. Described in this dissertation is the synthesis of C-/0-linked and S-/0-linked HA tetrasaccharide mimetics and S-/0-linked HA hexasaccharide mimetics. The C-/0-linked HA tetrasaccharide was synthesized in collaboration with Dr. Zhong-Xu Ren via trichloroacetimidate glycosylation of two specifically protected C-disaccharides as building blocks, which were obtained by C-coupling reactions of a glycosyl tin derivative and a glycosyl pyridinylsulfone with an aldehyde, promoted by MeLi/BuLi and Smlz, respectively.