Functionalized S-thio-di- and S-oligosaccharide precursors as templates for novel SLex/a mimetic antimetastatic...

Adhesive interactions between molecules expressed on vascular endothelium and circulating tumor cells are key early events in cancer metastasis. Best characterized to date is the selectin family of cell adhesion molecules, which can bind to and stabilize blood-borne cells on organ vasculature, facilitating the cell-cell and cell-substratum interactions leading to tumor seeding and proliferation. Major ligands of E-selectin, the selectin family member expressed on vascular endothelial cells, include sialylated, fucosylated glycans such as Sialyl Lewis type carbohydrate complexes (SLe(x) and SLe(a)). These carbohydrate antigens are ubiquitously expressed on tumor cells with high metastatic potential, including colon and pancreatic carcinomas, and have been found to selectively and avidly bind E-selectin. Compounds that prevent E-selectin-SLe(x/a)binding represent an attractive tool in the prevention of cancer dissemination. Review of preclinical in vitro and in vivo studies suggest that SLe(x/a) 'mimetics' may serve as a potent class of anti-metastatic compounds. These agents are designed to outcompete SLe(x/a) antigens expressed on tumor cell surfaces to prevent initial vascular adhesion. Critical in generating exogenous oligosaccharides as SLe(x/a) mimetics is the stereoselective joining of specific mono- and di- saccharides that express functional groups integral in E-selectin-SLe(x/a) binding. Employing sulfur linkages to couple saccharide units enhances the biological stability of these complex carbohydrates. The synthesis of novel S-thiodisaccharides and C-disaccharides as SLe(x/a) precursors using the chiral sugars levoglucosenone, isomeric isolevoglucosenone and their functionalized analogs is described. The highly stereoselective functionalization of both enones at the C-4, C-3 and C-2 positions by the set of Michael addition reactions of reactive 1-thiosugars is reviewed. These functionalized S-thio di- and S-oligosaccharide precursors have direct application for use as templates in the synthesis of novel SLe(x/a)mimetics.