Synthesis of a Novel Stable GM_3-Lactone Analogue as Hapten for a Possible Immunization against Cancer

摘要

In addition to proteins and lipids. carbohydrates—of which gangliosides constitute a large part—are essential elements of the cell surface. They are anchored to the lipid bilayer of the membrane with their ceramide portion, and the carbohydrate moiety is exposed to the outside. Gangliosides play an important role in cell-cell and cell-matrix recognition and are relevant for cellular growth since they interact with many growth receptors, for example the epidermal growth factor receptor. The GM_3 ganglioside is the smallest and most widespread ganglioside in human and animal tissue. It has been found in brain and nerve cells as well as in the membranes of melanoma and liver carcinoma cells in increased concentrations. However, immunization experiments with monoclonal antibodies indicate that the actual tumor-associated antigen is not the GM_3 ganglioside itself but its lactone form l. Consequently, a greatly increased density of the GM_3 lactone was discovered in melanoma cells. Furthermore, the existence of a threshold at which the antibody recognizes the cell has been shown. The GM_3 ganglioside lactone and lactam hitherto used to obtain antibodies are unstable towards hydrolysis under physiological conditions. Therefore, there is much interestin developing hydrolysis-resistant- analogues of 1 and. thus, making a defined immunogen available for immunization. Here we describe the synthesis of the hydrolysis-stable GM_3 ganglioside lactone analogue 2 containing an ether group.