Abstract
Gangliosides are complex glycosphingolipids that are ubiquitous components of mammalian cell membranes. GM3, which is a simple ganglioside, was known to inhibit cell proliferation and self-phosphorylation of EGFR stimulated by EGF. On the other hand, plasma membrane-associated human sialidase NEU3 hydrolyzes the glycosidic linkage of sialic acid in GM3 to produce lactosylceramide, and is up-regulated in various cancer cells. Recent reports suggested that enzymatic metabolism of GM3 by NEU3 may be involved in cancer malignancy. To clarify the relationship between GM3 metabolism and cancer malignancy by NEU3, we designed sialidase-resistant CF_2- and CH_2-linked GM3 analogues, in which the oxygen atom of sialoside linkage is replaced by the CF_2 or CH_2 group, as a ganglioside probe and a substrate-based NEU3 inhibitor. This time, we succeeded in the synthesis of both GM3 analogues. During the course of the synthesis, we developed the novel methodologies for the construction of the key C-sialoside linkages utilizing Ireland-Claisen rearrangement reaction. Both CF_2- and CH_2-sialoside linkages could be formed in highly stereo-selective manner. Moreover, we revealed the unique temperature effect in this rearrangement reaction, in which stereo-selectivity was increased when the reaction temperature was raised. Detail of synthesis and preliminary results of biological activity of GM3 analogues will be presented.
