A strategy for constructing C-sialosides based on Ireland-Claisen rearrangement and its application for synthesis of CF2-linked ganglioside GM4 analog

Sialidase-resistant ganglioside analogs having similar biological activities to natural gangliosides are expected to be important probes for clarifying the biological functions of gangliosides. Focusing on difluoromethylene-linked (CF2-linked) and methylene-linked (CH2-linked) alpha(2,3)sialylgalactose as a core structure of sialidasc-resistant ganglioside mimics, we have developed novel, stereocontrolled, and efficient methodologies to synthesize C-sialosides based on Ireland-Claisen rearrangement. These methods were employed to synthesize CF2-linked GM4. The CF2-linked GM4 inhibited human sialidases NEU2 and NEU4 with IC50 values of 754 and 930 mu M, respectively, and strongly inhibited human lymphocyte proliferation in the same concentration range as natural GM4.