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Pure Appl. Chem., 2009, Vol. 81, No. 2, pp. 205-215

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

Mikiko Sodeoka1, Go Hirai1, Toru Watanabe1 and Taeko Miyagi2

1 Synthetic Organic Chemistry Laboratory, RIKEN, Hirosawa, Wako, Saitama 351 0198, Japan
2 Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan, and CREST,JST Kawaguchi 332-1102, Japan

Abstract: 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) α(2,3)sialylgalactose as a core structure of sialidase-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 μM, respectively, and strongly inhibited human lymphocyte proliferation in the same concentration range as natural GM4.