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

Sodeoka, Mikiko; Hirai, Go; Watanabe, Toru; Miyagi, Taeko

doi:10.1351/PAC-CON-08-09-14

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

http://dx.doi.org/10.1351/PAC-CON-08-09-14

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.