Chemoenzymatic Synthesis of Sialylated Globosides and Their Derivatives

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Chemoenzymatic Synthesis of Sialylated Globosides and Their Derivatives

Peiyun Chiang 1 , Pei-Jhen Li 1 , Szu-Yu Huang 1 , Chen-Yo Fan 1 , Wei-Lun Liang 1 , Takashi Angata 2 , Chun-Cheng Lin 1

1 Department of Chemistry, National Tsing Hua University, Hsinchu city, Taiwan, 2 Institute of Biological Chemistry, Academia Sinica, Taipei city, Taiwan

Globosides, composed by ceramide and a series of glycans sharing a Gal-α1,4-Gal-β1,4-Glc trisaccharide core, have been found on various cancer cell surfaces and related to cancer development. Although many methods have been developed for the synthesis of globosides, the synthesis of disialo-globopentaosylceramide (DSGb5) has not been reported yet. We successfully synthesized DSGb5 glycan with azide-modified linker from Gb5 (SSEA-3) glycan with total 25% yield by one-pot multienzyme (OPME)¹ method and 12%~26% yields by three different chemoenzymatic methods. Moreover, Gb3, Gb4, and Gb5 glycans were sialylated with several kinds of sialyltransferases to afford mono-sialylated (α2,3- and α2,6-), linear di-sialylated (α2,8-α2,3- and α2,8-α2,6-), and branched di-sialylated (α2,6- and α2,3-) globo-series glycans.

Sialic acid-binding immunoglobulin-superfamily lectin-7 (Siglec-7) expressed on natural killer (NK) cell was reported to suppress the cytotoxicity of NK cell to cancer cells when it binds to disialylated glycans on the cancer cell surface. To investigate the binding affinity of IgG Fc-fused Siglec-7 (Siglec-7-Fc) with sialylated globo-series glycans, the glycans were first immobilized on the alkyne-modified glass slide by CuAAC, followed by binding with Siglec-7-Fc and visualized by anti-IgG-Cy3. Surprisingly, DSGb5 glycan showed lower affinity to Siglec-7-Fc compared with GD3 glycan, which is a well-known high-affinity ligand for Siglec-7. The unexpected low affinity may be caused by the linker difference with the naturally occurring ceramide, which motivated us to synthesize DSGb5 ceramide for further understanding the reason of relative low binding affinity.

Although the glycan moiety is considered to be the key of globoside’s bioactivity, the ceramide of globosides was also indicated to be critical for signal transduction in recent studies. Therefore, it is desirable to develop an efficient method to synthesize globosides and their derivatives for investigation of the bioactivities toward cancer cell. Herein, OPME method was applied to synthesize Gb3, Gb4, Gb5,² SSEA-4, and Globo-H sphingolipids by using chemically synthesized lactose (Lac) sphingolipid as starting material, which shows better water solubility than that of Lac-ceramide. The fatty acid was introduced to above glycosphingolipids at the late stage and give globosides.

Chen, X.; Varki, A. ACS Chem. Biol. 2010, 5, 163-176.

Li, S.-P.; Hsiao, W.-C.; Yu, C.-C.; Chien, W.-T.; Lin, H.-J.; Huang, L.-D.; Lin, C.-H.; Wu, W.-L.; Wu, S.-H.; Lin, C.-C. Adv. Synth. Catal. 2014, 356, 3199-3213.

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