Synthesis and Biological Functions of GPI Fragments; Inositol Phospholipids Containing Ceramide

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Synthesis and Biological Functions of GPI Fragments; Inositol Phospholipids Containing Ceramide

Etsuko Nabika 1 , Sae Suehara 1 , Toshihiko Aiba 1,2 , Ryota Saito 1 , Takanori Matsumaru 1 , Shinsuke Inuki 1,3 , Yukari Fujimoto 1

1 Graduate School of Science and Technology, Keio University, Japan, 2 Graduate School of Science, Osaka University, Japan, 3 Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

Glycosylphosphatidylinositol (GPI) is a glycoconjugate that connects to the C-terminus of a protein and anchors the protein to the plasma membrane via its lipid moiety. The various structures of the glycan and lipid moieties have been found depending on the organisms or the biosynthetic stages, and the lipid moieties attached to inositol include glycero, lyso-glycero and ceramide types. In the case of yeast such as Saccharomyces cerevisiae, the yeast has the biosynthetic pathway that the lipid moiety of GPI is transformed from the glycero-type to lyso-glycero, glycero-type and then the ceramide-type. We have developed a method to synthesize various GPI fragment structures containing characteristic lipid moieties; eg. mammalian phosphatidylinositols with unsaturated lipids, and the protozoan lyso-glycero type inositol phospholipids (EhPIa and EhPIb isolated from Entamoeba histolytica) [1] that have immunomodulatory activities and activate NKT cells in a CD1d-dependent manner [1,2]. However, as immunomodulators, the details of the structure-activity relationships of other glycero- or ceramide-type GPI are not known. In effort to analyze the biological activities, we synthesized inositol phospholipids containing ceramide from Ascaris suum.

The inositol phospholipids containing ceramide from a parasitic nematode, A. suum, are isolated and structurally determined by Sugita et al. [3]. As shown in Fig. 1, they have D-galactose connected to the myo-inositol containing phospho-ceramide. In this study, we established new synthetic methods for the compounds, and synthesized the compounds 1a–c based on our previously reported synthesis [1,2a]. We postulated that the structure of inositol phospholipids can be constructed using the key intermediates inositol phosphate moiety and N-acyl aziridines, which are precursors of ceramide moiety. The inositol phosphate moiety was prepared from protected myo-inositol using regioselective phosphorylation reaction, which was developed previously [1]. The N-acyl aziridines were synthesized starting from Garner’s aldehyde. The ring-opening reaction of N-acyl aziridines using inositol phosphate moiety as a nucleophile provided the protected inositol phospholipids containing ceramide. Followed by the removal of protecting groups, we achieved the first chemical synthesis of the compounds 1a–c. The immunomodulatory activities, especially cytokine induction of the compounds will be also reported.

Fig. 1 Inositol phospholipids containing ceramide from Ascaris suum

a) Aiba, T.; Suehara, S.; Choy, S. L.; Maekawa, Y.; Lotter, H.; Murai, T.; Inuki, S.; Fukase, K.; Fujimoto, Y. Chem. Eur. J. 2017, 23, 8304; b) Aiba, T., Sato, M., Umegaki, D., Fukase, K., Fujimoto, Y. Org. Biomol. Chem., 2016, 14, 6672.

a) Choy, S. L., Bernin, H., Aiba, T., Fukase, K., Clos, J., Tannich, E., Fujimoto, Y., Lotter, H. et al. Sci. Rep. 2017, 7, 9472. b) Lotter, H.; Holst, O.; Tannich, E. et al. PLoS Pathog. 2009, 5, e1000434.

Sugita, M.; Mizunoma, T.; Aoki, K.; Kurimoto, A. Biochim. Biophys. Acta. 1996, 1302, 185.

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