Skip to main content
SpringerLink
Log in

Design and efficient synthesis of novel GM2 analogues with respect to the elucidation of the function of GM2 activator

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

To elucidate the mechanism underlying the hydrolysis of the GalNAcβ1→4Gal linkage in ganglioside GM2 [GalNAcβ1→4(NeuAcα2→3)Galβ1→4Glcβ1→1′ Cer] by β-hexosaminidase A (Hex A) with GM2 activator protein, we designed and synthesized two kinds of GM2 linkage analogues—6′-NeuAc-GM2 and α-GalNAc-GM2. In this paper, the efficient and systematic synthesis of these GM2 analogues was described. The highlight of our synthesis process is that the key intermediates, newly developed sialyllactose derivatives, were efficiently prepared in sufficient quantities; these derivatives directly served as highly reactive glycosyl acceptors and coupled with GalNTroc donors to furnish the assembly of GM2 tetrasaccharides in large quantities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7

Similar content being viewed by others

References

  1. Varki, A.: Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3, 97–130 (1993)

    Article  PubMed  CAS  Google Scholar 

  2. Hakomori, S.-I.: Structure and function of sphingoglycolipids in transmembrane signaling and cell-cell interactions. Biochem. Soc. Trans. 21, 583–595 (1993)

    PubMed  CAS  Google Scholar 

  3. Hannun, Y.A.: Functions of ceramide in coordinating cellular responses to stress. Science 274, 1855–1859 (1996)

    Article  PubMed  CAS  Google Scholar 

  4. Kolter, T., Sandhoff, K.: Sphingolipid-their metabolic pathways and the pathobiochemistry of neurodegenerative diseases. Angew. Chem. Int. Ed. 38, 1532–1568 (1999)

    Article  CAS  Google Scholar 

  5. Okada, S., O’Brien, J.S.: Generalized gangliosidosis: beta-galactosidase deficiency. Science 160, 1002–1004 (1968)

    Article  PubMed  CAS  Google Scholar 

  6. Li, Y.-T., Mazzotta, M.Y., Wan, C.-C., Orth, R., Li, S.-C.: Hydrolysis of Tay-Sachs ganglioside by β-hexosaminidase A of human liver and urine. J. Biol. Chem. 248, 7512–7515 (1973)

    PubMed  CAS  Google Scholar 

  7. Wu, Y.Y., Lockyer, J.M., Sugiyama, E., Pavlova, N.V., Li, Y.-T., Li, S.-C.: Expression and specificity of human GM2 activator protein. J. Biol. Chem. 269, 16276–16283 (1994)

    PubMed  CAS  Google Scholar 

  8. Hama, Y., Li, Y.-T., Li, S.-C.: Interaction of GM2 activator protein with glycosphingolipids. J. Biol. Chem. 272, 2828–2833 (1997)

    Article  PubMed  CAS  Google Scholar 

  9. Ishida, H., Ito, Y., Tanahashi, E., Li, Y.-T., Kiso, M., Hasegawa, A.: Synthesis of 6′-GM2, regioisomer of ganglioside GM2, for studying the mechanism of action of GM2 activator. Carbohydr. Res. 302, 223–227 (1997)

    Article  PubMed  CAS  Google Scholar 

  10. Li, Y.-T., Li, S.-C., Hasegawa, A., Ishida, H., Kiso, M., Bernardi, A., Brocca, P., Raimondi, L., Sonnino, S.: Structural basis for the resistance of Tay-Sachs ganglioside GM2 to enzymatic degradation. J. Biol. Chem. 274, 10014–10018 (1999)

    Article  PubMed  CAS  Google Scholar 

  11. Hotta, K., Itoh, K.-I., Kameyama, A., Ishida, H., Kiso, M., Hasegawa, A.: Stereocontrolled synthesis of positional isomers of tumor-associated ganglioside antigens, sialyl lewis X and sialyl paragloboside. J. Carbohydr. Chem. 14, 115–133 (1995)

    Article  CAS  Google Scholar 

  12. Martichonok, V., Whitesides, G.M.: A practical method for the synthesis of sialyl α-glycoside. J. Am. Chem. Soc. 118, 8187–8191 (1996)

    Article  CAS  Google Scholar 

  13. Ando, H., Koike, Y., Ishida, H., Kiso, M.: Extending the possibility of an N-Troc protected sialic acid donor toward variant sialo-glycoside synthesis. Tetrahedron Lett. 44, 6883–6886 (2003)

    Article  CAS  Google Scholar 

  14. Tanaka, H., Adachi, M., Takahashi, T.: One-pot synthesis of sialo-containing glycosyl amino acids by use of an N-trichloroethoxycarbonyl-β-thiophenyl sialoside. Chem. Eur. J. 11, 849–862 (2005)

    Article  CAS  Google Scholar 

  15. Veeneman, G.H., van Leeuwen, S.H., van Boom, J.H.: Iodonium ion promoted reactions at the anomeric centre. ІІ An efficient thioglycoside mediated approach toward the formation 1,2-trans linked glycosides and glycosidic esters. Tetrahedron Lett. 31, 1331–1334 (1990)

    Article  CAS  Google Scholar 

  16. Fuse, T., Ando, H., Imamura, A., Sawada, N., Ishida, H., Kiso, M., Ando, T., Li, S.-C., Li, Y.-T.: Synthesis and enzymatic susceptibility of a series of novel GM2 analogs. Glycoconjugate J. 23, 329–343 (2006)

    Article  CAS  Google Scholar 

  17. Imamura, A., Ando, H., Korogi, S., Tanabe, G., Muraoka, O., Ishida, H., Kiso, M.: Di-tert-butylsilylene (DTBS) group-directed α-selective galactosylation unaffected by C-2 participating functionalities. Tetrahedron Lett. 44, 6725–6728 (2003)

    Article  CAS  Google Scholar 

  18. Imamura, A., Ando, H., Ishida, H., Kiso, M.: Di-tert-butylsilylene-directed α-selective synthesis of 4-methylumbelliferyl T-antigen. Organic Lett. 7, 4415–4418 (2005)

    Article  CAS  Google Scholar 

  19. Imamura, A., Kimura, A., Ando, H., Ishida, H., Kiso, M.: Extended applications of di-tert-butylsilylene-directed α-predominant galactosylation compatible with C2-participating groups toward the assembly of various glycosides. Chem. Eur. J. 12, 8862–8870 (2006)

    Article  CAS  Google Scholar 

  20. Furusawa, K.: Removal of cyclic di-t-butylsilanediyl protecting groups using tributylamine hydrofluoride (TBAHF) reagent. Chem. Lett. 3, 509–510 (1989)

    Google Scholar 

  21. Cook, A. F.: Use of 2,2,2-tribromoethyl chloroformate for the protection of nucleoside hydroxyl groups. J. Org. Chem. 33, 3589–3593 (1968)

    Article  PubMed  CAS  Google Scholar 

  22. Burke, S. D., Danheiser, R. L., Eds. Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents (Wiley, Chichester, 1999), p. 513–518

  23. Jansson, K., Ahlfor, S., Frejd, T., Kihlberg, J., Magnusson, G.: 2-(Trimethylsilyl)ethyl Glycoside. Synthesis, anomeric deblocking, and transformation into 1,2-trans 1-O-acyl sugars. J. Org. Chem. 53, 5629–5647 (1988)

    Article  CAS  Google Scholar 

  24. Schmidt, R.R.: New methods for the synthesis of glycosides and oligosaccharides-Are there alternatives to the Koenigs-Knorr method? Angew. Chem. Int. Engl. 25, 212–235 (1986)

    Article  Google Scholar 

  25. Ito, Y., Kiso, M., Hasegawa, A.: Studies on the thioglycoside of N-acetylneuraminic acid 6: Synthesis of ganglioside GM4 analogs. J. Carbohydr. Chem. 8, 285–294 (1989)

    Article  CAS  Google Scholar 

  26. Ehara, T., Kameyama, A., Yamada, Y., Ishida, H., Kiso, M., Hasegawa, A.: Total synthesis of VIM-2 ganglioside isolated from human chronic myelogenous leukemia cells. Carbohydr. Res. 281, 237–252 (1996)

    Article  PubMed  CAS  Google Scholar 

  27. Du, W., Gervay-Hague, J.: Efficient synthesis of α-galactosyl ceramide analogues using glycosyl iodide donors. Organic Lett. 7, 2063–2065 (2005)

    Article  CAS  Google Scholar 

  28. Kiso, M., Nakamura, A., Nakamura, J., Tomita, Y., Hasegawa, A.: A convenient synthesis of sphingosine and ceramide from D-xylose or D-galactose. J. Carbohydr. Chem. 5, 335–340 (1986)

    Article  CAS  Google Scholar 

  29. Kiso, M., Nakamura, A., Tomita, Y., Hasegawa, A.: A novel route to D-erythro-sphingosine and related compounds from mono-O-isopropylidene-D-xylose or -D-galactose. Carbohydr. Res. 158, 101–111 (1986)

    Article  CAS  Google Scholar 

  30. Nicolaou, K.C., Caulfield, T., Kataoka, H., Kumazawa, T.: A practical and enantioselective synthesis of glycosphingolipids and related compounds. Total synthesis of globotriaosylceramide (Gb3). J. Am. Chem. Soc. 110, 7910–7912 (1988)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported in part by MEXT of Japan (Grant-in-Aid for Scientific Research to H.I., no. 16580086 and M.K., no. 1701007) CREST of JST (Japan Science and Technology Agency) and National Institutes of Health Grant R01NS009626 (to Y.-T. L.). The authors are thankful to the referees for their valuable comments.

Author information

Authors and Affiliations

  1. Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, 501-1193, Japan

    Tatsuya Komori, Akihiro Imamura, Hideharu Ishida & Makoto Kiso

  2. Center for Emerging Infectious Diseases, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan

    Takayuki Ando

  3. Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu, 501-1193, Japan

    Takayuki Ando

  4. Institute for Integrated Cell Material Sciences (iCeMS), Kyoto University, Kyoto, 606-8501, Japan

    Makoto Kiso

  5. Department of Biochemistry, Tulane University Health Sciences Center School of Medicine, New Orleans, LA, 70112, USA

    Yu-Teh Li

Authors
  1. Tatsuya Komori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayuki Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihiro Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Teh Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideharu Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Makoto Kiso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Takayuki Ando or Makoto Kiso.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Komori, T., Ando, T., Imamura, A. et al. Design and efficient synthesis of novel GM2 analogues with respect to the elucidation of the function of GM2 activator. Glycoconj J 25, 647–661 (2008). https://doi.org/10.1007/s10719-008-9117-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-008-9117-9

Keywords

Search

Navigation