November 29
PROGRAM

10Glycoscience : diversity and integration

Synthetic gangliosides and analogs :Versatile probes to elucidate
the cell functions of sialoglycans
Makoto Kiso, Ph.D.

Makoto Kiso
ProfileMakoto Kiso was born in Kyoto in 1947,
and received his B.Sc. (1970) and Ph.D.
(1975) degrees in Agricultural Chemistryfrom Kyoto University. He then joined thegroup of Professor Akira Hasegawa at Gifu
University. After working as a research fellow (1977-78) at University of Wisconsin,
Madison (Prof. Laurens Anderson), he waspromoted to associate professor in 1979,and professor in 1990. He is a recipient ofJapan Society for Bioscience, Biotechnology and Agrochemisty (JSBBA) Award for
the Encouragement of Young Scientists(1983), JSBBA Award (2002), and Gifu
Newspaper Grand Award (2007), being
one of the ISI Highly Cited Researchers
since 2001. He is also working as satellite PI of the WPI program-Institute ofIntegrated Cell-Material Sciences (WPIiCeMS), Kyoto University since 2007. His
research interests include the chemical
synthesis of biofunctional carbohydrates,
especially sialoglycans and sialoglycoconjugates such as gangliosides, focusing on
their cell functions and applications in medicinal chemistry and cell biology.

Professor
Department of Applied Bioorganic Chemistry,
Faculty of Applied Biological Sciences, Gifu University, JAPAN

Sialic acid-containing oligosaccharides(sialoglycans) carry a variety of cell functions as the components of terminating
branches of N-/O-glycans and glycosphingolipids (gangliosides). Since 1988 1), we
have developed 2)-4) efficient methods for
systematically synthesizing sialoglycans
and gangliosides, involving their analogs
and derivatives, over 800 species (GSCseries), which have widely been utilized
for glycobiology researches by many collaborations in and out of the country.
Among the lacto- and neolacto-series gangliosides (Figure 1. Lower column), sialyl lacto-/
neolacto-tetraosylceramides (SPGs) werehighly effective for analyzing the receptorbinding specificity of influenza virus (J.
Virol., 74, 11825, 2000; Nature, 444, 378,2006; Nature Biotechnol., 27, 797, 2009;
J. Virol., 84, 12069, 2010). Since 1990,
the selectin ligands: sialyl Lewis X (sLex),
sialyl 6-sulfo Lewis X (6-sulfo sLex), andrelated gangliosides have played important roles not only for basic researches
on lymphocyte homing, inflammation,and cancer metastasis, but also for various applications in medicinal chemistry 5)
and cell biology. (PNAS, 88, 10372, 1991; J.
Cell Biol., 117, 895, 1992; Glycobiology, 3,633, 1993; BBRC, 240, 748, 1997; JBC, 273,11225, 1998; Angew. Chem. Int. Ed., 38,1131, 1999; Blood, 107, 3197, 2006 etc.).
It has been found that sialyl Lewis a (sLea),a ligand for E-selectin, and disialyl Lewis a(DsLea) are associated with human coloncancers (Cancer Res., 64, 4498, 2004), andthe DsLea structure in colon cancer cell is
produced only from disialyl lactotetraosyl
ceramide (DSLc4), which is a high affinity

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the 20th Anniversary of the Mizutani Foundation for Glycoscienceligand for siglec-7 (JBC, 278, 22787, 2003;
Biochem. J., 397, 271, 2006).
Among the ganglio-series gangliosides(Fig.1 Upper column), GT1b has successfully been utilized for elucidating thebinding mechanism of siglec-7 (JBC, 281,32774, 2006), bacterial toxins (JBC, 276,32274, 2001; PLoS Pathogens, 4, 1, 2008)and viral infections (PLoS Pathogens, 8,e1002738, 2012) by X-ray crystallography.
The α-series gangliosides GD1α, GT1aα,and GQ1bα have been studied as highaffinity ligands for myelin-associated glycoprotein (MAG, siglec-4) 6).
GM3 and GM1, which is well known as thereceptor of cholera toxin, have been suggested to serve as coordinators of multiple
receptor functions in the membrane system. We have recently developed a variety
of fluorescent GM3 and GM1 gangliosides,
in which a fluorescent group is linked tothe nonreducing end of the glycans, tosearch the functional roles of gangliosides
in the membrane microdomain called raft.
By conducting comprehensive syntheses
and intensive screening of diverse sialic
acid derivatives, we have developed several
sialoglycans which function as high affinity ligands for CD22 (siglec-2) (JMC, 51,6665, 2008; Tetrahedron Lett., 50, 4488,2009; Bioorg. Med. Chem., 19, 1966, 2011;
Current Med. Chem., 18, 3537, 2011).
Very recently, nanomolar CD22 ligands
were discovered from a library of MAG
antagonists 7). A set of C9 N-acyl Neu5Ac2en mimetics were also evaluated as viralsialidase selective inhibitors (Int. J. Med.
Chem., 2011).

Figure 1. Typical Synthetic Gangliosides and Analogs

References1) 	Murase, T., Ishida, H., Kiso, M. and Hasegawa, A.: A facile regio- and stereoselective synthesis of α-glycosides of N-acetylneuraminic acid. Carbohydr.
Res., (184): c1-c4, 1988.
2) 	Hasegawa, A. and Kiso, M.: Systematic synthesis of gangliosides toward theelucidation and biomedical application of their biological functions, In “Carbohydrates-Synthetic Methods and Applications in Medicinal Chemistry”, H.
Ogura, A. Hasegawa and T. Suami (Eds). Kodansha/VCH, Tokyo/Weinheim,
pp243-266, 1992.
3) 	Ando, H., Ishida, H. and Kiso, M.: Synthesis of sialic acid containing carbohydrates, In “Best Synthetic Methods: Carbohydrates”, H. M. I. Osborn (Ed).
Academic Press: Oxford, pp277-310, 2003.
4) 	Ando, H., Ishida, H. and Kiso, M.: Renewed synthetic approach to gangliosides exploiting versatile and powerful synthetic units, In “Methods In Enzy-mology”, F. Minoru (Ed.), Elsevier, Amsterdam, pp521-540, 2010.
5) 	Hasegawa, A. and Kiso, M.: Design and synthesis of cell adhesion carbohydrate ligands/inhibitors, In “Carbohydrates in drug design”, Z. J. Witczak andK. A. Nieforth (Eds.) Marcel Dekker, New York, pp137-155, 1997.
6) 	Schnaar, R.L., Collins, B.E., Wright, L.P., Kiso, M., Tropak, M.B., Roder, J.C.
and Crocker, P.R.: Myelin-associated glycoprotein binding to gangliosides:
Structural specificity and functional implications, In “Sphingolipids as Signaling Modulators in the Nervous System”, R.W. Leeden, S.-I. Hakomori, A.J.
Yates, J.S. Schneider, R.K. Yu (Eds.), Annals of the New York Academy ofScience, Vol.845, pp92-105, 1998.
7) 	Mesch, S. et al., From a library of MAG antagonists to nanomolar CD22 ligands, ChemMedChem, 7, 134-143, 2012.

Commemorative Symposium

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