3 -Sialyl-Lex

Fig. 3—Possible solution conformers of oligosaccharide sequences related to the Le and Leb antigens (Lea,Lex, sialyl Le", sialyl Lex, ALeb, ALey). As described in the text, oligosaccharides in solution sample 3D space in local energy-minima wells, so that the conformations shown are approximate only. The models stand only to show the stereochemical hindrance to movement in these branched oligosaccharides. The molecules are shown without the anomeric hydroxyl group. 

Scheme 10 Synthesis of a sialyl Lex derivative using an MOP disaccharide donor.

Sections (4 xm thick) of formalin-fixed and paraffin-embedded ovarian tissue are mounted on silane-coated slides and air-dried for 24hr at 3°C (Davidson et al., 2000). They are deparaffinized, rehydrated, placed in 0.01 M sodium citrate buffer (pH 6.0), and heated twice for 5 min each in a microwave oven. 2H5 antibody (PharMingen, Becton Dickinson, San Jose, CA) is used at a concentration of 2 p,g/ml to detect sialyl Lex antigen. Staining is performed with labeled avidin-biotin. Negative controls consist of the exclusion of the primary antibody, while positive controls consist of carcinomas that have been shown to be immunoreactive for the antigen in earlier studies. 

Fig. 3. O-glycans of the mucin type. A core 2 structure with poly-LacNAc and blood group epitope A B core 4 structure with sialyl Lex epitope. The core structures are written in bold letters...

Structurally, the O-polysaccharide chains of H. pylori clinical isolates have a poly-A-acetyl-lactosamine (-LacNAc) chain decorated with multiple lateral a-L-fucose residues forming internal Lex determinants with terminal Lex or Ley units (Fig. 10.4) or, in some strains with additional, D-glucose or D-galactose residues (Moran 2001 a,b, 2008 Monteiro, 2001). Moreover, Lea, Leb, sialyl-Lex, and H-1 antigens have been structurally described in other strains, as well as the related blood groups A and B (Fig. 10.4), but occur in association with Lex and LacNAc chains (Monteiro et al., 2000a,b Heneghan et al., 2000). 

Berg, E L, Robinson, M K, Mansson, O, Butcher, E C, Magnani, J L, A carbohydrate domain common to both sialyl Lea and sialyl Lex is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1, J. Biol. Chem., 266, 14869-14872, 1991. 

With the aid of monoclonal antibodies, sialylated carbohydrate structures, notably sialyl Lea and sialyl Lex, were discovered to function as receptors for the selectins [43]. Sialyl Lex is usually located on leukocytes, but also highly expressed on a variety of different cancer cells [45]. The same holds true for sialyl Lea, which serves as a tumor marker on gastrointestinal and pancreatic cancers [46]. Owing to the function of sialyl Lewis structures in the extravasation of cancer cells from the bloodstream and promoting metastatic spread to other tissues, a clear correlation of expression of sialyl Lea and sialyl Lex on tumors with enhanced progression and metastasis was observed. Since it is assumed that these tumor-associated carbohydrate markers enhance extravasation and metastasis by interactions with selectins, experiments were performed where selectin expression was inhibited. Long-term studies showed that cancer... 

Fig. 10) [165], The Cytel corporation in San Diego has been able to scale-up this process for the routine production of kilogram quantities in each run of reactions [144]. The sialyl Le tetrasaccharide and its analogs are of pharmaceutical interest in the context of new treatments for chronic inflammatory diseases (psoriasis, rheumatoid arthritis), tumors, and tissue injuries following a heart attack, stroke, or organ transplant. Sialyl Lex and its analogs are therefore enthusiastically pursued by several pharmaceutical companies. Strategies for the solid-phase chemoenzymatic synthesis of glycopeptides (and glycolipids) containing sialyl Lex have also been designed and reported [144,156, and references therein].

Nicolaou KC, Hummel CW, Bockovich NJ, Wong C-H (1991) Stereoctuitrolled synthesis of sialyl lex, the oligosaccharide binding ligand to ELAM-1 (Sialyl = JV-acetylneuramin). J Chem Soc Chem Commun 1991 870-872... 

Walz, G., Aruffo, A., Kolanus, W., Bevilacqua, M., and Seed, B., 1990, Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells, Science 250 1132-1135. 

Irimura, T., Nakamori, S., Matsushita, Y., Taniuchi, Y., Todoroki, N., Tsuji, T., Izumi, Y., Ka-wamura, Y., Hoff, S. D., Cleary, K. R., and Ota, D. M., 1993, Colorectal cancer metastasis determined by carbohydrate-mediated cell adhesion Role of sialyl-Lex antigens. Cancer Biol. 4 319-324. 

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