Sialyl conformation

The data for these oligosaccharides have been incorporated into the molecular models shown in Figs. 3 and 4. The conformation and molecular recognition of sialylated oligosaccharides are an important area for future investi-... 

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. 

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

DeFrees, S., Kosch, W., Way, W., Paulson, J., Sabesan, S., Halcomb, R., etal. (1995) Ligand recognition by E-selectin Synthesis, inhibitory activity and conformational analysis of bivalent sialyl Lewis x analogs. J. Am. Chem. Soc., 117, 66-79. 

The frequent occurrence of sialylated enzymes, or even of multiple forms, which are sometimes tissue-dependent, with a varying number of sialyl residues as, for example, in y-glutamyltranspeptida.se (EC 2.3.2.2),456,457 is not yet fully understood. Although the activity of most of these enzymes is not influenced by removal of sialic acid,454 the activity of monoamine oxidase A (EC 1.4.3.4) of outer mitochondrial membranes of rat liver has been shown to be destroyed by treatment with sialidase438 the substrate specificity of acetylcholinesterase (EC 3.1.1.7) is altered,459 the kinetic properties of human acid and alkaline phosphatases (EC 3.1.3.1 and 3.1.3.2) are changed, and the stability of a-D-galactosidase (EC 3.2.1.22) is drastically lowered.415 In these cases, an influence of sialyl residues on the conformation of the enzyme is assumed, but awaits firm evidence. 

SCHEME 5.2 Stereoelectronic considerations for the reaction of interconverting conformers of a sialyl oxocarbenium ion. 

Conformationally Restrained C-Glycoside Probes for Sialyl Lewis X-Selectin Recognition... 

A number of functional sialyl Lewis mimetics have been synthesized. Their activities in vitro are equal or even better than those of the tetrasac-charide itself. To overcome synthetic problems, efficient stereoselective glycosylations as well as new chemoenzymatic methods for C-C bond formations had to be developed. The substitution of neuraminic acid by (5)-phenyl- and (5)-cyclohexyl lactic acid, as less flexible glycol acid residues, turned out to be very successful [10]. Also, a phosphate and a sulfate group, respectively, mimic neuraminic acid without loss of activity [11]. (5)-Cyclohexyl lactic acid-mimetic 2 shows a more than ten-fold efficacy compared with sialyl Lewis, whereas the corresponding (/ )-isomer 3 is almost inactive [10]. The deviating orientation of the carboxylic acid functionality compared to the bioactive sialyl Lewis conformation leads to the examined loss of activity. It was shown by transfer-NOE measurements of the corresponding E-selectin complexes that the coordinates of the bioactive conformation of sialyl Lewis and of compound 2 are similar. Con.se-quently structure 2 should bind to E-selectin in the same manner as that of sialyl Lewis [ 10a, b]. 

Ichikawa Y, Lin Y-C, Dumas DP, Shen G-J, Garcia-Junceda E, Williams MA, Bayer R, Ketcham C, Walker LE, Paulson JC, Wong C-H. Chemical-enzymatic synthesis and conformational analysis of Sialyl Lewis X and derivatives. J. Am. Chem. Soc. 1992 114 9283-9298. 

Thoma, G, Schwarzenbach, F, Duthaler, R O, Synthesis of sialyl Lewis mimic with carboxyhc acid group chemical approach toward the elucidation of the bioactive conformation of sialyl Lewis, J. Org. Chem., 61, 514-524, 1996. 

Thoma, G, Magnani, J L, Patton, J T, Ernst, B, Jahnke, W, Preorganization of the bioactive conformation of sialyl Lewis analogues correlates with their affinity to E-selectin, Angew. Chem. Int. Ed., 40, 1941-1945, 2001. 

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