Sialyl Lewis* acids

Figure 26 The sialyl Lewis acid x (sLe ) determinant 54 is recognized by the selectins.

White blood oells oontinually patrol the circulatory system and interstitial spaces, ready for mobilization at a site of trauma. The frontline scouts for leukocytes are carbohydrate groups on their surface called sialyl Lewis acids. When injury occurs, cells at the site of trauma display proteins, called selectins, that signal the site of injury and bind sialyl Lewis acids. Binding between selectins and the sialyl Lewis acids on the leukocytes causes adhesion of leukocytes at the affected area. Recruitment of leukocytes in this way is an important step in the inflammatory cascade. It is a necessary part of the healing process as well as part of our natural defense against infection. A molecular model of a sialyl Lewis acid is shown below, and its structural formula is given in Section 22.16. 

Efforts like these to prepare finely tuned molecular agents are typical of research in drug discovery and design. In the case of sialyl Lewis acid analogs, chemists hope to create new therapies for chronic inflammatory diseases by making ever-improved agents for blocking undesired leukocyte adhesion. 

THE CHEMISTRY OF... Patroling Leukocytes and Sialyl Lewis Acids 1018... 

A strategy for combating undesirable initiation of the inflammatory cascade is to disrupt the adhesion of leukocytes. This can be done by blocking the selectin binding sites for sialyl Lewis acids. Chemists have advanced this approach by synthesizing both natural and mimetic sialyl Lewis acids for studies on the binding process. These compounds have helped identify key functional groups in sialyl Lewis acids that are required... 

Yang W, Fan H, Gao X et al (2004) The first fluorescent diboronic acid sensor specific for hepatocellular carcinoma cells expressing sialyl Lewis X. Chem Biol 11 439 148... 

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... 

SCHEME 5.24 Sialylation of a thiol under Lewis acid-mediated conditions by an A-acetyl oxazolidinone-protected sialyl phosphate. 

With the realization that the efficiency and reproducibility in the conventional flask reaction is sensitive to the heat generated during syringe addition of the Lewis acid to the donor and acceptor, the reaction conditions of the sialylation using the N-acetylated donor was reinvestigated in pursuit of a practical route to a-sialylation. The initial optimization of the a-sialylation utilized the N-acetylated imidate 15 [27, 50, 51] and the galactose acceptor 6 in the presence of TMSOTf as an activator in... 

Efficient activation of the N-acetylated sialyl donor required l.Oequiv. of the Lewis acid under -78°C, giving the disaccharide 16 in 77% yield with excellent a selectivity (a/p=96/4, Table 8.2, entry 1). The conditions in entry 1 were reproducible under the microfluidic conditions (entry 2, 89% yield, a/p=94/6). Because the excess donor 15 inhibited the purification of sialoside 16 from the glycal by-product due to similar polarities on silica gel, the ratio between the donor and the acceptor... 

Brinkman-Van der Linden, E.C., van Ommen, E.C. and van Dijk, W. (1996) Glycosylation of ai-acid glycoprotein in septic shock changes in degree of branching and in expression of sialyl Lewis(x) groups. Glycoconjugate Journal 13,27-31. 

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]. 

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