Several sialyl Lewis X (SLex) mimics that contain the essential functional groups for receptor interaction and a negative charge or a hydrophobic group have been developed as inhibitors of E-, P-, and L-selectins. Some of the mimics exhibit selectin inhibition activities 103−104-fold more potent than does the natural ligand tetrasaccharide, with IC50 in the low micromolar to high nanomolar range. The syntheses of these mimics are relatively simple, using TMSOTf-Ac2O mediated C-glycosylation with concurrent selective deprotection of the primary benzyl group and enzymatic aldol addition reactions as key steps.

A combined NMR and computer modeling approach is applied to study and compare the structures of O-sialyl-Lewis-X (SLex) and its synthetic intermediates attached to an octapeptide fragment of the mucin domain of MAdCAM-1. The conformation of the carbohydrate moiety of the O-SLex peptide is found to be the same as that of free SLex. The conformation of the polypeptide backbone and the orientation of the carbohydrate moiety relative to the peptide bond, however, depend on the extent of glycosylation. Glycosylation-induced conformational change of the octapeptide from a random structure to a turn-like structure was observed. The extent of glycosylation appears to have a subtle effect on the turn structure, including the dynamics of cis − trans-proline isomerization. On the basis of structural constraints obtained from the NMR study, computer modeling and molecular dynamics calculations were then used to obtain low-energy conformations of the glycopeptides. The conformational differences observed between the individual glycopeptides can be rationalized as a balance between hydrophobic (carbohydrate−peptide) and hydrophilic (carbohydrate−carbohydrate and carbohydrate−water) interactions. These differences provide some insight into the conformational specificity of glycosyltransferases used in this study. Comparison of the structure of the polypeptide backbone in the presence and absence of carbohydrate attachment also provides an explanation for the lack of N-glycosylation in the Asn-containing mucin domain of MAdCAM-1, as well as for the glycosylation-induced cleavage of the glycopeptide esters linked to a solid support during synthesis.

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