LIGAND RECOGNITION BY E-SELECTIN - SYNTHESIS, INHIBITORY ACTIVITY, AND CONFORMATIONAL-ANALYSIS OF BIVALENT SIALYL-LEWIS-X ANALOGS

Several sialyl Lewis x dimers anchored onto a galactose template or at tached to 1,4-butanediol or 1,5-pentanediol have been prepared chemoen zymatically and evaluated as inhibitors of E-selectin-mediated cell ad hesion. Two monosaccharide units were simultaneously incorporated (i.e ., Gal, NeuAc, Fuc) by a glycosyltransferase into a chemically synthes ized core structure containing GlcNAc and Gal. Each of the galactose-a nchored dimers had higher activity than the sialyl Lewis x pentasaccha ride la, with the general trend being 3,6-linked > 2,3 greater than or equal to 4,6 greater than or equal to 2,6 monomer. The dimers linked to butanediol or pentanediol showed the same level of activity as the pentasaccharide monomer. Conformational analysis of these dimers with NMR indicated that each sialyl Lewis x domain of the dimers retains th e same conformation as the monomer. The differences in activity of the dimers most likely derive from differences in the relative orientatio n and distance between the monomer domains, suggesting the importance of the linker used in the preparation of dimers.