Probing the carbohydrate recognition domain of E-selectin: the importance of the acid orientation in sLex mimetics.

Alexander Titz, John Patton, Martin Smiesko, Zorana Radic, Oliver Schwardt, John L Magnani, Beat Ernst

Index: Bioorg. Med. Chem. 18(1) , 19-27, (2010)

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Abstract

The selectin-leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis(x) (sLe(x)), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe(x) as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe(x) mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-selectin.Copyright (c) 2009 Elsevier Ltd. All rights reserved.