Sialyl Lewis X (sLex) is an important antigenic determinant attached at the terminus of glycolipids that plays key roles in different cell-to-cell recognition events. Leukocyte rolling and extravasation along the vascular walls are, for example, mediated by well characterized interactions between the sLeX tetrasaccharide epitope and selectins (E and P). Excessive recruitment of leukocytes is associated with several acute and chronic conditions that include vaso-occlusive crisis for sickle-cell anemic patients, asthma, psoriasis and respiratory diseases. We report herein a novel series of sLex analogues that antagonize selectins. They feature tartrate-based tethers with defined conformational bias, ester functionalizations to afford favorable interactions with the tyrosine sulphate binding site, as well as a novel galactopyranoside bicyclic scaffold to lock the carboxylic acid orientation. These trans-bicyclogalactopyranosides are accessed through stereocontrolled intramolecular cyclization reactions that have been studied both experimentally and by DFT calculations.

Synthesis of sialyl Lewis-x analogues as selectin antagonists for the treatment of vascular occlusions and inflammatory disease

2019 Fall National Meeting

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