Design of sialyl Lewisx glycomimetics: A novel approach towards the synthesis of sugar-coated anti-inflammatory drugs.

Abstract

The tetrasaccharide sialyl Lewisx (SLex) is the smallest recognizable ligand for selectins. The binding of SLe x to the selectins triggers the inflammatory cascade and recruits leukocytes to the injured cells. Chronic and acute inflammatory diseases result from the over-recruitment of leukocytes leading to damage of normal cells. Carbohydrate-based mimetics, maintaining functionality while improving stability, binding affinity and structural simplicity, are ideal candidates for anti-inflammatory drugs. Sialyl Lewisx glycomimetics were synthesized using two different convergent approaches. Each synthesis used an enzyme-resistant alpha-carbon-linked fucosyl moiety (C-glycoside) to replace the unstable anomeric oxygen linkage of the natural ligand. One synthetic route coupled a rigid proline ring to the fucosyl carboxylic acid derivative made from L-fucose to form one branch of the mimetic. The second branch was synthesized by coupling modified amines to form functionalized peptide chains of various lengths. The second convergent approach used novel olefin metathesis chemistry in the preparation to orchestrate a stereoselective cis-alkene bond formation extending from the fucosyl branch of the synthetic pathway. (Abstract shortened by UMI.)