| 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 α-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.)... |
