STUDIES ON SELECTIN BLOCKERS .2. NOVEL SELECTIN BLOCKER AS POTENTIAL THERAPEUTICS FOR INFLAMMATORY DISORDERS

As a part of our studies of selectin blockers, we prepared 1-(2-tetrad ecylhexadecyl)-3'-O-sulfo Le(X) 1 and 1-(2-tetradecylhexadecyl) sLe(X) 2 and examined their inhibitory activities against natural ligand (sL e(X)) binding to E-, P-, and L-selectins. Compounds 1 and 2 were 2 tim es more potent than the sLe(X) tetrasaccharide toward E-selectin bindi ng and up to 4 times more potent than sLe(X) toward P- and L-selectin binding. Interestingly, compound 1 provided dose-dependent protective effects against an immunoglobulin E-mediated skin reaction in mouse ea rs. This protective effect was associated with diminished tissue accum ulation of neutrophils in the ear (as assessed by myeloperoxidase). Th ese findings indicate that the modification of sLe(X) or 3'-O-sulfo Le (X) with a ''branched anchor'', a 2-tetradecylhexadecyl group, is usef ul in the design of a more potent selectin blocker, which has broad in hibitory activities toward all selectins.