Sulfated disaccharide inhibitors of L-selectin: deriving structural leads from a physiological selectin ligand

The selectins are a family of three adhesion molecules (L-, P-, and E-) that direct the interaction of circulating leukocytes with endothelial cells during the first step in recruitment to tissue sites. Their involvement in inflammatory disease makes the selectins attractive targets for anti-inflammatory therapy. The sialyl Lewis x tetrasaccharide binds weakly to all three selectins and has demonstrated anti-inflammatory activity in vivo. However, the synthetic difficulties inherent to sialylated and fucosylated oligosaccharides motivate the search for alternative antagonists. Here we demonstrate that information gained from the biochemical analysis of a physiological selectin ligand can provide new leads for small molecule design. Previous structural analysis of the oligosaccharide chains on GlyCAM-1, an endothelial-derived ligand for L-selectin, revealed two novel structures: 6'-sulfo sialyl Lewis x and 6-sulfo sialyl Lewis x. The sulfate esters on these structures are thought to be essential for high-affinity binding to L-selectin. By incorporating sulfate esters on the analogous positions of the disaccharide lactose, we generated a simple small molecule (lactose 6',6-disulfate) with greater inhibitory potency for L-selectin than sialyl Lewis x.