SULFATED GALACTOCEREBROSIDES AS POTENTIAL ANTIINFLAMMATORY AGENTS

Native sulfatides, as well as many sulfated glycolipids, have been sho wn to avidly bind to the selectin receptors. In vivo, native sulfatide s significantly block activity in selectin-dependent inflammatory resp onses. The fact that nonsulfated galactocerebrosides did not inhibit s electin-mediated adhesion identified a critical role for the anionic s ulfate residue. We therefore initiated a program to evaluate the activ ity of position isomers. This study showed a binding selectivity for t he positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs, Furthermore, it was discovered that the attachment of lipophilic substituents on the c arbohydrate ring was tolerated, consistent with the presence of a lipo philic pocket in the binding cavity. This resulted in compounds with a 6-fold increased potency.