The 2-aminogluconate isomer of Rhizobium sin-1 lipid A can antagonize TNF-α production induced by enteric LPS

The naturally occurring lipopolysaccharide (LPS) from Rhizobium sin-1, a nitrogen-fixing bacterial species, can prevent the induction of the tumor necrosis factor TNF-α induced by enteric LPS. The proximal saccharide moiety of R. sin-7 lipid A can exist in two forms, namely as a 2-aminogluconolactone or 2-aminogluconate. As it is unknown which of these forms is responsible for the antagonistic properties of R. sin-1 lipid A, compound 4 was prepared, and its inflammatory properties were studied. This compound contains a methyl ether at the C-5 hydroxyl, which prevents lactonization and therefore is ideally suited to determine whether the 2-aminogluconate possesses antagonistic properties. Compound 4 was synthesized by a highly convergent approach with a key disaccharide building block functionalized with a set of orthogonal protecting groups. The novel synthetic compound lacks proinflammatory properties, as indicated by an absence of TNF-a protein production. This compound was, however, able to antagonize the production of TNF-α induced by enteric LPS; this indicates that the 2-aminogluconate form of R. sin-1 lipid A is responsible for its biological properties. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.