Acyclic analogues of lipid A: synthesis and biological activities.

ABSTRACT

The synthesis of a series of novel acyclic analogues of lipid A, the lipophilic terminal of lipopolysaccharide (LPS), is reported. In these compounds, the reducing glucose unit of lipid A has been replaced by an acyclic analogue unit (abbreviated as AAU) consisting of a spacer (of varying length), an (R)-3-hydroxytetradecanamido moiety (of varying configuration at the carbon of attachment), and a CO2H group. The AAU has been attached to the anomeric carbon of the nonreducing glucose unit of lipid A, either through glycosidic linkage or through an acyl linkage. Further, amide isosteres of these acyclic analogues have been prepared using suitably protected 2,3-diamino-2,3-dideoxyglucose instead of 2-amino-2-deoxyglucose. All the compounds were well characterized and were tested for their ability to induce TNF-alpha in mouse bone marrow-derived macrophages, to enhance nonspecific resistance to infection in mice and to induce endotoxic shock in mice. The results showed a dramatic dependence, for the first time, on the length of the spacer and on the configuration of the carbon bearing the amido group in the AAU part of the analogues.