3-O-desacyl monophosphoryl lipid a derivatives: Synthesis and immunostimulant activities

The synthesis of a series of novel analogues of lipid A, the active princip le of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphon o and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R5 95 lipid A have been replaced with hydrogen and the length of the normal fa tty acyl residues has been systematically varied. Normal fatty acid chain l ength in the 3-O-desacyl monophosphoryl lipid A (MLS) series is shown to be a critical determinant of iNOS gene expression in activated mouse macropha ges and the induction of proinflammatory cytokines in human peripheral mono cytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-gala ctosamine-treated mice shows that toxic effects in the MLA series can be am eliorated by modifying fatty acid chain length. When used as an adjuvant fo r tetanus toroid vaccines, certain MLA derivatives enhance the production o f tetanus toroid-specific antibodies in mice.