The influence of the long chain fatty acid on the antagonistic activities of Rhizobium sin-1 lipid A.
The lipid A from nitrogen-fixing bacterial species Rhizobium sin-1 is structurally unusual due to lack of phosphates and the presence of a 2-aminogluconolactone and a very long chain fatty acid, 27-hydroxyoctacosanoic acid (27OHC28:0), moiety. This structurally unusual lipid A can antagonize TNF-alpha production by human monocytes induced by Escherichia coli LPS. To establish the relevance of the unusual long chain 27-hydroxyoctacosanoic acid for antagonistic properties, a highly convergent strategy for the synthesis of several derivatives of the lipid A of R. sin-1 has been developed. Compound 1 is a natural R. sin-1 lipid A having a 27-hydroxyoctacosanoic acid at C-2', compound 2 contains an octacosanoic acid moiety at this position, and compound 3 is modified by a short chain tetradecanoic acid. Cellular activation studies with a human monocytic cell line have shown that the octacosanoic acid is important for optimal antagonistic properties. The hydroxyl of the natural 27-hydroxyoctacosanoic moiety does, however, not account for inhibitory activity. The resulting structure-activity relationships are important for the design of compounds for the treatment of septic shock.
Zhang
Yanghui
Y
Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
Wolfert
Margreet A
MA
Boons
Geert-Jan
GJ
D002460:Cell Line; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008050:Lipid A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012231:Rhizobium / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D008050:Lipid A