Synthesis and biological evaluation of Rhizobium sin-1 lipid A derivatives.
A highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. The approach employed the advanced intermediate 3-O-acetyl-6-O-(3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-beta-d-glucopyrano-syl)-2-azido-4-O-benzyl-2-deoxy-1-thio-alpha-d-glucopyranoside (5), which is protected in such a way that the anomeric center, the C-2 and C-2' amino groups, and the C-3 and C-3' hydroxyls can be selectively functionalized. The synthetic strategy was used for the preparation of 2-deoxy-6-O-[2-deoxy-3-O-[(R)-3-hydroxy-hexadecanoyl]-2-[(R)-3-octacosanoyloxy-hexadecan]amido-beta-d-glucopyranosyl]-2-[(R)-3-hydroxy-hexadecan]amido-3-O-[(R)-3-hydroxy-hexadecanoyl]-alpha-d-glucopyranose (11) and 2-deoxy-6-O-[2-deoxy-3-O-[(R)-3-hydroxy-hexadecanoyl]-2-[(R)-3-octacosanoyloxy-hexadecan]amido-beta-d-glucopyranosyl]-2-[(R)-3-hydroxy-hexadecan]amido-3-O-[(R)-3-hydroxy-hexadecanoyl]-d-glucono-1,5-lactone (13), which contain an unusual octacosanoic acid moiety and differ in the oxidation state of the anomeric center. The results of biological studies indicate that 11 and 13 lack the proinflammatory effects of Escherichia coli lipopolysaccharides (LPS). Furthermore, 13 emulated the ability of heterogeneous R. sin-1 LPS to antagonize enteric LPS, providing evidence for the critical role of the gluconolactone moiety of R. sin-1 LPS in mediating this antagonistic effect. Compound 13 is the first example of a lipid A derivative that is devoid of phosphate but possesses antagonistic properties, making it an attractive lead compound for development of a drug to use in the treatment of Gram-negative septicemia.
Demchenko
Alexei V
AV
Complex Carbohydrate Research Center, The University of Georgia, 220 Riverbend Road, Athens 30602, USA.
Wolfert
Margreet A
MA
Santhanam
Balaji
B
Moore
James N
JN
Boons
Geert-Jan
GJ
D002460:Cell Line; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012231:Rhizobium / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha