Synthesis and biological evaluation of a lipid A derivative that contains an aminogluconate moiety

Balaji Santhanam, Margreet A. Wolfert, James N. Moore, Geert-Jan Boons

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

A highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. The synthetic derivatives are 2-aminogluconate 3 and 2-aminogluconolactone 4, both of which lack C-3 acylation. These derivatives were obtained by the preparation of disaccharides in which the two amino groups and the C-3′ hydroxy group could be modified individually with acyl or β-hydroxy fatty acyl groups. Detailed NMR spectroscopy and MS analysis of 3 and 4 revealed that, even under neutral conditions, the two compounds equilibrate. The synthetic compounds lack the proinflammatory effects of Escherichia coli lipopolysaccharide (LPS), as indicated by an absence of tumor necrosis factor production. Although 3 and 4 were able to antagonize E. coli LPS, they were significantly less potent than the synthetic compound 2, which is acylated at C-3, and R. sin-1 LPS; these results indicate that the β-hydroxy fatty acyl group at C-3 contributes to the antagonistic properties of R. sin-1 LPS. Based on a comparison of the biological responses of the synthetic lipid A derivatives with those of the R. sin-1 LPS and lipid A, the 3-deoxy-D-manno-octulosonic moieties appear to be important for the optimal antagonization of enteric LPS-induced cytokine production.
Original languageEnglish
Pages (from-to)4798-4807
Number of pages10
JournalChemistry - A European Journal
Volume10
Issue number19
DOIs
Publication statusPublished - 4 Oct 2004
Externally publishedYes

Keywords

  • Carbohydrates
  • Cytokines
  • Glycolipids
  • Inhibitors
  • Lipopolysaccharides
  • aminogluconate
  • cytokine
  • gluconic acid
  • lipid A
  • lipopolysaccharide
  • tumor necrosis factor
  • unclassified drug
  • acylation
  • article
  • bacterial outer membrane
  • derivatization
  • drug screening
  • drug synthesis
  • Gram negative sepsis
  • hydrolysis
  • mediator release
  • nonhuman
  • nuclear magnetic resonance spectroscopy
  • protein domain
  • Rhizobium
  • septicemia

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