Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines

Wenyan Wu, Diptesh Sil, Michal L. Szostak, Subbalakshmi S. Malladi, Hemamali J. Warshakoon, Matthew R. Kimbrell, Jens R. Cromer, Sunil A. David

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The toxicity of Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of Gram-negative sepsis. We had previously identified in rapid-throughput screens several guanylhydrazones as potent LPS binders. We were desirous of examining if the presence of the guanylhydrazone (rather than an amine) functionality would afford greater LPS sequestration potency. In evaluating a congeneric set of guanylhydrazone analogues, we find that C16 alkyl substitution is optimal in the N-alkylguanylhydrazone series; a homospermine analogue with the terminal amine N-alkylated with a C16 chain with the other terminus of the molecule bearing an unsubstituted guanylhydrazone moiety is marginally more active, suggesting very slight, if any, steric effects. Neither C16 analogue is significantly more active than the N-C16-alkyl or N-C16-acyl compounds that we had characterized earlier, indicating that basicity of the phosphate-recognizing cationic group, is not a determinant of LPS sequestration activity.

Original languageEnglish (US)
Pages (from-to)709-715
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2009

Bibliographical note

Funding Information:
This work was supported from NIH Grants 1R01 AI50107 and 1U01AI077947.

Keywords

  • Endotoxin
  • Guanylhydrazones
  • Lipopolyamines
  • Lipopolysaccharide
  • Sepsis
  • Shock

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