Selective inhibition of bacterial and human topoisomerases by N-arylacyl O-sulfonated aminoglycoside derivatives

Amanda M. Fenner, Lisa M. Oppegard, Hiroshi Hiasa, Robert J. Kerns

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Numerous therapeutic applications have been proposed for molecules that bind heparin-binding proteins. Development of such compounds has primarily focused on optimizing the degree and orientation of anionic groups on a scaffold, but utility of these polyanions has been diminished by their typically large size and nonspecific interactions with many proteins. In this study, N-arylacyl O-sulfonated aminoglycosides were synthesized and evaluated for their ability to selectively inhibit structurally similar bacterial and human topoisomerases. It is demonstrated that the structure of the aminoglycoside and of the N-arylacyl moiety imparts selective inhibition of different topoisomerases and alters the mechanism. The results here outline a strategy that will be applicable to identifying small, structurally defined oligosaccharides that bind heparin-binding proteins with a high degree of selectivity.

Original languageEnglish (US)
Pages (from-to)470-474
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume4
Issue number5
DOIs
StatePublished - May 9 2013

Keywords

  • Topoisomerase inhibitor
  • aminoglycoside derivatives
  • ciprofloxacin-induced DNA cleavage
  • glycosaminoglycan mimic
  • sulfated oligosaccharide

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