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

ACS Med Chem Lett. 2013 May 9;4(5):470-474. doi: 10.1021/ml3004507.

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 non-specific 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 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.

Keywords: aminoglycoside derivatives; ciprofloxacin-induced DNA cleavage; glycosaminoglycan mimic; sulfated oligosaccharide; topoisomerase inhibitor.