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BioMetals

, Volume 28, Issue 3, pp 541–551 | Cite as

Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity

  • Cheng Ji
  • Marvin J. Miller
Article

Abstract

Syntheses of two Siderophore–fluoroquinolone conjugates with a potential reduction triggered linker for drug release are described. The “trimethyl lock” based linker incorporated in the conjugates was designed to be activated by taking advantage of the reductive pathway of bacterial iron metabolism. Electrochemical and LC–MS studies indicated that the linker is thermodynamically reducible by common biological reductants and the expected lactonization proceeds rapidly with concomitant release of the drug. Antibacterial activity assays revealed that conjugates with the reduction-triggered linker were more potent than their counterparts with a stable linker, which suggests that drug release occurs inside bacterial cells.

Keywords

Siderophores Antibiotics Trojan horse Iron transport Drug delivery Drug release 

Notes

Acknowledgments

Partial funding for this work was provided by NIH Grant AI054193. C. J. gratefully acknowledges the UND Chemistry-Biochemistry-Biology (CBBI) Interface Program funded by NIH (T32GM075762) for fellowship support. We gratefully acknowledge the use of the NMR facilities provided by the Lizzadro Magnetic Resonance Research Center at the University of Notre Dame (UND) under the direction of Dr. Jaroslav Zajicek and the mass spectrometry services provided by The UND Mass Spectrometry & Proteomics Facility (Mrs. N. Sevova, Dr. W. Boggess, and Dr. M. V. Joyce; supported by the National Science Foundation under CHE-0741793). We gratefully thank Mrs. Patricia A. Miller (UND) for antibacterial susceptibility testing.

Supplementary material

10534_2015_9830_MOESM1_ESM.doc (3.7 mb)
Experimental procedures, copies of spectral data, and characterization data. This material is available free of charge via the internet (DOC 3814 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre DameUSA

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