Medicinal Chemistry Research

, Volume 27, Issue 5, pp 1517–1527 | Cite as

Synthesis of nucleobase-neomycin conjugates and evaluation of their DNA binding, cytotoxicities, and antibacterial properties

  • Siwen Wang
  • Mandeep Singh
  • Mingheng Ling
  • Danni Li
  • Krege M. Christison
  • Joan Lin-Cereghino
  • Geoff P. Lin-Cereghino
  • Liang Xue
Original Research
  • 26 Downloads

Abstract

Neomycin is known to preferentially bind to A-form nucleic acid structures including triplex DNA, DNA and RNA hybrid, and duplex RNA. Tethering a DNA intercalator moiety to the C5” position of the ring III of neomycin is a practical approach to develop potent binders targeting various nucleic acid secondary structures via a synergistic effect; however, the minimal stacking surface of the intercalating moiety required to exhibit the effect remains unclear. In the present work, we synthesized four nucleobase and neomycin conjugates via click chemistry. All four conjugates stabilized a DNA oligonucleotide triplex in the thermal denaturation experiments monitored by UV. The guanine-neomycin conjugate (6b) showed a better triplex stabilization effect than neomycin. All the conjugates, as well as neomycin, exhibited no thermal stabilization effect on a human telomeric DNA G-quadruplex. These results suggest that the synergistic effect of binding is vastly dependent on the surface area of the stacking moiety of the conjugates. In addition, tethering a nucleobase to the C5” position of neomycin enhanced the cytotoxicity of neomycin toward MCF-7 and HeLa cancer cells but decreased the antibacterial effect of neomycin against several Gram-negative and Gram-positive bacterial species.

Keywords

Neomycin DNA binding ligands Cell viability Antibacterial effect 

Abbreviations

Neo

neomycin

rRNA

ribosomal RNA

TAR

trans-activation response element

AMEs

aminoglycoside-modifying enzymes

BQQ

benzo[f]quino[3,4-b]quinoxaline

DMSO

dimethyl sulfoxide

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

IC50

half maximal inhibitory concentration

MIC

minimum inhibitory concentration

NMR

nuclear magnetic resonance

UHPLC

ultra-high-performance liquid chromatography

IR

infrared

ESI

electrospray ionization

HRMS

high-resolution mass spectrometry

TOF

time of flight

FBS

fetal bovine serum

DMEM

Dulbecco’s modified eagle’s medium

KB test

Kirby–Bauer test

OD

optical density

Notes

Acknowledgements

This work was supported by the University of the Pacific. We also thank Dr. William K. Chan for providing MCF-7 and HeLa cells.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2169_MOESM1_ESM.docx (6.4 mb)
Supplementary Data

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of the PacificStocktonUSA
  2. 2.Department of Biological SciencesUniversity of the PacificStocktonUSA

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