Use of neomycin as a structured amino-containing side chain motif for phenanthroline-based G-quadruplex ligands and telomerase inhibitors

Chem Biol Drug Des. 2020 Nov;96(5):1292-1304. doi: 10.1111/cbdd.13741. Epub 2020 Jul 26.

Abstract

In this paper, we report the synthesis of a phenanthroline and neomycin conjugate (7). Compound 7 binds to a human telomeric G-quadruplex (G1) with a higher affinity compared with its parent compounds (phenanthroline and neomycin), which is determined by several biophysical studies. Compound 7 shows good selectivity for G-quadruplex (G4) DNA over duplex DNA. The binding of 7 with G1 is predominantly enthalpy-driven, and the binding stoichiometry of 7 with G1 is one for the tight-binding event as determined by ESI mass spectrometry. A plausible binding mode is a synergistic effect of end-stacking and groove interactions, as indicated by docking studies. Compound 7 can inhibit human telomerase activity at low micromolar concentrations, which is more potent than previously reported 5-substituted phenanthroline derivatives.

Keywords: DNA-binding ligands; G-quadruplex DNA; neomycin; phenanthroline; telomerase inhibition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • G-Quadruplexes*
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Neomycin / pharmacology*
  • Phenanthrolines / metabolism*
  • Telomerase / antagonists & inhibitors*
  • Thermodynamics

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Ligands
  • Phenanthrolines
  • Telomerase
  • Neomycin