Molecular Recognition of Parallel DNA Quadruplex d(TTAGGGT)4 by Mitoxantrone: Binding with 1:2 Stoichiometry Leading to Thermal Stabilization and Telomerase Inhibition

Chembiochem. 2016 Apr 1;17(7):554-60. doi: 10.1002/cbic.201500588. Epub 2016 Feb 16.

Abstract

The interaction of the anthraquinone derivative mitoxantrone, a semisynthetic anti-cancer drug with two non-planar side chains, with heptamer G-quadruplex d(TTAGGGT)4 , which contains the human telomere DNA sequence, was evaluated by differential scanning calorimetry, fluorescence Job plotting, absorption, and NMR and CD spectroscopy. Binding led to thermal stabilization of DNA (ΔTm =13-20 °C). The spectra revealed that two mitoxantrone molecules bind externally at two sites of the DNA quadruplex as monomers, by partial insertion of the chromophore and side-chain interaction at the grooves. The inhibition of telomerase (IC50 =2 μM), as determined by a TRAP assay, can be attributed to thermal stabilization of the DNA quadruplex because of the interactions with mitoxantrone. The studies revealed highly specific molecular recognition between a ligand and a parallel-stranded G-quadruplex; this might serve as a platform for the rational design of new drugs.

Keywords: G-quadruplexes; NMR spectroscopy; circular dichroism; mitoxantrone; telomerase inhibition; thermal stabilization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calorimetry, Differential Scanning
  • Circular Dichroism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • G-Quadruplexes*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mitoxantrone / chemistry*
  • Mitoxantrone / pharmacology
  • Protein Binding
  • Protein Stability
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism
  • Temperature

Substances

  • Enzyme Inhibitors
  • Mitoxantrone
  • Telomerase