Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders

J Inorg Biochem. 2016 Jul:160:275-86. doi: 10.1016/j.jinorgbio.2016.04.002. Epub 2016 Apr 9.

Abstract

The formation of quadruple-stranded DNA induced by planar metal complexes has particular interest in the development of novel anticancer drugs. This is especially relevant for the inhibition of telomerase, which plays an essential role in cancer cell immortalization and is overexpressed in ca. 85-90% of cancer cells. Moreover, G-quadruplexes also exist in other locations in the human genome, namely oncogene promoter regions, and it has been hypothesized that they play a regulatory role in gene transcription. Herein we report a series of new anthracene-containing terpyridine ligands and the corresponding Cu(II) and Pt(II) complexes, with different linkers between the anthracenyl moiety and the terpyridine chelating unit. The interaction of these ligands and metal complexes with different topologies of DNA was studied by several biophysical techniques. The Pt(II) and Cu(II) complexes tested showed affinity for quadruplex-forming sequences with a good selectivity over duplex DNA. Importantly, the free ligands do not have significant affinity for any of the DNA sequences used, which shows that the presence of the metal is essential for high affinity (and selectivity). This effect is more evident in the case of the Pt(II) complexes. Moreover, the presence of a longer linker between the chelating terpyridine unit and the anthracene moiety enhances the interaction with G-quadruplex-forming sequences. We further evaluated the ability of the Cu(II) complexes to interact with, and stabilize G-quadruplex containing regions in oncogene promoters via a polymerase stop assay. These studies indicated that the metal complexes are able to induce G-quadruplex formation and stop polymerase activity.

Keywords: Copper complexes; DNA interaction; G-quadruplex; Platinum complexes; Terpyridine derivatives; c-myc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / chemistry*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Binding Sites
  • Cations, Divalent
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Copper / chemistry
  • Crystallography, X-Ray
  • Fluorescence Resonance Energy Transfer
  • Gene Expression
  • Humans
  • Oligonucleotides / chemistry
  • Platinum / chemistry
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyridines / chemistry*
  • Solutions

Substances

  • Anthracenes
  • Antineoplastic Agents
  • Cations, Divalent
  • Coordination Complexes
  • Oligonucleotides
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Solutions
  • Platinum
  • Copper