Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting

Bioconjug Chem. 2016 Jun 15;27(6):1456-70. doi: 10.1021/acs.bioconjchem.6b00079. Epub 2016 May 17.

Abstract

G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA / chemistry*
  • DNA / metabolism
  • G-Quadruplexes / drug effects*
  • Humans
  • Ligands
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacology*
  • Protein Transport / drug effects
  • Stereoisomerism
  • Telomere / drug effects*
  • Telomere / genetics
  • Telomere / metabolism
  • Telomeric Repeat Binding Protein 2 / metabolism

Substances

  • Antineoplastic Agents
  • Ligands
  • Organoplatinum Compounds
  • Pt-NHC complex
  • Telomeric Repeat Binding Protein 2
  • DNA