Molecular basis of structure-activity relationships between salphen metal complexes and human telomeric DNA quadruplexes

J Med Chem. 2012 Jan 12;55(1):209-22. doi: 10.1021/jm201140v. Epub 2011 Dec 13.


The first X-ray crystal structures of nickel(II) and copper(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these salphen-metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure-activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Copper*
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • G-Quadruplexes*
  • Humans
  • Models, Molecular*
  • Molecular Structure
  • Nickel*
  • Phenylenediamines / chemical synthesis
  • Phenylenediamines / chemistry*
  • Phenylenediamines / pharmacology
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors
  • Telomere / genetics*


  • Antineoplastic Agents
  • Coordination Complexes
  • Phenylenediamines
  • salphen
  • Copper
  • Nickel
  • Telomerase

Associated data

  • PDB/3QSC
  • PDB/3QSF