Correlation between DNA interactions and cytotoxic activity of four new ternary compounds of copper(II) with N-donor heterocyclic ligands

J Inorg Biochem. 2014 Mar:132:67-76. doi: 10.1016/j.jinorgbio.2013.09.014. Epub 2013 Oct 5.

Abstract

Four new ternary complexes of copper(II) were synthesized and characterized: [Cu(hyd)(bpy)(acn)(ClO4)](ClO4)] (1), [Cu(hyd)(phen)(acn)(ClO4)](ClO4)] (2), [Cu(Shyd)(bpy)(acn)(ClO4)](ClO4)] (3) and [Cu(Shyd)(phen)(acn)(ClO4)](ClO4)] (4), in which acn=acetonitrile; hyd=2-furoic acid hydrazide, bpy=2,2-bipyridine; phen=1,10-phenanthroline and Shyd=2-thiophenecarboxylic acid hydrazide. The cytotoxic activity of the complexes in a chronic myelogenous leukemia cell line was investigated. All complexes are able to enter cells and inhibit cellular growth in a concentration-dependent manner, with an activity higher than that of the corresponding free ligands. The substitution of Shyd for hyd increases the activity, while the substitution of bpy for phen renders the complex less active. Therefore, the most potent complex is 4 with an IC50 value of 1.5±0.2μM. The intracellular copper concentration needed to inhibit 50% of cell growth is approximately 7×10(-15)mol/cell. It is worth notifying that a correlation between cytotoxic activity, DNA binding affinity and DNA cleavage was found: 1<3<2<4.

Keywords: Cellular concentration; Cytotoxicity; DNA binding; DNA cleavage; Ternary copper compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Coordination Complexes* / chemical synthesis
  • Coordination Complexes* / chemistry
  • Coordination Complexes* / toxicity
  • Copper / chemistry*
  • Copper / toxicity*
  • Crystallography, X-Ray
  • DNA / chemistry*
  • Growth Inhibitors / chemical synthesis
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / toxicity
  • Heterocyclic Compounds* / chemistry
  • Heterocyclic Compounds* / toxicity
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • K562 Cells
  • Ligands
  • Models, Molecular
  • Nitrogen / chemistry

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Growth Inhibitors
  • Heterocyclic Compounds
  • Ligands
  • Copper
  • DNA
  • Nitrogen