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

• Four new complexes of CuII with mixed ligands were synthesized and characterized.
• The complexes enter cells, bind and cleave DNA molecule, and inhibit cellular growth.
• The higher the DNA binding constant, the greater is the cytotoxic effect.
• A good correlation between cytotoxicity and DNA cleavage activity was found.

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 ± 0.2 μM. 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.

The synthesis, characterization, DNA interactions, cellular uptake and cytotoxic effect of four copper(II) complexes containing 2-furoic acid hydrazide derivatives and N-donor heterocyclic ligands are reported. The complexes enter tumoral cells, bind and cleave DNA molecule, and inhibit cellular growth. A good correlation between cytotoxicity and DNA cleavage activity was found.Figure optionsDownload as PowerPoint slide