Development of copper(II)-diimine-iminodiacetate mixed ligand complexes as potential antitumor agents

In order to seek for new compounds with antitumor activity, our research group is focused on copper complexes with mixed ligands. This work presents the synthesis and characterization of eight compounds with general formula [Cu(iminodiacetate)(diimine)(H2O)(x)], with x = 0 or 1, and their cytotoxic activities against tumor cells. The chosen diimine ligands were: 2,2-dipyridil-amine (bam), 2,2-bipyridine (bipy), 4,4-dimethy1-2,2-bipyridine (dmb), 1,10-phenanthroline (phen), 4-methyl-1,10-phenanthroline (4met-phen), 5-nitro-1,10-phenanthroline (5nitro-phen), neocuproine (neo) and bathophenanthroline (batho). Compounds were characterized in solid state using FT-IR, TGA, DSC and single crystal X-ray diffraction analyses by which five new crystal structures were determined. Common features of the coordination scheme include fac-NO + O isomerism of the iminodiacetate (ida) ligand, except for the complex with neo where the ida presents mer-NO2 isomerism. The diimine ligand completes the equatorial plane for the facial isomers, with different degrees of distortion in the octahedral or square-based pyramid geometry depending on the diimine ligand, whereas the neo is perpendicular to the equatorial plane in the latter. Studies in solution, using EPR, UV-Vis spectroscopy and conductimetry, showed that the copper coordination observed in solid state is retained except for the batho complex. DNA interaction studies evidenced that the complexes bind to this biomolecule, inducing different conformational changes. Biological experiments evidenced that all complexes induce cell death in the cell line MDA-MD-231 (metastasic breast cancer line). [Cu(ida)(neo)] and [Cu(ida)(batho)] presented the highest activity. Taken all these data together we propose that [Cu(ida)(neo)] and [Cu(ida)(batho)] are good candidates for further studies in vitro and in vivo.