Efficient DNA cleavage mediated by mononuclear mixed ligand copper(II) phenolate complexes: The role of co-ligand planarity on DNA binding and cleavage and anticancer activity

The new mononuclear copper(II) complexes [Cu(L)(H2O)2]+1 and [Cu(L)(diimine)]+2–6, where LH = 2-[(2-dimethylaminoethylimino)methyl]phenol and diimine = 2,2′-bipyridine (bpy) (2), or 1,10-phenanthroline (phen) (3), or dipyrido[3,2-f:2′,3′-h]quinoxaline (dpq) (4) or dipyrido[3,2-a:2′,3′-c]phenazine (dppz) (5) or 11,12-dimethyldipyrido[3,2-a:2′,3′-c]phenazine (dmdppz) (6), have been isolated and characterized. The X-ray crystal structures of 2 contains the monomeric complex molecule with a trigonal bipyramidal distorted square pyramidal (TBPDSP) coordination geometry, while 4 and 6 with square pyramidal distorted trigonal bipyramidal (SPDTBP) coordination geometry. The amine nitrogen of − NMe2 group of the tridentate primary ligand is located at one of the corners of the square plane in 2 and 6 but in the axial position in 4. The interaction of the complexes with calf thymus DNA has been investigated using UV-visible and fluorescence spectroscopy, and viscosity measurements to understand the effect of diimine co-ligands on the mode and extent of DNA binding. The complexes 4 and 5 interact with calf thymus DNA more strongly than the other complexes through partial intercalation of the extended planar ring of the dpq (4) and dppz (5) co-ligands with the DNA base stack. All the complexes, except 1, effect the double strand DNA cleavage of plasmid DNA and 5 cleaves plasmid DNA in the absence of a reductant at a concentration (40 μM) lower than 4. It is remarkable that all the complexes display cytotoxicity against human breast cancer cell lines (MCF-7) and human cervical epidermoid carcinoma cell lines (ME 180) with potency higher than the currently used chemotherapeutic agent cisplatin and that 5 exhibits cytotoxicity higher than the other complexes.

Both [Cu(L)(dpq)]+ and [Cu(L)(dppz)]+ complexes display stronger DNA binding affinity, prominent DNA cleavage activity without requiring a co-reactant and higher cytotoxicity than the other complexes, due to the enhanced planarity and hydrophobicity of dpq and dppz co-ligands. They induce cell death through apoptosis and necrosis against MCF-7 cancer cell lines.Figure optionsDownload as PowerPoint slide