Abstract
Copper(II) complexes containing non-steroidal anti-inflammatory drugs (NSAIDs) have been the subject of many research papers and reviews. Here we report the synthesis, spectroscopic study and biological activity of novel mixed copper(II) complexes with NSAIDs: tolfenamic (tolf), mefenamic (mef) and flufenamic (fluf) acids and phenanthroline (phen): [Cu(tolf-O,O′)2(phen)] (1), [Cu(mef-O,O′)2(phen)] (2), [Cu(fluf-O,O′)2(phen)] (3). Complexes were characterized by X-ray analysis and EPR spectroscopy. Complexes 1–3 are monomeric, six-coordinate and crystallize in a monoclinic space group. Interaction of Cu(II) complexes with DNA was studied by means of absorption titrations, viscosity measurements and gel electrophoresis. The relative ability of the complexes to cleave DNA even in the absence of hydrogen peroxide is in the order 3 > 2 > 1. Application of the reactive oxygen species (ROS) scavengers, L-histidine, DMSO and SOD confirmed that singlet oxygen, hydroxyl radicals (Fenton reaction) and superoxide radical were formed, respectively. Thus, in addition to mechanism of intercalation, redox-cycling mechanism which in turn lead to the formation of ROS contribute to DNA damage. Cu(II) complexes exhibit excellent SOD-mimetic activity in the order 3~1 > 2. The fluorescence spectroscopy revealed that albumin may act as a targeted drug delivery vehicle for Cu(II) complexes (K~106). The anticancer activities of complexes 1–3 were investigated using an MTS assay (reduction of the tetrazolium compound) against three cancer cell lines (HT-29 human colon adenocarcinoma, HeLa and T-47D breast cancer cells) and mesenchymal stromal cells (MSC). The most promising compound, from the viewpoint of its NSAID biological activity is 3, due to the presence of the three fluorine atoms participating in the formation of weak hydrogen-bonds at the DNA surface.
Proposed orientation of aryl substituents of the Cu(II) complexes 1–3 in their interaction with DNA. The intercalation efficiency of complexes and consequent unwinding of the helix depend on the orientation of remote substituents attached to aromatic rings of the non-steroidal anti-inflammatory drugs (NSAIDs) which can interact with the DNA strand. [Display omitted]
•Three novel mixed Cu(II) fenamates with phenanthroline were prepared and studied.•Cu(II) complexes are efficient superoxide dismutase-mimetics and DNA intercalators.•Reactive oxygen species-induced DNA damage is a result of a redox-cycling mechanism.•Cu(II) complexes interact with human serum albumin.•Complexes exhibit cytotoxic activity against several cancer cell lines.