Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds

Abstract

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu3(AlaLeu)3(H2O)3(CO3)]·PF6·H2O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H2O2 produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu–amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu–dipeptide–phen complexes are good SOD mimics but poor ROS producers. The activity of Cu–dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.

New anti-cancer explorations based on metal ions

“…Their findings showed that Cu-amino acid complexes were strong ROS producers and moderate SOD mimics. Conversely, Cu-dipeptide-phen complexes were good SOD mimics but poor ROS producers [ 185 ]. Therefore, their intrinsic reactivity needs to be evaluated when selecting coordination compounds.…”

New Copper(II)-L-Dipeptide-Bathophenanthroline Complexes as Potential Anticancer Agents—Synthesis, Characterization and Cytotoxicity Studies—And Comparative DNA-Binding Study of Related Phen Complexes

“…Our research group has been working to develop new copper compounds with a cytotoxic activity which may lead to anticancer agents. Different series of [Cu(L-dipeptide)(diimine)] compounds were synthesized and characterized (where diimine: phenanthroline, phen, 5-NO 2 -phenanthroline, 5-NO 2 -phen, neocuproine, neo and 3,4,7,8-tetramethyl-phenanthroline, tmp) [ 18 , 19 , 20 , 21 , 22 ]. In general, they are potent cytotoxic agents, more active than cisplatin, with neo and tmp complexes being the most active of the group.…”

Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential

“…In this way, antioxidants are being studied to develop more effective anticancer therapy [ 85 ]. Furthermore, it has been reported that some oxidants may act as the inducers of DNA damage response, which may result in cell death [ 86 , 87 ].…”