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.

Nicolás Veiga,Natalia Alvarez,Gianella Facchin,Eduardo E Castellano,María H Torre,Javier Ellena

doi:10.3390/molecules26216520

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.

Highlights

Metal-based drugs have played an important role in cancer treatment and in the expansion of research groups focused on the development of new antitumor drugs
The charge neutrality in the complexes was achieved by the monodeprotonation of each AA and bideprotonation of each dipeptide, both in the homoleptic and the heteroleptic complexes
Almost all the homoleptic copper dipeptide complexes presented similar stoichiometry, except for [Cu(AlaLeu)3 (H2 O)(CO3 )]·PF6 ·H2 O where the carbonate anion acts as a bridging ligand, which was not observed for the other complexes synthesized and crystallized following the same procedure

Summary

Introduction

Metal-based drugs have played an important role in cancer treatment and in the expansion of research groups focused on the development of new antitumor drugs It is well-known that cisplatin and subsequent generations (carboplatin, oxalylplatin, heptaplatin and picoplatin) have shown high effectiveness for the treatment of tumors in clinical practice and present several toxic effects [1]. Kellett et al [2] suggest that this could be due to the fact that metal-coordination compounds are reactive They can exchange ligands, participate in redox reactions and have multiple mechanisms of action. This intrinsic reactivity of the coordination compounds presents two opposing aspects that should be evaluated On one hand, it contributes to the prodrug character of these compounds, whereas, on the other hand, it has established the idea that these compounds’ mechanisms of action are difficult to study and understand. The latter is changing and several metal-based drugs are in clinical trials and many more are awaiting ethical approval to join the tests [3,4,5]

Methods

Results

Conclusion