Copper complexes as artificial DNA metallonucleases: From Sigman’s reagent to next generation anti-cancer agent?

Abstract

Abstract Platinum drugs continue to dominate medical oncology treatments but they have shortcomings associated with their use including dose-limiting toxic side effects and acquired or intrinsic drug resistance. Copper complexes have been extensively investigated as an alternative class of cancer therapeutic. In contrast to Pt drugs which covalently bind DNA nucleobases, Cu derivatives predominantly form non-covalent interactions with DNA – either via intercalation, electrostatic forces of attraction and/or major or minor groove binding. Sigman et al. pioneered research in the late 1970s into Cu complexes as potential chemical nuclease agents. Copper complexes have since been shown to induce DNA cleavage via nucleobase oxidation, hydrolysis of DNA phosphate esters and/or deoxyribose sugar oxidation. The scope of this review covers the period 2014 – present, with a distinct focus on Cu(II) systems which have been investigated as chemical nuclease agents. Specifically we describe how Cu complexes exert their chemical nuclease activity prior to presenting an overview of Cu complexes incorporating Schiff bases, amino acids, peptides, azoles, terpyridines or polypyridyls as ligands as well as including a section on dinuclear Cu complexes and Cu complexes incorporating natural products or bioactive ligands.