Macrocyclic Cu^II complexes with [N_XO_Y] donor sets of different N/O ratios were synthesised resulting in a series ranging from cyclen (X = 4, Y = 0: 1) to 12-crown-4 (X = 0, Y = 4: 6) complexes. In order to elucidate the structure of the complexes UV/Vis spectroscopy and X-ray crystallography were applied, focusing especially on the literature-unknown compounds with regioisomeric [N₂O₂] and [NONO] donor sets (3, 4). The complexes were subjected to DNA cleavage experiments under reducing conditions and were also tested in the absence of a reducing agent. Although 3 and 6 were the most active DNA cleavers in the presence of reducing ascorbate, both of them and 4 also cleaved DNA (not hydrolytically) in its absence. This brings up questions regarding the cleavage mechanism. The present study is an expansion of our previously reported finding that heterosubstitution in macrocyclic ligands leads to changes in oxidative DNA cleavage activity of Cu^II complexes.

This microreview summarizes recent research in the field of artificial nucleases, in particular those based on copper(II) in an N-donating ligand environment. This review is divided into three parts describing different ligand classes that have shown promising results in DNA cleavage chemistry: aromatic N-donors, aliphatic N-donors, and peptide ligands. Whereas nature has created very efficient nucleases, artificial nucleases aim at different selectivities and higher stability under various conditions. Artificial nucleases based on metal complexes comprise Lewis acidic or redox-active metal centers allowing for either hydrolytic or oxidative DNA cleavage. The focus of our research and thus also of this microreview is copper, whose Cu^II ion combines both properties. Depending on the ligand scaffold and reaction conditions, either pathway or even both are thus conceivable. Those different pathways lead to molecular biological and medicinal applications.

Invited for the cover of this issue is the group of Nora Kulak at Freie Universität Berlin. The cover image shows metal complexes capable of cleaving DNA, so-called artificial metallonucleases based on copper as the central atom and comprising N-donor ligands. Heteroaromatic, macrocyclic, and peptidic ligand systems are adumbrated in the background.

The reaction of the ditopic bis(benzoylhydrazone) of isophthalaldehyde (H₂L) with copper(II) acetate in methanol under aerobic conditions afforded a green solid that contains the tetranuclear complex [Cu₄L*₂(OCH₃)₂] (1). The ligand L*, a bis(benzoylhydrazone) of 2,6-diformylphenol, resulted from hydroxylation of the corresponding isophthalaldehyde derivative. H₂L and 1 were characterized by different spectroscopic techniques, and their molecular structures were confirmed by single-crystal X-ray diffraction. The reaction of H₂L with copper(II) under argon, on the other hand, resulted in a brown diamagnetic solid [Cu₂L]·H₂O (2) containing copper(I), which was readily transformed into 1 when exposed to air. In contrast, the reaction with [Cu(CH₃CN)₄][BF₄] afforded a mononuclear complex [Cu(H₂L)][BF₄]·H₂O (3), and single crystals of [Cu(H₂L)₂][BF₄] (4) were isolated from its dichloromethane solution. H₂L cleaved plasmid DNA in the presence of copper(II) independently of any reducing agent, but more efficiently when ascorbate was present. The cleavage process is likely oxidative because the enzyme catalase, which decomposes hydrogen peroxide, quenched the reaction. In the absence of ascorbate, the ligand H₂L presumably acts as the reductant in the redox reaction, as exploited also in the synthesis of 1. As a consequence, a variety of reactive oxygen species were generated, eventually also leading to the cleavage of DNA (“self-activating” chemical nuclease).