Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)(2)](2+) Shows Unattended DNA Cleavage Activity upon Fluorination

[Cu(phen)(2)](2+) (phen=1,10‐phenanthroline) is the first and still one of the most efficient artificial nucleases. In general, when the phen ligand is modified, the nucleolytic activity of its Cu(II) complex is significantly reduced. This is most likely due to higher steric bulk of such ligands and thus lower affinity to DNA. Cu(II) complexes with phen ligands having fluorinated substituents (F, CF(3), SF(5), SCF(3)) surprisingly showed excellent DNA cleavage activity—in contrast to the unsubstituted [Cu(phen)(2)](2+)—in the absence of the otherwise required classical, bioabundant external reducing agents like thiols or ascorbate. This nucleolytic activity correlates well with the half‐wave potentials E (1/2) of the complexes. Cancer cell studies show cytotoxic effects of all complexes with fluorinated ligands in the low μm range, whereas they were less toxic towards healthy cells (fibroblasts).