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We report a series of copper(II) artificial metallo‐nucleases (AMNs) and demonstrate their DNA damaging properties and in‐vitro cytotoxicity against human‐derived pancreatic cancer cells. The compounds combine a tris‐chelating polypyridyl ligand, di‐(2‐pycolyl)amine (DPA), and a DNA intercalating phenanthrene unit. Their general formula is Cu‐DPA‐N,N' (where N,N'=1,10‐phenanthroline (Phen), dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ)). Characterisation was achieved by X‐ray crystallography and continuous‐wave EPR (cw‐EPR), hyperfine sublevel correlation (HYSCORE) and Davies electron‐nuclear double resonance (ENDOR) spectroscopies. The presence of the DPA ligand enhances solution stability and facilitates enhanced DNA recognition with apparent binding constants (Kapp) rising from 105 to 107 m−1 with increasing extent of planar phenanthrene. Cu‐DPA‐DPPZ, the complex with greatest DNA binding and intercalation effects, recognises the minor groove of guanine–cytosine (G‐C) rich sequences. Oxidative DNA damage also occurs in the minor groove and can be inhibited by superoxide and hydroxyl radical trapping agents. The complexes, particularly Cu‐DPA‐DPPZ, display promising anticancer activity against human pancreatic tumour cells with in‐vitro results surpassing the clinical platinum(II) drug oxaliplatin. [ABSTRACT FROM AUTHOR]

Cover Feature: Polypyridyl-Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition (Chem. Eur. J. 3/2021) Keywords: copper; DNA damage; DNA repair; electrochemistry; EPR spectroscopy EN copper DNA damage DNA repair electrochemistry EPR spectroscopy 828 828 1 01/18/21 20210113 NES 210113 B A new class of DNA intercalating metallodrug is reported b . Copper, DNA damage, DNA repair, electrochemistry, EPR spectroscopy. [Extracted from the article]