Polypyridyl-Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition

Nicoló Zuin Fantoni, Zara Molphy, Sinéad O'Carroll, Georgia Menounou, George Mitrikas, Marios G. Krokidis, Chryssostomos Chatgilialoglu, John Colleran, Anna Banasiak, Martin Clynes, Sandra Roche, Suainibhe Kelly, Vickie McKee, Andrew Kellett*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
JournalChemistry - A European Journal
Volume27
Issue number3
Pages (from-to)971-983
ISSN0947-6539
DOIs
Publication statusPublished - 13. Jan 2021

Keywords

  • copper
  • DNA damage
  • DNA repair
  • electrochemistry
  • EPR spectroscopy

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