Copper bis-Dipyridoquinoxaline Is a Potent DNA Intercalator that Induces Superoxide-Mediated Cleavage via the Minor Groove

Zara Molphy, Vickie McKee, Andrew Kellett

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Abstract

Herein, we report the synthesis, characterisation, X-ray crystallography, and oxidative DNA binding interactions of the copper artificial metallo-nuclease [Cu(DPQ)2(NO3)](NO3), where DPQ = dipyrido[3,2-f:2',3'-h]quinoxaline. The cation [Cu(DPQ)2]2+ (Cu-DPQ), is a high-affinity binder of duplex DNA and presents an intercalative profile in topoisomerase unwinding and viscosity experiments. Artificial metallo-nuclease activity occurs in the absence of exogenous reductant but is greatly enhanced by the presence of the reductant Na-L-ascorbate. Mechanistically, oxidative DNA damage occurs in the minor groove, is mediated aerobically by the Cu(I) complex and is dependent on both superoxide and hydroxyl radical generation. To corroborate cleavage at the minor groove, DNA oxidation of a cytosine-guanine (5'-CCGG-3')-rich oligomer was examined in tandem with a 5-methylcytosine (5'-C5mCGG-3') derivative where 5mC served to sterically block the major groove and direct damage to the minor groove. Overall, both the DNA binding affinity and cleavage mechanism of Cu-DPQ depart from Sigman's reagent [Cu(1,10-phenanthroline)2]2+; however, both complexes are potent oxidants of the minor groove.

Original languageEnglish
Article number4301
JournalMolecules (Basel, Switzerland)
Volume24
Issue number23
Number of pages11
ISSN1420-3049
DOIs
Publication statusPublished - 26. Nov 2019

Keywords

  • chemical nuclease
  • copper
  • DNA damage
  • free radical oxidation
  • intercalation

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