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.
Highlights
Since the structural elucidation of duplex DNA, the construction of small molecules that recognise and react at specific sites to modify DNA structure, reactivity and biological repair processes has been an area of considerable research interest
[Cu(1,10-phenanthroline)2 ]2+ (Cu-Phen) in 1979, sparked efforts toward the development of new artificial metallonucleases with DNA cleavage mediated through the generation of reactive oxygen species (ROS) at the DNA interface [1]
Orbitrap (Waltham, MA, USA) mass spectrometer coupled to an Advion TriVersa Nanomate (Ithaca, NY, USA) injection system with samples prepared in 100% High-performance liquid chromatography (HPLC)-grade CH3 CN prior to analysis
Summary
Since the structural elucidation of duplex DNA, the construction of small molecules that recognise and react at specific sites to modify DNA structure, reactivity and biological repair processes has been an area of considerable research interest. Including minor groove binders netropsin and distamycin [19,20,21,22,23], intercalating acridine conjugates phenanthroline complexes—with general formula [Cu(N,N′)(Phen)]. Cu-DPQ-Phen as the most active chemical nuclease in the series and later, the hydroxyl radical was modifications using coordinatedspecies carboxylate groupsfor [13]; groups event GC), leading us to hypothesise that this general class of compound may oxidatively was compared to the well-studied Cu-Phen and Cu–DPQ-Phen complexes previously developed in target cytosine–phosphate–guanine our laboratory [32,33]. The DNA binding and oxidative DNA damage profile of Cu–DPQ was compared to the well-studied Cu-Phen and Cu–DPQ-Phen complexes previously developed in our laboratory [32,33]
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