A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage. Issue 19 (17th September 2018)

• Record Type: Journal Article
• Authors: Molphy, Zara; Montagner, Diego; Bhat, Satish S; Slator, Creina; Long, Conor; Erxleben, Andrea; Kellett, Andrew
• Is Part Of: Nucleic acids research. Volume 46:Issue 19(2018)
• Page Start: 9918
• Page End: 9931
• Publication Date: 2018-09-17
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky806
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Free radical generation is an inevitable consequence of aerobic existence and is implicated in a wide variety of pathological conditions including cancer, cardiovascular disease, ageing and neurodegenerative disorder. Free radicals can, however, be used to our advantage since their production is catalysed by synthetic inorganic molecules—termed artificial metallonucleases—that cut DNA strands by oxidative cleavage reactions. Here, we report the rational design and DNA binding interactions of a novel di -Cu 2+ artificial metallonuclease [Cu2 ( tetra -(2-pyridyl)-NMe-naphthalene)Cl4 ] (Cu2 TPNap). Cu2 TPNap is a high-affinity binder of duplex DNA with an apparent binding constant ( K app ) of 10 7 M(bp) −1 . The agent binds non-intercalatively in the major groove causing condensation and G-C specific destabilization. Artificial metallonuclease activity occurs in the absence of exogenous reductant, is dependent on superoxide and hydrogen peroxide, and gives rise to single strand DNA breaks. Pre-associative molecular docking studies with the 8-mer d(GGGGCCCC)2, a model for poly[d(G-C)2 ], identified selective major groove incorporation of the complex with ancillary Cu 2+ -phosphate backbone binding. Molecular mechanics methods then showed the d(GGGGCCCC)2 adduct to relax about the complex and this interaction is supported by UV melting experiments where poly[d(G-C)2 ] is selectively destabilized.