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    A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage


    Molphy, Zara and Montagner, Diego and Bhat, Satish S. and Slator, Creina and Long, Conor and Erxleben, Andrea and Kellett, Andrew (2018) A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage. Nucleic Acids Research, 46 (19). pp. 9918-9931. ISSN 0305-1048

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    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-Cu2+ artificial metallonuclease [Cu2(tetra-(2-pyridyl)-NMe-naphthalene)Cl4] (Cu2TPNap). Cu2TPNap is a high-affinity binder of duplex DNA with an apparent binding constant (Kapp) of 107 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 Cu2+-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.

    Item Type: Article
    Additional Information: © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Cite as: Zara Molphy, Diego Montagner, Satish S Bhat, Creina Slator, Conor Long, Andrea Erxleben, Andrew Kellett, A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage, Nucleic Acids Research, Volume 46, Issue 19, 02 November 2018, Pages 9918–9931, https://doi.org/10.1093/nar/gky806
    Keywords: phosphate-targeted dinuclear Cu(II) complex; DNA cleavage; Free radicals;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 10750
    Identification Number: https://doi.org/10.1093/nar/gky806
    Depositing User: Diego Montagner
    Date Deposited: 25 Apr 2019 16:39
    Journal or Publication Title: Nucleic Acids Research
    Publisher: Oxford University Press
    Refereed: Yes
    URI:

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