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A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage
Molphy, Zara; Montagner, Diego; Bhat, Satish S .; Slator, Creina; Long, Conor; Erxleben, Andrea; Kellett, Andrew
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. A.K. and Z.M. acknowledge funding from Science Foundation Ireland Career Development Award (SFI-CDA) [15/CDA/3648]; Marie Skłodowska-Curie Innovative Training Network (ITN) ClickGene [H2020-MSCA-ITN-2014-642023]; Circular dichroism analysis was carried out at the Nano Research Facility in Dublin City University which was funded under the Programme for Research in Third Level Institutions (PRTLI) Cycle 5. The PRTLI is co-funded through the European Regional Development Fund (ERDF), part of the European Union Structural Funds Programme 2011–2015. D.M. acknowledges funding from the European Commission [Marie Curie FP7-IEF]. Funding for open access charge: H2020 Marie Skłodowska-Curie Actions. The authors wish to acknowledge the DJEI/DES/SFI/HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities and support. This work was also supported by the Synthesis and Solid-State Pharmaceutical Centre (SSPC) and Science Foundation Ireland (SFI) under grant number 12/RC/2275.
Keyword(s): Phosphate-targeted dinuclear Cu(II) complex; Groove binding; Oxidative DNA cleavage
Publication Date:
2019
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Contributor(s): Science Foundation Ireland; H2020 Marie Skłodowska-Curie Actions; European Regional Development Fund
Institution: NUI Galway
Publisher(s): Oxford University Press
File Format(s): application/pdf
First Indexed: 2019-03-23 06:44:16 Last Updated: 2019-09-20 06:41:39