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

Nucleic Acids Research
Zara MolphyAndrew Kellett

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(GGG...Continue Reading

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Citations

Apr 5, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Ziga UdeCeline J Marmion
Oct 28, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Stephen BarrettDiego Montagner
Feb 5, 2019·Chemical Society Reviews·Andrew KellettNicholas P Farrell
Sep 18, 2018·Chemistry : a European Journal·Nicoló Zuin FantoniAndrew Kellett
Jun 11, 2020·Chemistry : a European Journal·Nicoló Zuin FantoniAndrew Kellett
Jul 25, 2020·Chemistry : a European Journal·Teresa LauriaAndrew Kellett
Nov 24, 2020·International Journal of Biological Macromolecules·Chuye JiLi Liang
Aug 6, 2020·Chembiochem : a European Journal of Chemical Biology·Nicolò Zuin FantoniAndrew Kellett
Mar 13, 2021·International Journal of Pharmaceutics·Jacinta O PinhoM Manuela Gaspar
Feb 12, 2021·Chembiochem : a European Journal of Chemical Biology·Nicolò Zuin FantoniAndrew Kellett
Sep 28, 2021·Nucleic Acids Research·Natasha McStayAndrew Kellett
Oct 1, 2021·Chemical Reviews·Eric LargyValérie Gabelica

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Methods Mentioned

BETA
column chromatography
electrophoresis
PCR
ELISA
X-ray
saturation binding
circular dichroism
enzyme-linked immunosorbent assay

Software Mentioned

GaussView
Gaussian
AutoDock
PyMOL Molecular Graphics System

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