Di-copper metallodrugs promote NCI-60 chemotherapy via singlet oxygen and superoxide production with tandem TA/TA and AT/AT oligonucleotide discrimination

Nucleic Acids Research
Creina SlatorAndrew Kellett

Abstract

In order to expand the current repertoire of cancer treatments and to help circumvent limitations associated with resistance, the identification of new metallodrugs with high potency and novel mechanisms of action is of significant importance. Here we present a class of di-copper(II) complex based on the synthetic chemical nuclease [Cu(Phen)2]+ (where Phen = 1,10-phenanthroline) that is selective against solid epithelial cancer cells from the National Cancer Institute's 60 human cell line panel (NCI-60). Two metallodrug leads are studied and in each case two [Cu(Phen)2]+ units are bridged by a dicarboxylate linker but the length and rigidity of the linkers differ distinctly. Both agents catalyze intracellular superoxide (O2•-) and singlet oxygen (1O2) formation with radical species mediating oxidative damage within nuclear DNA in the form of double strand breaks and to the mitochondria in terms of membrane depolarization. The complexes are effective DNA binders and can discriminate AT/AT from TA/TA steps of duplex DNA through induction of distinctive Z-like DNA or by intercalative interactions.

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Citations

Sep 18, 2018·Chemistry : a European Journal·Nicoló Zuin FantoniAndrew Kellett
Feb 5, 2019·Chemical Society Reviews·Andrew KellettNicholas P Farrell
Apr 5, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Ziga UdeCeline J Marmion
Nov 5, 2019·Chembiochem : a European Journal of Chemical Biology·Alessandro PanattoniMichal Hocek
Oct 28, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Stephen BarrettDiego Montagner
Nov 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zara MolphyAndrew Kellett
Jun 24, 2020·Drug Delivery and Translational Research·Cristiano Ceron JaymeAntonio Claudio Tedesco
Jun 11, 2020·Chemistry : a European Journal·Nicoló Zuin FantoniAndrew Kellett
Jul 25, 2020·Chemistry : a European Journal·Teresa LauriaAndrew Kellett
Nov 12, 2020·International Journal of Molecular Sciences·Laísa de P FernandesCarolina G Oliveira
Aug 6, 2020·Chembiochem : a European Journal of Chemical Biology·Nicolò Zuin FantoniAndrew Kellett
Feb 12, 2021·Chembiochem : a European Journal of Chemical Biology·Nicolò Zuin FantoniAndrew Kellett
Sep 28, 2021·Nucleic Acids Research·Natasha McStayAndrew Kellett
Jan 11, 2022·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Anna Clara Milesi GaldinoAndré Luis Souza Dos Santos

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Methods Mentioned

BETA
footprinting
Circular Dichroism
Assay
electrophoresis
three
X-ray
confocal microscopy
flow cytometry
atomic force microscopy

Software Mentioned

OLYP
MitoPotential
Viacount
Guava Caspase
AutoDock
Cary Thermal
GaussView
GraphPad Prism
Nexin
AOMix

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