A dinuclear ruthenium(II) phototherapeutic that targets duplex and quadruplex DNA

Journal article


Archer, Stuart, Raza, Ahtasham, Dröge, Fabian, Robertson, Craig C., Auty, Alexander J, Chekulaev, Dimitri M, Weinstein, Julia, Keane, Theo, Meijer, Anthony J. H. M., Haycock, John, MacNeil, Sheila and Thomas, Jim A 2019. A dinuclear ruthenium(II) phototherapeutic that targets duplex and quadruplex DNA. Chemical Science. https://doi.org/10.1039/C8SC05084H
AuthorsArcher, Stuart, Raza, Ahtasham, Dröge, Fabian, Robertson, Craig C., Auty, Alexander J, Chekulaev, Dimitri M, Weinstein, Julia, Keane, Theo, Meijer, Anthony J. H. M., Haycock, John, MacNeil, Sheila and Thomas, Jim A
Abstract

With the aim of developing a sensitizer for photodynamic therapy, a previously reported luminescent dinuclear complex that functions as a DNA probe in live cells was modified to produce a new isostructural derivative containing RuII(TAP)2 fragments (TAP = 1,4,5,8- tetraazaphenanthrene). The structure of the new complex has been confirmed by a variety of techniques including single crystal X-ray analysis. Unlike its parent, the new complex displays RuL-based 3MLCT emission in both MeCN and water. Results from electrochemical studies and emission quenching experiments involving guanosine monophosphate are consistent with an excited state located on a TAP moiety. This hypothesis is further supported by detailed DFT calculations, which take into account solvent effects on excited state dynamics. Cell-free steady-state and time-resolved optical studies on the interaction of the new complex with duplex and quadruplex DNA show that the complex binds with high affinity to both structures and indicate that its photoexcited state is also quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products. Like the parent complex, this new compound is taken up by live cells where it primarily localizes within the nucleus and displays low cytotoxicity in the absence of light. However, in complete contrast to [{RuII(phen)2}2(tpphz)]4+, the new complex is therapeutically activated by light to become highly phototoxic toward malignant human melanoma cell line showing that it is a promising lead for the treatment of this recalcitrant cancer.

Keywordsnatural sciences; chemistry; physical chemistry; spectroscopy; theoretical chemistry; bio-inorganic chemistry
Year2019
JournalChemical Science
PublisherRoyal Society of Chemistry
ISSN2041-6520
2041-6539
Digital Object Identifier (DOI)https://doi.org/10.1039/C8SC05084H
Web address (URL)http://hdl.handle.net/10545/623510
http://creativecommons.org/licenses/by-nc-nd/3.0/us/
hdl:10545/623510
Publication dates18 Feb 2019
Publication process dates
Deposited21 Feb 2019, 12:29
Accepted15 Feb 2019
Rights

Attribution-NonCommercial-NoDerivs 3.0 United States

ContributorsUniversity of Sheffield
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