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

Stuart A Archer,Julia A Weinstein,Dimitri Chekulaev,Anthony J H M Meijer,Craig Robertson,James A Thomas,Alexander J Auty,Theo Keane,Fabian Dröge,Ahtasham Raza,Sheila Macneil,John W Haycock

doi:10.1039/c8sc05084h

Stuart A Archer, Julia A Weinstein + Show 10 more

Open Access

https://doi.org/10.1039/c8sc05084h

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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 iso-structural 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 lines showing that it is a promising lead for the treatment of this recalcitrant cancer.

Highlights

A promising and emerging therapeutic regime for the treatment of cancer is photo-dynamic therapy (PDT).[1,2] In this approach a photo-excitable sensitizer molecule is used to generate highly reactive species, most commonly singlet oxygen, 1O2, in situ
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 quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products

Summary

Introduction

A promising and emerging therapeutic regime for the treatment of cancer is photo-dynamic therapy (PDT).[1,2] In this approach a photo-excitable sensitizer molecule is used to generate highly reactive species, most commonly singlet oxygen, 1O2, in situ. 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 quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products.

Results

Conclusion