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|Title:||Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity||Authors:||Davey, Curt Alexander
Davey, Gabriela E.
Clavel, Catherine M.
Nazarov, Alexey A.
Yeo, Charmian Hui Fang
Ang, Wee Han
Dyson, Paul J.
|Issue Date:||2014||Source:||Adhireksan, Z., Davey, G. E., Campomanes, P., Groessl, M., Clavel, C. M., Yu, H., . . . Davey, C. A. (2014). Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity. Nature Communications, 5, 3462-. doi:10.1038/ncomms4462||Series/Report no.:||Nature Communications||Abstract:||Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.||URI:||https://hdl.handle.net/10356/89056
|DOI:||http://dx.doi.org/10.1038/ncomms4462||Rights:||© 2014 Macmillan Publishers Limited. This work is licensed under a Creative Commons AttributionNonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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