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Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics

Murray, Benjamin S.; Menin, Laure; Scopelliti, Rosario; Dyson, Paul J.

Authors

Laure Menin

Rosario Scopelliti

Paul J. Dyson



Abstract

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents.

Journal Article Type Article
Publication Date May 7, 2014
Journal Chemical science
Print ISSN 2041-6520
Electronic ISSN 2041-6539
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 5
Issue 6
Pages 2536-2545
Institution Citation Murray, B. S., Menin, L., Scopelliti, R., & Dyson, P. J. (2014). Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics. Chemical science, 5(6), 2536-2545. https://doi.org/10.1039/c4sc00116h
DOI https://doi.org/10.1039/c4sc00116h
Keywords Anticancer activity, Dinuclear metal complexes , Arene-linked dinuclear organometallic Ru(II) complexes, Cytotoxicity
Publisher URL http://pubs.rsc.org/en/Content/ArticleLanding/2014/SC/c4sc00116h#!divAbstract
Additional Information Copy of article first published in: Chemical science, 2014, v.5, issue 6.

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Copyright Statement
This work is licensed under a Creative Commons Attribution 3.0 Unported License.





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