In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance

James P C Coverdale, Hannah Bridgewater, Ji-Inn Song, Nicola A Smith, Nicolas P E Barry, Ian Bagley, Peter J Sadler, Isolda Romero-Canelón

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)
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Abstract

Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.
Original languageEnglish
Pages (from-to)9246–9255
Number of pages10
JournalJournal of Medicinal Chemistry
Volume61
Early online date19 Sept 2018
DOIs
Publication statusPublished - 25 Oct 2018
Externally publishedYes

Bibliographical note

This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

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