In vivo selectivity and localization of reactive oxygen species (ROS) induction by osmium anticancer complexes that circumvent platinum resistance

Research output: Contribution to journalArticlepeer-review

Authors

  • Hannah E. Bridgewater
  • Ji-Inn Song
  • Nichola A Smith
  • Nicolas P E Barry
  • Ian Bagley
  • Peter J Sadler

Colleges, School and Institutes

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 towards 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 co-localization with reactive oxygen species generated in zebrafish.

Details

Original languageEnglish
Pages (from-to)9246–9255
Number of pages10
JournalJournal of Medicinal Chemistry
Volume61
Issue number20
Early online date19 Sep 2018
Publication statusPublished - 25 Oct 2018

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