ZFIN ID: ZDB-PUB-180921-9
In vivo selectivity and localization of reactive oxygen species (ROS) induction by osmium anticancer complexes that circumvent platinum-resistance
Coverdale, J.P.C., Bridgewater, H.E., Song, J.I., Smith, N.A., Barry, N.P.E., Bagley, I., Sadler, P.J., Romero Canelon, I.
Date: 2018
Source: Journal of medicinal chemistry   61(20): 9246-9255 (Journal)
Registered Authors: Bagley, Ian
Keywords: none
MeSH Terms:
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Drug Resistance, Neoplasm/drug effects*
  • Drug Screening Assays, Antitumor
  • Humans
  • Organometallic Compounds/chemistry*
  • Organometallic Compounds/pharmacology*
  • Osmium/chemistry*
  • Platinum/pharmacology*
  • Reactive Oxygen Species/metabolism*
PubMed: 30230827 Full text @ J. Med. Chem.
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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.
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