In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance
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′)]...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-10, Vol.61 (20), p.9246-9255 |
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| container_title | Journal of medicinal chemistry |
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| creator | Coverdale, James P. C Bridgewater, Hannah E Song, Ji-Inn Smith, Nichola A Barry, Nicolas P. E Bagley, Ian Sadler, Peter J Romero-Canelón, Isolda |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.8b00958 |
| format | Article |
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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. 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C</creatorcontrib><creatorcontrib>Bridgewater, Hannah E</creatorcontrib><creatorcontrib>Song, Ji-Inn</creatorcontrib><creatorcontrib>Smith, Nichola A</creatorcontrib><creatorcontrib>Barry, Nicolas P. E</creatorcontrib><creatorcontrib>Bagley, Ian</creatorcontrib><creatorcontrib>Sadler, Peter J</creatorcontrib><creatorcontrib>Romero-Canelón, Isolda</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coverdale, James P. C</au><au>Bridgewater, Hannah E</au><au>Song, Ji-Inn</au><au>Smith, Nichola A</au><au>Barry, Nicolas P. 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| subjects | 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 |
| title | In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance |
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