In-Cell Activation of Organo-Osmium(II) Anticancer Complexes

Russell J. Needham; Carlos Sanchez-Cano; Xin Zhang; Isolda Romero-Canelón; Abraha Habtemariam; Margaret S. Cooper; Levente Meszaros; Guy J. Clarkson; Philip J. Blower; Peter J. Sadler

doi:10.1002/anie.201610290

In-Cell Activation of Organo-Osmium(II) Anticancer Complexes

Russell J. Needham, Carlos Sanchez-Cano, Xin Zhang, Isolda Romero-Canelón, Abraha Habtemariam, Margaret S. Cooper, Levente Meszaros, Guy J. Clarkson, Philip J. Blower, Peter J. Sadler^*

^*Corresponding author for this work

University of Warwick
Fédération d'anesthésiologie-réanimation et de médecine hyperbare, hôpital d'instruction des armées du Val-de-Grâce, 75005 Paris, France; Inserm U676, hôpital Robert-Debré, 48, boulevard Sérurier, 75019 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS 676, 75013 Paris, France; Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, London, Royaume-Uni. Electronic address: [email protected].

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

Abstract

The family of iodido Os^II arene phenylazopyridine complexes [Os(η⁶-p-cym)(5-R¹-pyridylazo-4-R²-phenyl))I]⁺ (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I⁻ ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R¹=OEt, R²=H) and 2-I (R¹=H, R²=NMe₂). They were labelled with the radionuclide ¹³¹I (β⁻/γ emitter, t_1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[¹³¹I] and 2-[¹³¹I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H₂O₂ generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.

Original language	English
Pages (from-to)	1017-1020
Number of pages	4
Journal	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume	56
Issue number	4
DOIs	https://doi.org/10.1002/anie.201610290
Publication status	Published - 19 Jan 2017

Keywords

anticancer agents
bioinorganic chemistry
glutathione
metallodrugs
organo-osmium complexes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.201610290

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title = "In-Cell Activation of Organo-Osmium(II) Anticancer Complexes",

abstract = "The family of iodido OsII arene phenylazopyridine complexes [Os(η6-p-cym)(5-R1-pyridylazo-4-R2-phenyl))I]+ (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I− ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R1=OEt, R2=H) and 2-I (R1=H, R2=NMe2). They were labelled with the radionuclide 131I (β−/γ emitter, t1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[131I] and 2-[131I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.",

keywords = "anticancer agents, bioinorganic chemistry, glutathione, metallodrugs, organo-osmium complexes",

author = "Needham, {Russell J.} and Carlos Sanchez-Cano and Xin Zhang and Isolda Romero-Canel{\'o}n and Abraha Habtemariam and Cooper, {Margaret S.} and Levente Meszaros and Clarkson, {Guy J.} and Blower, {Philip J.} and Sadler, {Peter J.}",

year = "2017",

month = jan,

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doi = "10.1002/anie.201610290",

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T1 - In-Cell Activation of Organo-Osmium(II) Anticancer Complexes

AU - Needham, Russell J.

AU - Sanchez-Cano, Carlos

AU - Zhang, Xin

AU - Romero-Canelón, Isolda

AU - Habtemariam, Abraha

AU - Cooper, Margaret S.

AU - Meszaros, Levente

AU - Clarkson, Guy J.

AU - Blower, Philip J.

AU - Sadler, Peter J.

PY - 2017/1/19

Y1 - 2017/1/19

N2 - The family of iodido OsII arene phenylazopyridine complexes [Os(η6-p-cym)(5-R1-pyridylazo-4-R2-phenyl))I]+ (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I− ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R1=OEt, R2=H) and 2-I (R1=H, R2=NMe2). They were labelled with the radionuclide 131I (β−/γ emitter, t1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[131I] and 2-[131I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.

AB - The family of iodido OsII arene phenylazopyridine complexes [Os(η6-p-cym)(5-R1-pyridylazo-4-R2-phenyl))I]+ (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I− ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R1=OEt, R2=H) and 2-I (R1=H, R2=NMe2). They were labelled with the radionuclide 131I (β−/γ emitter, t1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[131I] and 2-[131I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.

KW - anticancer agents

KW - bioinorganic chemistry

KW - glutathione

KW - metallodrugs

KW - organo-osmium complexes

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JF - ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

IS - 4

ER -

In-Cell Activation of Organo-Osmium(II) Anticancer Complexes

Abstract

Keywords

UN SDGs

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