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

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• 作者：Russell J. Needham ; Dr. Carlos Sanchez-Cano ; Xin Zhang ; Dr. Isolda Romero-Canel&oacute ; n ; Dr. Abraha Habtemariam ; Dr. Margaret S. Cooper ; Dr. Levente Meszaros ; Dr. Guy J. Clarkson ; Prof. Dr. Philip J. Blower and Prof. Dr. Peter J. Sadler
• 刊名：Angewandte Chemie International Edition
• 出版年：2017
• 出版时间：January 19, 2017
• 年：2017
• 卷：56
• 期：4
• 页码：1017-1020
• 全文大小：937K
• ISSN：1521-3773

文摘

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.