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

被引:86
作者
Needham, Russell J. [1 ]
Sanchez-Cano, Carlos [1 ]
Zhang, Xin [1 ]
Romero-Canelon, Isolda [1 ]
Habtemariam, Abraha [1 ]
Cooper, Margaret S. [2 ]
Meszaros, Levente [2 ]
Clarkson, Guy J. [1 ]
Blower, Philip J. [2 ]
Sadler, Peter J. [1 ]
机构
[1] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England
[2] Kings Coll London, Div Imaging Sci & Biomed Engn, St Thomas Hosp, London SE1 7EH, England
基金
英国惠康基金; 英国工程与自然科学研究理事会;
关键词
anticancer agents; bioinorganic chemistry; glutathione; metallodrugs; organo-osmium complexes; CANCER CELLS; GLUTATHIONE; CYTOTOXICITY; APOPTOSIS;
D O I
10.1002/anie.201610290
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The family of iodido Os-II arene phenylazopyridine complexes [Os(eta(6)-p-cym)(5-R-1-pyridylazo-4-R-2-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 (R-1 = OEt, R-2 = H) and 2-I (R-1 = H, R-2 = NMe2). They were labelled with the radionuclide I-131 (beta(-)/gamma emitter, t(1/2) 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[I-131] and 2-[I-131] 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.
引用
收藏
页码:1017 / 1020
页数:4
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