期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 4, 页码 1017-1020出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201610290
关键词
anticancer agents; bioinorganic chemistry; glutathione; metallodrugs; organo-osmium complexes
资金
- ERC [247450]
- Science City (AWM/ERDF)
- EPSRC [EP/F034210/1]
- Wellcome Trust [107691/Z/15/Z]
- Bloodwise
- Centre of Excellence in Medical Engineering - Wellcome Trust [WT088641/Z/09/Z]
- King's College London Comprehensive Cancer Imaging Centre - CRUK
- MRC (England)
- DoH (England)
- National Institutes for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London
- University College London Comprehensive Cancer Imaging Centre - CRUK
- Wellcome Trust [107691/Z/15/Z] Funding Source: Wellcome Trust
- Cancer Research UK [16463] Funding Source: researchfish
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.
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