1. In-Cell Activation of Organo-Osmium(II) Anticancer Complexes
- Author
-
Russell J. Needham, Carlos Sanchez-Cano, Xin Zhang, Isolda Romero-Canelón, Abraha Habtemariam, Margaret S. Cooper, Levente Meszaros, Guy J. Clarkson, Philip J. Blower, and Peter J. Sadler
- Subjects
Models, Molecular ,Stereochemistry ,Radical ,Iodide ,Molecular Conformation ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Catalysis ,Adduct ,bioinorganic chemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Blood serum ,Cell Line, Tumor ,Organometallic Compounds ,medicine ,Humans ,QD ,glutathione ,organo-osmium complexes ,Cell Proliferation ,chemistry.chemical_classification ,010405 organic chemistry ,Ligand ,Communication ,General Medicine ,General Chemistry ,Glutathione ,Osmium ,QP ,Communications ,0104 chemical sciences ,Mechanism of action ,chemistry ,metallodrugs ,Cancer cell ,MCF-7 Cells ,Anticancer Agents ,Dose Fractionation, Radiation ,Drug Screening Assays, Antitumor ,medicine.symptom - 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.
- Published
- 2016
- Full Text
- View/download PDF