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In‐Cell Activation of Organo‐Osmium(II) Anticancer Complexes
Author(s) -
Needham Russell J.,
SanchezCano Carlos,
Zhang Xin,
RomeroCanelón Isolda,
Habtemariam Abraha,
Cooper Margaret S.,
Meszaros Levente,
Clarkson Guy J.,
Blower Philip J.,
Sadler Peter J.
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201610290
Subject(s) - chemistry , osmium , ligand (biochemistry) , glutathione , adduct , cisplatin , iodide , stereochemistry , in vivo , radical , hydrolysis , mechanism of action , in vitro , medicinal chemistry , biochemistry , enzyme , catalysis , receptor , organic chemistry , ruthenium , medicine , surgery , microbiology and biotechnology , chemotherapy , biology
The family of iodido Os II arene phenylazopyridine complexes [Os(η 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 =NMe 2 ). They were labelled with the radionuclide 131 I (β − /γ emitter, t 1/2 8.02 d), and their activity in MCF‐7 human breast cancer cells was studied. 1 ‐[ 131 I] and 2 ‐[ 131 I] 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 H 2 O 2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo‐osmium complexes.