title: In-Cell Activation of Organo-Osmium(II) Anticancer Complexes.
abstract: The family of iodido OsIIarene 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 radionuclide131I (β-/γ emitter, t1/28.02 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 H2O2generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Russell J
authors.identifier: 0000-0001-9801-2808
authors.initials: RJ
authors.lastname: Needham
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Carlos
authors.identifier: 0000-0002-9522-0019
authors.initials: C
authors.lastname: Sanchez-Cano
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Xin
authors.identifier: 0000-0002-6366-9890
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Isolda
authors.identifier: 0000-0003-3847-4626
authors.initials: I
authors.lastname: Romero-Canelón
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Abraha
authors.identifier: 0000-0003-2128-800X
authors.initials: A
authors.lastname: Habtemariam
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas Hospital, London, SE1 7EH, UK.
authors.forename: Margaret S
authors.identifier: 0000-0001-9103-6639
authors.initials: MS
authors.lastname: Cooper
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas Hospital, London, SE1 7EH, UK.
authors.forename: Levente
authors.identifier: 0000-0002-4698-0943
authors.initials: L
authors.lastname: Meszaros
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Guy J
authors.identifier: 0000-0003-3076-3191
authors.initials: GJ
authors.lastname: Clarkson
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas Hospital, London, SE1 7EH, UK.
authors.forename: Philip J
authors.identifier: 0000-0001-6290-1590
authors.initials: PJ
authors.lastname: Blower
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Peter J
authors.identifier: 0000-0001-9160-1941
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019583:Dose Fractionation, Radiation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D009992:Osmium
keywords: anticancer agents; bioinorganic chemistry; glutathione; metallodrugs; organo-osmium complexes