title: Biological properties of novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles.
abstract: Since the discovery that nitric oxide (NO) is a physiologically relevant molecule, there has been great interest in the use of metal nitrosyl compounds as antitumor pharmaceuticals. Particularly interesting are those complexes which can deliver NO to biological targets. Ruthenium- and osmium-based compounds offer lower toxicity compared to other metals and show different mechanisms of action as well as different spectra of activity compared to platinum-based drugs. Novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles were studied to elucidate their cytotoxicity and possible interactions with DNA. Apoptosis induction, changes of mitochondrial transmembrane potential and possible formation of reactive oxygen species were investigated as indicators of NO-mediated damage by flow cytometry. Results suggest that ruthenium- and osmium-nitrosyl complexes with the general formula (indazolium)[cis/trans-MCl4(NO)(1H-indazole)] have pronounced cytotoxic potency in cancer cell lines. Especially the more potent ruthenium complexes strongly induce apoptosis associated with depolarization of mitochondrial membranes, and elevated reactive oxygen species levels. Furthermore, a slight yet not unequivocal trend to accumulation of intracellular cyclic guanosine monophosphate attributable to NO-mediated effects was observed.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, 1090, Vienna, Austria.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Novak
authors.affiliation: Division of Physical Sciences and Engineering, KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Büchel
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, 1090, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, 1090, Vienna, Austria. michael.jakupec@univie.ac.at.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D017382:Reactive Oxygen Species; D009992:Osmium; D009569:Nitric Oxide; D012428:Ruthenium
keywords: Apoptosis; Cancer; Nitrosyl complexes; Ruthenium; cGMP level