title: Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates.
abstract: Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(η6-p-cym)RuCl(κ2-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC50values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC50values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution.
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Riedl
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Lea S
authors.initials: LS
authors.lastname: Flocke
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Hejl
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roller
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Matthias H M
authors.initials: MH
authors.lastname: Klose
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.identifier: http://orcid.org/0000-0002-5630-712X
authors.initials: W
authors.lastname: Kandioller
authors.affiliation: Institute of Inorganic Chemistry, Faculty of Chemistry, and ‡Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009992:Osmium / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D009992:Osmium; D012428:Ruthenium; D004250:DNA Topoisomerases, Type II