title: Structure-Related Mode-of-Action Differences of Anticancer Organoruthenium Complexes with β-Diketonates.
abstract: A series of organoruthenium(II) chlorido complexes with fluorinated O,O-ligands [(η(6)-p-cymene)Ru(F3C-acac-Ar)Cl] (1a-6a) and their respective 1,3,5-triaza-7-phosphaadamantane (pta) derivatives [(η(6)-p-cymene)Ru(F3C-acac-Ar)pta]PF6 (1b-6b) were synthesized and fully characterized in both solution and solid state. All complexes were inactive against nonmalignant keratinocytes but displayed variable activity against cancer cell models (ovarian, osteosarcoma). Compounds with a ligand containing the 4-chlorophenyl substituent (6a and 6b) exhibited the strongest anticancer effects. Despite a marginally lower cellular Ru accumulation compared to the chlorido complexes, pta analogues showed higher activity especially in the osteosarcoma model. Reduction of glutathione levels by buthionine sulfoximine (BSO) significantly enhanced the activity of all compounds with the most pronounced effects being observed for the pta series resulting in IC50 values down to the nanomolar range. While all chlorido complexes potently induce reactive oxygen species, DNA damage, and apoptosis, the respective pta compounds widely lacked ROS production but blocked cell cycle progression in G0/G1 phase.
authors: †Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
authors: Sara
authors: S
authors: Seršen
authors: †Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
authors: Jakob
authors: J
authors: Kljun
authors: ‡Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Kushtrim
authors: K
authors: Kryeziu
authors: §Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, 79005, Ukraine.
authors: Rostyslav
authors: R
authors: Panchuk
authors: ‡Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Beatrix
authors: B
authors: Alte
authors: ∥Department of Environmental Geosciences, University of Vienna, 1090, Vienna, Austria.
authors: Wilfried
authors: W
authors: Körner
authors: ‡Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Petra
authors: P
authors: Heffeter
authors: ‡Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Walter
authors: W
authors: Berger
authors: †Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
authors: Iztok
authors: I
authors: Turel
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000081007:Cymenes; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012428:Ruthenium; D013329:Structure-Activity Relationship
chemical_list: C000599960:((eta6-p-cymene)Ru(4,4,4-trifluoro-1-(4-chlorophenyl)-1,3-butanedione)-1,3,5-triaza-7-phosphaadamantane); D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D017382:Reactive Oxygen Species; D012428:Ruthenium; D005978:Glutathione