title: A new promising application for highly cytotoxic metal compounds: η6-areneruthenium(II) phosphite complexes for the treatment of alveolar echinococcosis.
abstract: Two series of η(6)-areneruthenium(II) phosphite complexes were prepared, characterized, and evaluated in vitro for their toxic potential against Echinococcus multilocularis metacestodes. Neutral complexes of general formula [(η(6)-p-cymene)RuCl(2){P(OR)(3)}] (R = Et, (i)Pr, Ph) with two easily exchangable chloride ligands showed only minor toxicity, whereas the substitution of these moieties against a β-diketonate (2,2,6,6-tetramethylheptanedionate) ligand led to hydrolytically stable complex salts of type [(η(6)-p-cymene)Ru(β-diketonate){P(OR)(3)}][BF(4)] (R = Et, (i)Pr, Ph) with comparable in vitro toxicity (50% PGI release at c = 1.4 - 4.7 μM) to the reference drug nitazoxanide (50% PGI release at c = 1.2 μM). In addition, the latter complexes were highly toxic against rat hepatoma cells (IC(50) = 0.40-2.0 μM) and less toxic against human foreskin fibroblasts (IC(50) = 1.1-2.9 μM) and Vero cells (IC(50) = 1.2-8.9 μM). The measured cytotoxicities against mammalian cells are, to the best of our knowledge, among the highest ever observed for ruthenium-based complexes. In conclusion, complex salts of type [(η(6)-p-cymene)Ru(β-diketonate){P(OR)(3)}][BF(4)] might be interesting candidates for further development toward anthelmintic drugs and/or highly cytotoxic metal compounds.
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Küster
authors.forename: Nadine
authors.initials: N
authors.lastname: Lense
authors.forename: Fabienne
authors.initials: F
authors.lastname: Barna
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
authors.forename: Markus K
authors.initials: MK
authors.lastname: Kindermann
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Heinicke
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Vock
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004443:Echinococcosis; D004444:Echinococcosis, Hepatic / Q000188:drug therapy* / Q000469:parasitology; D048210:Echinococcus multilocularis / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D039821:Monoterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017905:Phosphites / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012428:Ruthenium / Q000737:chemistry*; D014709:Vero Cells
chemical_list: D000871:Anthelmintics; D056831:Coordination Complexes; D039821:Monoterpenes; D017905:Phosphites; D012428:Ruthenium