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J Med Chem ; 55(9): 4178-88, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22489925

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 ß-diketonate (2,2,6,6-tetramethylheptanedionate) ligand led to hydrolytically stable complex salts of type [(η(6)-p-cymene)Ru(ß-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(ß-diketonate){P(OR)(3)}][BF(4)] might be interesting candidates for further development toward anthelmintic drugs and/or highly cytotoxic metal compounds.


Subject(s)
Anthelmintics/pharmacology , Coordination Complexes/pharmacology , Echinococcosis, Hepatic/drug therapy , Echinococcus multilocularis/drug effects , Phosphites/pharmacology , Ruthenium/chemistry , Animals , Anthelmintics/chemical synthesis , Anthelmintics/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chlorocebus aethiops , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Echinococcosis , Echinococcosis, Hepatic/parasitology , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Monoterpenes/pharmacology , Phosphites/chemical synthesis , Phosphites/chemistry , Rats , Vero Cells
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