Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(η6- p -MeC6H4Pr i )2Ru2(SC6H4- p -X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential

Abstract

A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(η6-p-MeC6H4Pr i )2Ru2(SC6H4-p-X)3]+ (1 Xis H, 2 Xis Me, 3 Xis Ph, 4 Xis Br, 5 Xis OH, 6 Xis NO2, 7 Xis OMe, 8 Xis CF3, 9 Xis F, 10 Xis Pr i , 11 Xis Bu t ) have been synthesized from the reaction of [(η6-p-MeC6H4Pr i )RuCl2]2 with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(η6-C6H6)2Ru2(SC6H5)3]+ (12) and [(η6-C6Me6)2Ru2(SC6H5)3]+ (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50% inhibition of cancer cell growth (IC50 values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC50 value of 0.03µM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC50 values and the turnover frequencies at about 50% conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants σ p) and the lipophilicity of the thiols p-XC6H4SH (calculated logP parameters