Highly cytotoxic diruthenium trithiolato complexes of the type [(η6-p-MeC6H4Pri)2Ru2(μ2-SR)3]+: synthesis, characterization, molecular structure and in vitro anticancer activity

Abstract

A new series of cationic dinuclear p-cymene ruthenium complexes bridged by three thiophenolato ligands containing various substituents mainly in meta and ortho positions, [(η⁶-p-MeC₆H₄Prⁱ)₂Ru₂(μ₂-SR)₃]⁺ (R = 3-C₆H₄Me: 1; R = 3-C₆H₄OMe: 2; R = 3-C₆H₄OEt: 3; R = 3-C₆H₄CF₃: 4; R = 3-C₆H₄NH₂: 5; R = 3-C₆H₄Cl: 6; R = 2-C₆H₄Me: 7; R = 2-C₆H₄OMe: 8; R = 2-C₆H₄Prⁱ: 9; R = 2-C₆H₄CF₃: 10; R = npt: 11 (npt = 2-naphthyl); R = mco: 12 (mco = 4-methylcoumarinyl); R = 3,5-C₆H₃Me₂: 13; R = 3,5-C₆H₃(CF₃)₂: 14; R = 3,5-C₆H₃Cl₂: 15; R = 3,4-C₆H₃(OMe)₂: 16), have been prepared from the reaction of the neutral p-cymene diruthenium dichloride dimer, [(η⁶-p-MeC₆H₄Prⁱ)₂Ru₂Cl₄], with the corresponding thiophenol RSH. All cationic complexes have been isolated as their chloride salts and fully characterized by spectroscopic and analytical methods. The molecular structures of 10 and 15 have been solved by a single-crystal X-ray structure analysis of [10]Cl and [15]Cl, which show that the two ruthenium atoms adopt a pseudo-octahedral geometry without a metal–metal bond in accordance with the noble gas rule. All complexes are highly cytotoxic towards human ovarian cancer cells, the IC₅₀ values being mostly in the nanomolar range. Complex 9 shows the highest cytotoxicity with an IC₅₀ value of 0.03 μM towards the A2780 cell line and the cisplatin-resistant mutant A2780cisR. The cytotoxicity of these complexes, which belong to the most active ruthenium anticancer compounds reported so far, can be correlated with the lipophilicity of the corresponding thiols. In comparison with the previous series, the results demonstrate that the positions of the substituents in the thiopenolato bridges are not as important as the nature of the substituents, alkyl substituents being the best ones in line with their lipophilic character.