Synthesis, characterization and in vitro anticancer activity of highly cytotoxic trithiolato diruthenium complexes of the type [(η6-p-MeC6H4iPr)2Ru2(μ2-SR1)2(μ2-SR2)]+ containing different thiolato bridges

A series of cationic dinuclear p-cymene ruthenium complexes containing three thiolato bridges with different substituents at the sulfur atoms, [(η6-p-MeC6H4iPr)2Ru2(μ2-SR1)2(μ2-SR2)]+ (R1 = CH2Ph, R2 = Ph: 4; R1 = CH2Ph, R2 = p-C6H4iPr: 5; R1 = CH2Ph, R2 = p-C6H4tBu: 6; R1 = CH2Ph, R2 = p-C6H4OH: 7; R1 = CH2Ph, R2 = p-C6H4Br: 8; R1 = CH2Ph, R2 = p-C6H4F: 9; R1 = CH2CH2Ph, R2 = Ph: 10; R1 = CH2CH2Ph, R2 = p-C6H4iPr: 11; R1 = CH2CH2Ph, R2 = p-C6H4tBu: 12; R1 = CH2CH2Ph, R2 = p-C6H4OH: 13; R1 = CH2CH2Ph, R2 = p-C6H4Br: 14; R1 = CH2CH2Ph, R2 = p-C6H4F: 15; R1 = CH2C6H4–p-tBu, R2 = Ph: 16; R1 = CH2C6H4–p-tBu, R2 = p-C6H4iPr: 17; R1 = CH2C6H4–p-tBu, R2 = p-C6H4tBu: 18; R1 = CH2C6H4–p-tBu, R2 = p-C6H4OH: 19; R1 = CH2C6H4–p-tBu, R2 = p-C6H4Br: 20; R1 = CH2C6H4–p-tBu, R2 = p-C6H4F: 21), have been obtained from the reaction of the neutral dithiolato intermediates [(η6-p-MeC6H4iPr)2Ru2Cl2(μ2-SR1)2] (R1 = CH2Ph: 1; R1 = CH2CH2Ph: 2; R1 = CH2C6H4–p-tBu: 3) with the corresponding thiophenol R2SH. All cationic complexes have been isolated as their chloride salts and fully characterized by spectroscopic and analytical methods. All complexes are highly cytotoxic against human ovarian cancer cells, the IC50 values being in the submicromolar range. The highest activity is shown by complex 6 with IC50 values of 48 nM against the A2780 cell line and 42 nM against the cisplatin-resistant line A2780cisR. This family of cationic trithiolato complexes belongs to the most cytotoxic ruthenium compounds ever reported. The catalytic activity selected representatives for the oxidation of glutathione (GSH) to GSSG has been investigated by NMR spectroscopy.