Solution equilibrium, structural and cytotoxicity studies on Ru(η6-p-cymene) and copper complexes of pyrazolyl thiosemicarbazones.

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η⁶-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV-visible spectrophotometry, ¹H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙H₂O, [Ru(η⁶-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH_-1)₂] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η⁶-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η⁶-p-cymene))₂(L)₂]²⁺ complex with μ₂-bridging sulphur donor atoms is formed (where L^- is the deprotonated thiosemicarbazone). [CuL]⁺ and [CuL₂] complexes show much higher stability compared to that of complexes of the reference compound benzaldehyde thiosemicarbazone. [CuL₂] complexes predominate at neutral pH. Me-pyrTSC and Ph-pyrTSC exhibited moderate cytotoxicity against human colonic adenocarcinoma cell lines (IC₅₀ = 33-76 μM), while their complexation with Ru(η⁶-p-cymene) (IC₅₀ = 11-24 μM) and especially Cu(II) (IC₅₀ = 3-6 μM) resulted in higher cytotoxicity. Cu(II) complexes of the tested thiosemicarbazones were also cytotoxic in three breast cancer and in a hepatocellular carcinoma cell line. No reactive oxygen species production was detected and the relatively high catalase activity of SUM159 breast cancer cells was decreased upon addition of the ligands and the complexes. In the latter cell line the tested compounds interfered with the glutathione synthesis as they decreased the concentration of this cellular reductant.