Tuning the cytotoxicity of ruthenium(ii) para-cymene complexes by mono-substitution at a triphenylphosphine/phenoxydiphenylphosphine ligand

Abstract

The new complexes [RuCl₂(η⁶-p-cymene)(κP-Ph₂PR)] [R = 4-C₆H₄OSiMe₂^tBu, 1; R = 4-C₆H₄Br, 2; R = OC(O)CHCl₂, 3; R = OPh, 4; R = O(2-C₆H₄SiMe₂^tBu), 5] and [Ru(C₂O₄)(η⁶-p-cymene){κP-Ph₂PO(2-C₆H₄(SiMe₂^tBu))}], 6, were obtained in 83–98% yield from Ru(II) arene precursors by three different synthetic strategies. The unprecedented phosphine Ph₂P(O(2-C₆H₄SiMe₂^tBu)) was synthesized in 86% yield from 2-C₆H₄Br(OSiMe₂^tBu) and Ph₂PCl, via intramolecular oxygen to carbon 1,3 migration of the silyl group (retro-Brook rearrangement). All the complexes were fully characterized by analytical and spectroscopic methods, and by single crystal X-ray diffraction in the cases of 3, 4, 5 and 6. Complexes 1–6 and the model compounds [RuCl₂(η⁶-p-cymene)(κP-PPh₃)] (Ru-PPh₃) and [Ru(C₂O₄)(η⁶-p-cymene)(κP-PPh₃)] (Ru-PPh₃-O) underwent slow degradation in chloroform solutions upon air contact; the mixed valence complex [(η⁶-p-cymene)Ru(μ-Cl)₃RuCl₂(κP-PPh₃)], 7, was isolated from a solution of Ru-PPh₃ in CHCl₃, and X-ray identified. The antiproliferative activity of 1–6 and Ru-PPh₃, Ru-PPh₃-O and [RuCl₂(η⁶-p-cymene)(κP-PTA)] (RAPTA-C) was assessed towards the triple-negative breast cancer cell line MDA-MB-231, the ovarian carcinoma cell line A2780 and human skin fibroblasts (HSF). Complexes 1, 2, 5 and 6 displayed IC₅₀ values significantly lower than that of cisplatin, with 2 providing a more potent cytotoxic effect on MDA-MB-231 and A2780 cancer cells compared to the noncancerous cell line (HSF). The stability of all complexes in DMSO/water solution was elucidated by NMR and conductivity measurements, and in particular ³⁵Cl NMR spectroscopy was helpful to check the possible chloride dissociation. The stability studies suggest that the cytotoxic activity in vitro of the compounds is mainly ascribable to Ru(II) species still bound to the phosphorus ligand.