Facile Entry to Germanate and Stannate Complexes [(η⁶-Arene)RuCl(η²-dppm)]⁺[ECl₃]^- (E = Ge, Sn) As Potent Anti-Cancer Agents

A series of arene Ru(II) salt complexes of the type [(η ⁶-arene)RuCl(η ²-dppm)] ⁺[ECl ₃] ^- (arene = C ₆H ₆, p-cymene, 1,3,5-Me ₃C ₆H ₃; E = Ge, Sn) bearing trichlorogermanate and trichlorostannate anions are reported. Starting from the known complexes: [(η ⁶-C ₆H ₆)RuCl ₂(η ¹-dppm)] (1), [(η ⁶-p-cymene)RuCl ₂(η ¹-dppm)] (3) and the novel complex [(η ⁶-1,3,5-Me ₃C ₆H ₃)RuCl ₂(η ¹-dppm)] (7) (dppm = 1,1-bis(diphenylphosphino)methane), reactions with SnCl ₂ or GeCl ₂(dioxane) respectively afforded, by halide abstraction at the ruthenium(II) centres in 1, 3 or 7 the salts: [(η ⁶-C ₆H ₆)RuCl(η ²-dppm)] ⁺ SnCl ₃ ⁻ (2), [(η ⁶-p-cymene)RuCl(η ²-dppm)] ⁺ SnCl ₃ ⁻ (4), [(η ⁶-C ₆H ₆)RuCl(η ²-dppm)] ⁺ GeCl ₃ ⁻ (5), [(η ⁶-p-cymene)RuCl(η ²-dppm)] ⁺ GeCl ₃ ⁻ (6), [(η ⁶-1,3,5-Me ₃C ₆H ₃)RuCl(η ²-dppm)] ⁺ SnCl ₃ ⁻ (8) and [(η ⁶-1,3,5-Me ₃C ₆H ₃)RuCl(η ²-dppm)] ⁺ GeCl ₃ ⁻ (9). The trichlorostannate complexes 2, 4 and 8 are extremely rare examples of ruthenium complexes bearing the SnCl ₃ ⁻ counter anion, and the complexes 5, 6 and 9 are the first examples of ruthenium trichlorogermanate complexes to be reported. All compounds were isolated in high yields as air stable materials and were spectroscopically characterized by multinuclear NMR: ( ¹H, ³¹P{ ¹H}, ¹³C{ ¹H}), Infra-red (IR), UV–Vis, and high resolution electrospray ionization mass spectrometry (HR-ESI-MS), the latter both in (+) and (−) mode. Additionally, single crystal X-ray diffraction analyses of salts 4 and 6 are reported, revealing pseudotetrahedral Ru(II) centres with η ⁶ bound p-cymene ligands and η ²-bound dppm ligands with statistical disorder on the ECl ₃ ^- anions (E = Ge (6), Sn (4)). Density functional theory calculations (B3LYP with the basis set 6-31 + G(d,p) for H, C, P and Cl atoms; while for Ru, Ge, and Sn atoms DGDZVP basis set) are reported for salts 4 and 6 revealing localization of the LUMOs on the ruthenium-arene rings and some localization on the chloride atom. Finally, MTT in vitro cytotoxicity assays for the MCF-7 and MDA-MB-231 breast cancer cell lines are reported for all complexes and compared to cisplatin. All complexes show remarkable in vitro cytotoxic activity and most are considerably more cytotoxic than cisplatin in both breast cancer cell lines: IC ₅₀ values range from 2.25 μM (compound 2) to 5.97 μM (compound 9) (cisplatin = 5.74 μM) in MCF-7 cells; 2.20 μM (compound 2) to 6.39 μM (compound 5) (cisplatin = 13.98 μM) in MDA-MB-231. Moreover, when compared to non-malignant breast epithelial cells (MCF12A), all complexes exhibit promising selectivity indices (SI) with compound 5 having the highest SI in MCF-7 cells at 4.8; and compound 6 at 3.65 in MDA-MB-231, with most of the other compounds also being considerably more selective than cisplatin on both cell-lines (SI = 2.26 on MCF-7 and 0.93 on MDA-MB-231). A clonogenic assay was conducted for salts 5 and 6 and the results reveal that both compounds inhibited long-term (14 days) survival in both breast cancer cell lines tested indicating these drugs are very promising candidates for pre-clinical studies.