Influence of the Polypyridyl (pp) Ligand Size on the DNA Binding Properties, Cytotoxicity and Cellular Uptake of Organoruthenium(II) Complexes of the Type [(η6-C6Me6)Ru(L)(pp)]n+ [L = Cl, n = 1; L = (NH2)2CS, n = 2]

The DNA binding of polypyridyl (pp) (η6-hexamethylbenzene)ruthenium(II) complexes of the type [(η6-C6Me6)RuCl(pp)](CF3SO3) (pp = phen, tap, dpq, dppz, dppn) 1–5 and [(η6-C6Me6)Ru{(NH2)2CS}(pp)](CF3SO3)2 (pp = dpq, dppz, dppn) 6–8 has been studied by UV/Vis spectroscopy, circular dichroism and viscosity measurements. Complexes 3–5, 7 and 8 are potent cytotoxic agents towards the human cancer cell lines MCF-7 and HT-29. Stable intercalative binding into CT DNA is indicated for the dpq and dppz complexes by large increases ΔTm of 12–25 °C in the DNA thermal denaturation temperature for r = [complex]/[DNA] = 0.1. Large viscosity increases for DNA in the presence of 3 and 4 are also in accordance with this binding mode as are the pronounced hypochromic UV/Vis shifts for the π–π* transitions of the dppz ligands of 4 and 7 in the range 360–400 nm. A small ΔTm value of 2 °C and effectively unchanged viscosity suggest that Ru–N (nucleobase) coordinative binding is thermodynamically preferred for the larger polypyridyl ligand of 5 under equilibrium conditions, as is also the case for the small ligands phen and tap in complexes 1 and 2. CD spectra indicate that the B DNA conformation is essentially retained for interaction with the chloro complexes 1–5 but that very significant distortions occur for the thiourea complexes 6–8. The in vitro cytotoxicities of the chloro complexes 3–5 are dependent on the size of the polypyridyl ligand with IC50 values increasing in the order dppn < dppz < dpq: for instance IC50 values of 11.1, 2.12, and 0.13 μM were determined for 3–5 towards MCF-7. These values correlate well with the cellular uptake efficiency which increases from 1.1 over 146.6 to 906.7 ng(Ru)/mg (protein) within the series 3–5. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)