Influence of the Polypyridyl (pp) Ligand Size on the DNA Binding Properties, Cytotoxicity and Cellular Uptake of Organoruthenium(II) Complexes of the Type [(η 6 ‐C 6 Me 6 )Ru(L)(pp)] n + [L = Cl, n = 1; L = (NH 2 ) 2 CS, n = 2]

The DNA binding of polypyridyl (pp) (η 6 ‐hexamethylbenzene)ruthenium(II) complexes of the type [(η 6 ‐C 6 Me 6 )RuCl(pp)](CF 3 SO 3 ) (pp = phen, tap, dpq, dppz, dppn) 1 – 5 and [(η 6 ‐C 6 Me 6 )Ru{(NH 2 ) 2 CS}(pp)](CF 3 SO 3 ) 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 Δ T m 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 Δ T m 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 IC 50 values increasing in the order dppn < dppz < dpq: for instance IC 50 values of 11.1, 2.12, and 0.13 μ M 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)