Cytotoxic half-sandwich rhodium(III) complexes: Polypyridyl ligand influence on their DNA binding properties and cellular uptake

Abstract

The DNA binding of polypyridyl (pp) (η 5-C 5Me 5)Rh III complexes of the types [(η 5-C 5Me 5)RhCl(pp)](CF 3SO 3) ( 2– 6) (pp = bpy, phen, dpq, dppz, dppn), [(η 5-C 5Me 5)Rh{(Me 2N) 2CS}(pp)](CF 3SO 3) 2 ( 7– 9) (pp = dpq, dppz, dppn) and [(η 5-C 5Me 5)Rh(L)(pp)](CF 3SO 3) ( 10) (L = C 6H 5S −) and ( 11) (L = C 10H 7S −) has been studied by UV/Vis spectroscopy, circular dichroismus and viscosity measurements. Complexes 3– 11 are cytotoxic towards the human MCF-7 breast and HT-29 colon cancer cell lines and exhibit IC 50 values in the range 0.56–10.7 μM. Stable intercalative binding into CT-DNA is indicated for the dpq and dppz complexes by large increases Δ T m of 6–12 °C in the DNA thermal denaturation temperature for r = [complex]/[DNA] = 0.1 and by induced CD bands and large viscosity increases. In contrast, significant DNA lengthening is not observed after incubation of the biopolymer with the dppn complexes 2 and 9 at molar ratios of r < 0.08. Pronounced hypochromic shifts for the π–π ∗ transitions of the dppn ligands in the range 320–425 nm indicate the possible presence of surface stacking. The in vitro cytotoxicities of the chloro complexes 4– 6 and the (Me 2N) 2CS complexes 7– 9 are dependent on the size of the polypyridyl ligand with IC 50 values decreasing in the order dpq > dppz > dppn. For instance, IC 50 values of 5.3, 1.5 and 0.91 μM were determined for 7– 9 against MCF-7 cells. Rapid Cl −/H 2O exchange leads the formation of aqua dications for 4– 6, whose levels of cellular uptake and cytotoxicities are similar to those established for 7– 9. Intramolecular interactions between the aromatic thiolate and dppz ligands of 10 and 11 prevent significant DNA intercalation. X-ray structural determinations have been performed for 2– 7 and 11.