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

The DNA binding of polypyridyl (pp) (η5-C5Me5)RhIII complexes of the types [(η5-C5Me5)RhCl(pp)](CF3SO3) (2–6) (pp = bpy, phen, dpq, dppz, dppn), [(η5-C5Me5)Rh{(Me2N)2CS}(pp)](CF3SO3)2 (7–9) (pp = dpq, dppz, dppn) and [(η5-C5Me5)Rh(L)(pp)](CF3SO3) (10) (L = C6H5S−) and (11) (L = C10H7S−) 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 IC50 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 ΔTm 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 (Me2N)2CS complexes 7–9 are dependent on the size of the polypyridyl ligand with IC50 values decreasing in the order dpq > dppz > dppn. For instance, IC50 values of 5.3, 1.5 and 0.91 μM were determined for 7–9 against MCF-7 cells. Rapid Cl−/H2O 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.

Graphical abstractThe DNA binding of half-sandwich complexes of the types [(η5-C5Me5)RhCl(pp)]+ and [(η5-C5Me5)Rh{(MeN)2CS}(pp)]2+ has been studied by spectroscopic and viscosity measurements. Strong intercalation is observed for the dpq and dppz complexes. The uptake and cytotoxicity for human MCF-7 and HT-29 cells increase with increasing polypyridyl (pp) ligand size in the order dpq < dppz < dppn.Figure optionsDownload full-size imageDownload as PowerPoint slide