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

The DNA binding of polypyridyl ( pp) (eta(5)-C5Me5) Rh-III complexes of the types [(eta(5)-C5Me5) RhCl( pp)]( CF3SO3) ( 2-6) ( pp = bpy, phen, dpq, dppz, dppn), [(eta(5)-C5Me5)Rh{(Me2N)(2)CS}( pp)]( CF3SO3)(2) ( 7-9) ( pp = dpq, dppz, dppn) and [(eta(5)-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 mu M. Stable intercalative binding into CT-DNA is indicated for the dpq and dppz complexes by large increases Delta T-m of 6-12 degrees 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 pi-pi* 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)(2)CS 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 mu M 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. (C) 2008 Elsevier B.V. All rights reserved.