Synthesis, cellular uptake and structure-activity relationships for potent cytotoxic trichloridoiridium(III) polypyridyl complexes

The complexes fac-[IrCl3(DMSO)(pp)] 1a–5a may be prepared by stepwise reaction of IrCl3 · 3H2O with the appropriate polypyridyl ligand (pp = bpy, phen, dpq, dppz, dppn) and DMSO in CH3OH solution in the dark. The fac isomers of 1a–5a are stable in light-protected CD2Cl2 solution but, with the exception of 5a, isomerize rapidly to a mixture of the fac and mer isomers in the presence of light. In contrast, solutions of the fac isomers in the polar solvents D2O and CD3OD are stable under such conditions. The isomer mer-[IrCl3(DMSO-κS)(phen)] 2b was, however, isolated by slow evaporation of an H2O/CH3OH solution of 2a and characterized by X-ray structural analysis. UV/Vis and CD studies of the interaction of 1a–5a with calf thymus DNA are in accordance with an effective absence of intercalation. 1H NMR studies indicate that the complexes react slowly with compounds containing soft S donor atoms (e. g. N-acetylmethionine) but do not react with the guanine base of 5′-GMP2−. The complexes 2a–5a are potent in vitro cytotoxic agents toward the human cell lines MCF-7 and HT-29 and their IC50 values are dependent on the size of the polypyridyl ligand in the order phen, dpq > dppz > dppn. For instance IC50 values of 5.5 (0.9), 0.8 (0.3) and 0.21 (0.11) μM were established for 3a–5a against MCF-7 cells and 6.1 (0.7), 1.5 (0.2) and 1.3 (0.4) μM against HT-29 cells. These values correlate with the cellular uptake efficiency which, on exposure to 10 μM solutions, reaches its highest levels (19.3(0.8) and 37.4(8.9) ng Ir/mg protein for MCF-7 and HT-29, respectively) for the dppn compound 5a.