Organometallic Iridium(III) Cyclopentadienyl Anticancer Complexes Containing C,N-Chelating Ligands

Organometallic IrIII cyclopentadienyl complexes [(η5-Cpx)Ir(C∧N)Cl] {Cpx = Cp*, C∧N = 2-(p-tolyl)pyridine (1), 2-phenylquinoline (2), 2-(2,4-difluorophenyl)pyridine (3), Cpx = tetramethyl(phenyl)cyclopentadienyl (Cpxph), C∧N = 2-phenylpyridine (4), and Cpx = tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), C∧N = 2-phenylpyridine (5)} have been synthesized and characterized. The X-ray crystal structures of 2 and 5 have been determined and show typical “piano-stool” geometry. All the complexes hydrolyzed rapidly in aqueous solution (Ka values of the aqua adducts 1A–5A are in the range 8.31–8.87 and follow the order 1A > 2A > 4A > 5A ≈ 3A. Hydroxo-bridged dimers {[(η5-Cpx)Ir]2(μ-OD)3}+ (Cpx = Cp*, 6; Cpxph, 7; Cpxbiph, 8) are readily formed during pH titrations at ca. pH 8.7. Complexes 1 and 3–5 bind strongly to 9-ethylguanine (9-EtG), moderately strongly to 9-methyladenine (9-MeA), and hence preferentially to 9-EtG when in competition with 9-MeA. The extent of guanine and adenine binding to complex 2 was significantly lower for both purines due to steric hindrance from the chelating ligand. All complexes showed potent cytotoxicity, with IC50 values ranging from 6.5 to 0.7 μM toward A2780 human ovarian cancer cells. Potency toward these cancer cells increased with additional phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*. Cpxbiph with complex 5 exhibited submicromolar activity (2× as active as cisplatin). These data demonstrate how the aqueous chemistry, nucleobase binding, and anticancer activity of C,N-bound IrIII cyclopentadienyl complexes can be controlled and fine-tuned by the modification of the chelating and cyclopentadienyl ligands.