Organometallic Half-Sandwich Iridium Anticancer Complexes

Abstract

The low-spin 5d⁶ Ir^III organometallic half-sandwich complexes [(η⁵-Cp^x)Ir(XY)Cl]^0/+, Cp^x = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp^xph), or tetramethyl(biphenyl)cyclopentadienyl (Cp^xbiph), XY = 1,10-phenanthroline (4−6), 2,2′-bipyridine (7−9), ethylenediamine (10 and 11), or picolinate (12−14), hydrolyze rapidly. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; picolinate complexes bind to both purines. Cytotoxic potency toward A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cp^xbiph > Cp^xph > Cp*; Cp^xbiph complexes 6 and 9 have submicromolar activity. Guanine residues are preferential binding sites for 4−6 on plasmid DNA. Hydrophobicity (log P), cell and nucleus accumulation of Ir correlate with cytotoxicity, 6 > 5 > 4; they distribute similarly within cells. The ability to displace DNA intercalator ethidium bromide from DNA correlates with cytotoxicity and viscosity of Ir−DNA adducts. The hydrophobicity and intercalative ability of Cp^xph and Cp^xbiph make a major contribution to the anticancer potency of their Ir^III complexes.