title: Organometallic half-sandwich iridium anticancer complexes.
abstract: The low-spin 5d(6) Ir(III) organometallic half-sandwich complexes [(η(5)-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.
authors: Department of Chemistry, University of Warwick, Coventry, United Kingdom.
authors: Zhe
authors: Z
authors: Liu
authors: Abraha
authors: A
authors: Habtemariam
authors: Ana M
authors: AM
authors: Pizarro
authors: Sally A
authors: SA
authors: Fletcher
authors: Anna
authors: A
authors: Kisova
authors: Oldrich
authors: O
authors: Vrana
authors: Luca
authors: L
authors: Salassa
authors: Pieter C A
authors: PC
authors: Bruijnincx
authors: Guy J
authors: GJ
authors: Clarkson
authors: Viktor
authors: V
authors: Brabec
authors: Peter J
authors: PJ
authors: Sadler
mesh_terms: D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007495:Iridium / Q000737:chemistry*; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009942:Organometallic Compounds; D007495:Iridium