Organometallic Half-Sandwich Iridium Anticancer Complexes

• Published in: Journal of medicinal chemistry Vol. 54; no. 8; pp. 3011 - 3026
• Main Authors: Liu, Zhe, Habtemariam, Abraha, Pizarro, Ana M, Fletcher, Sally A, Kisova, Anna, Vrana, Oldrich, Salassa, Luca, Bruijnincx, Pieter C. A, Clarkson, Guy J, Brabec, Viktor, Sadler, Peter J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.04.2011; Amer Chemical Soc
• Subjects: Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Female; Humans; Iridium - chemistry; Life Sciences & Biomedicine; Models, Molecular; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pharmacology & Pharmacy; Science & Technology; (ETA-PENTAMETHYLCYCLOPENTADIENYL)IRIDIUM(III) COMPLEXES; RUTHENIUM(II) ARENE COMPLEXES; N-HETEROCYCLIC CARBENE; MOLECULAR CALCULATIONS; CYCLOMETALATED IRIDIUM(III); DNA-BINDING PROPERTIES; LIGAND SUBSTITUTION-REACTIONS; ANTITUMOR COMPLEXES; PLATINUM COMPLEXES; METAL-COMPLEXES
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm2000932

The low-spin 5d6 IrIII organometallic half-sandwich complexes [(η5-Cpx)Ir(XY)Cl]0/+, Cpx = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cpxph), or tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), 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*: Cpxbiph > Cpxph > Cp*; Cpxbiph 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 Cpxph and Cpxbiph make a major contribution to the anticancer potency of their IrIII complexes.