Organometallic Half-Sandwich Iridium Anticancer Complexes

The low-spin 5d(6) Ir-III organometallic half-sandwich complexes [(eta(5)-Cp-x)Ir(XY)Cl](0/+), Cp-x = Cp*, tetramethyl(phenyl, cyclopentadienyl (Cp-xph), or tetramethyl(biphenyl)-cyclopertadienyl (Cp-xbiph), XY = 1,10-phenanthroline (4-6), 2,2'-bipyridine (7-9), ethylenediamine (10 and 11), or...

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Bibliographic Details
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 Amer Chemical Soc 28.04.2011
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
Online Access:Get more information
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Summary:The low-spin 5d(6) Ir-III organometallic half-sandwich complexes [(eta(5)-Cp-x)Ir(XY)Cl](0/+), Cp-x = Cp*, tetramethyl(phenyl, cyclopentadienyl (Cp-xph), or tetramethyl(biphenyl)-cyclopertadienyl (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 male a major contribution to the anticancer potency of their Ir-III complexes.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm2000932