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Potent half-sandwich iridium(III) anticancer complexes containing C∧N-Chelated and pyridine ligands
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Liu, Zhe , Romero-Canelón, Isolda, Habtemariam, Abraha, Clarkson, Guy J. and Sadler, P. J. (2014) Potent half-sandwich iridium(III) anticancer complexes containing C∧N-Chelated and pyridine ligands. Organometallics, 33 (19). pp. 5324-5333. doi:10.1021/om500644f ISSN 0276-7333.
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Official URL: http://dx.doi.org/10.1021/om500644f
Abstract
We report the synthesis and characterization of eight half-sandwich cyclopentadienyl Ir(III) pyridine complexes of the type [(η(5)-Cp(xph))Ir(phpy)Z]PF6, in which Cp(xph) = C5Me4C6H5 (tetramethyl(phenyl)cyclopentadienyl), phpy = 2-phenylpyridine as C(∧)N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe2) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt2) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(η(5)-Cp(xph))Ir(phpy)(py)](+) (1) and [(η(5)-Cp(xph))Ir(phpy)(4-NMe2-py)](+) (5) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC50 concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (ΔΨm), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.
Item Type: | Journal Article | ||||||
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Subjects: | Q Science > QD Chemistry | ||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Iridium, Organometallic compounds -- Physiological effect | ||||||
Journal or Publication Title: | Organometallics | ||||||
Publisher: | American Chemical Society | ||||||
ISSN: | 0276-7333 | ||||||
Official Date: | 9 September 2014 | ||||||
Dates: |
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Volume: | 33 | ||||||
Number: | 19 | ||||||
Number of Pages: | 10 | ||||||
Page Range: | pp. 5324-5333 | ||||||
DOI: | 10.1021/om500644f | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 29 December 2015 | ||||||
Date of first compliant Open Access: | 29 December 2015 | ||||||
Funder: | European Research Council (ERC), Birmingham Science City, Advantage West Midlands (AWM), European Regional Development Fund (ERDF) | ||||||
Grant number: | 247450 (ERC) |
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