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Contrasting reactivity and cancer cell cytotoxicity of isoelectronic organometallic iridium(III) complexes
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Liu, Zhe , Salassa, Luca, Habtemariam, Abraha, Pizarro, Ana M., Clarkson, Guy J. and Sadler, P. J. (2011) Contrasting reactivity and cancer cell cytotoxicity of isoelectronic organometallic iridium(III) complexes. Inorganic Chemistry, Vol.50 (No.12). pp. 5777-5783. doi:10.1021/ic200607j ISSN 0020-1669.
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WRAP_Sadler_80811-5_sadler_ic-2011-00607j.pdf - Accepted Version Download (835Kb) |
Official URL: http://dx.doi.org/10.1021/ic200607j
Abstract
Replacing the N,N-chelating ligand 2,2′-bipyridine (bpy) in the IrIII pentamethylcyclopentadienyl (Cp*) complex [(η5-C5Me5)Ir(bpy)Cl]+ (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(η5-C5Me5)Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC50 values of >100 μM for 1 and 10.8 μM for 2). Ir–Cl hydrolysis is rapid for both complexes (hydrolysis equilibrium reached in <5 min at 278 K). Complex 2 forms adducts with both 9-ethylguanine (9-EtG) and 9-methyladenine (9-MeA), but preferentially with 9-EtG when in competition (ca. 85% of total Ir after 24 h). The X-ray crystal structure of [(η5-C5Me5)Ir(phpy)(9-EtG-N7)]NO3·1.5CH2Cl2 confirms N7 binding to guanine. Two-dimensional NMR spectra show that complex 2 binds to adenine mainly through N1, consistent with density functional theory (DFT) calculations. DFT calculations indicate an interaction between the nitrogen of the NH2 group (9-MeA) and carbons from phpy in the adenine adduct of complex 2. Calculations show that the most stable geometry of the adduct [(η5-C5Me5)Ir(phpy)(9-EtG-N7)]+ (3b) has the C6O of 9-EtG orientated toward the pyridine ring of phpy, and for [(η5-C5Me5)Ir(phpy)(9-MeA-N1)]+ (4(N1)a), the NH2 group of 9-EtA is adjacent to the phenyl ring side of phpy. Complex 2 is more hydrophobic than complex 1, with log P values of 1.57 and −0.95, respectively. The strong nucleobase binding and high hydrophobicity of complex 2 probably contribute to its promising anticancer activity.
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): | Chelates, Organoiridium compounds, Antineoplastic agents, Ovaries -- Cancer -- Treatment | ||||
Journal or Publication Title: | Inorganic Chemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0020-1669 | ||||
Official Date: | 27 May 2011 | ||||
Dates: |
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Volume: | Vol.50 | ||||
Number: | No.12 | ||||
Page Range: | pp. 5777-5783 | ||||
DOI: | 10.1021/ic200607j | ||||
Status: | Peer Reviewed | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 17 December 2015 | ||||
Date of first compliant Open Access: | 17 December 2015 | ||||
Funder: | University of Warwick, European Research Council (ERC), Engineering and Physical Sciences Research Council (EPSRC), Overseas Research Students Awards Scheme (ORSAS), European Regional Development Fund (ERDF), Advantage West Midlands (AWM), Birmingham Science City | ||||
Grant number: | 220281 PHOTORUACD (ERC), 247450 (ERC) |
Data sourced from Thomson Reuters' Web of Knowledge
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