Liu, Zhe , Habtemariam, Abraha, Pizarro, Ana M., Fletcher, Sally A., Kisova, Anna, Vrana, Oldrich, Salassa, Luca, Bruijnincx, Pieter C. A., Clarkson, Guy J., Brabec, V. (Viktor) and Sadler, P. J. (2011) Organometallic half-sandwich iridium anticancer complexes. Journal of Medicinal Chemistry, Vol.54 (No.8). pp. 3011-3026. doi:10.1021/jm2000932 ISSN 0022-2623.

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Abstract

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.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH):	Antineoplastic agents, Organoiridium compounds, Ovaries -- Cancer -- Treatment
Journal or Publication Title:	Journal of Medicinal Chemistry
Publisher:	American Chemical Society
ISSN:	0022-2623
Official Date:	28 March 2011
Dates:	Date Event 28 March 2011 Published
Volume:	Vol.54
Number:	No.8
Page Range:	pp. 3011-3026
DOI:	10.1021/jm2000932
Status:	Peer Reviewed
Publication Status:	Published
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), Nederlandse Organisatie voor Wetenschappelijk Onderzoek [Netherlands Organisation for Scientific Research] (NWO), Czech Republic. National Foundation, 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), P303/11/P047 (CNF), P301/10/0598 (CNF), 247450 (ERC)

Data sourced from Thomson Reuters' Web of Knowledge

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