van Rijt, Sabine H., Hebden, Andrew J., Amaresekera, Thakshila, Deeth, Robert J., Clarkson, Guy J., Parsons, S. (Simon), McGowan, Patrick C. and Sadler, P. J.. (2009) Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes. Journal of Medicinal Chemistry, Vol.52 (No.23). pp. 7753-7764. ISSN 0022-2623

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Abstract

We show that the binding mode adopted by picolinamide derivatives in organometallic Os-II and Ru-II half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os-II (1, 3-5, 7, 9) and Ru-II (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9),can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible), The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) <= min), exhibited significant (32-70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian,and cisplatin-resistant ovarian human cancer cell lines (3 >> 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Organometallic compounds -- Therapeutic use, Ruthenium compounds -- Therapeutic use, Osmium compounds -- Therapeutic use, Antineoplastic agents, Transition metal complexes, Amides, Isomerism
Journal or Publication Title:	Journal of Medicinal Chemistry
Publisher:	American Chemical Society
ISSN:	0022-2623
Official Date:	10 December 2009
Volume:	Vol.52
Number:	No.23
Number of Pages:	12
Page Range:	pp. 7753-7764
Identification Number:	10.1021/jm900731j
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Engineering and Physical Sciences Research Council (EPSRC), Advantage West Midlands (AWM)
URI:	http://wrap.warwick.ac.uk/id/eprint/16838

Data sourced from Thomson Reuters' Web of Knowledge

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