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Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes
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Rijt, Sabine H. van, 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. doi:10.1021/jm900731j
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Official URL: http://dx.doi.org/10.1021/jm900731j
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 | ||||
| Dates: |
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| Volume: | Vol.52 | ||||
| Number: | No.23 | ||||
| Number of Pages: | 12 | ||||
| Page Range: | pp. 7753-7764 | ||||
| DOI: | 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) |
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