Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes

S.H. Van Rijt, A.J. Hebden, T. Amaresekera, R.J. Deeth, Guy Clarkson, S. Parsons, P.C. McGowan, P.J. Sadler

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Abstract

We show that the binding mode adopted by picolinamide derivatives in organometallic OsII and RuII half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in OsII (1, 3-5, 7, 9) and RuII (2, 6, 8, 10) complexes [(η6-arene)(Os/Ru)(XY)Cl]n+, where arene=p-cymene (1-8, 10) or biphenyl (9), can act asN,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 (t1/2 ≤ 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. © 2009 American Chemical Society.
Original languageEnglish
Pages (from-to)7753-7764
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number23
DOIs
Publication statusPublished - 30 Sep 2009
Externally publishedYes

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    Van Rijt, S. H., Hebden, A. J., Amaresekera, T., Deeth, R. J., Clarkson, G., Parsons, S., ... Sadler, P. J. (2009). Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes. Journal of Medicinal Chemistry, 52(23), 7753-7764. https://doi.org/10.1021/jm900731j