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

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Pages7753-7764
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number23
DOIs
Publication statusPublished - 30 Sep 2009
Externally publishedYes

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Isomerism
Osmium
Ruthenium
Guanine
Adenine
Amides
Electrons
Ovarian Neoplasms
Cisplatin
Colon
Cell Line
Temperature
Neoplasms
picolinamide
4-cymene
diphenyl

Cite this

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
Van Rijt, S.H. ; Hebden, A.J. ; Amaresekera, T. ; Deeth, R.J. ; Clarkson, Guy ; Parsons, S. ; McGowan, P.C. ; Sadler, P.J. / Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 23. pp. 7753-7764.
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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. {\circledC} 2009 American Chemical Society.",
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Van Rijt, SH, Hebden, AJ, Amaresekera, T, Deeth, RJ, Clarkson, G, Parsons, S, McGowan, PC & Sadler, PJ 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. https://doi.org/10.1021/jm900731j

Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes. / Van Rijt, S.H.; Hebden, A.J.; Amaresekera, T.; Deeth, R.J.; Clarkson, Guy; Parsons, S.; McGowan, P.C.; Sadler, P.J.

In: Journal of Medicinal Chemistry, Vol. 52, No. 23, 30.09.2009, p. 7753-7764.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes

AU - Van Rijt, S.H.

AU - Hebden, A.J.

AU - Amaresekera, T.

AU - Deeth, R.J.

AU - Clarkson, Guy

AU - Parsons, S.

AU - McGowan, P.C.

AU - Sadler, P.J.

PY - 2009/9/30

Y1 - 2009/9/30

N2 - 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.

AB - 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.

KW - adenine

KW - amide

KW - antineoplastic agent

KW - biphenyl derivative

KW - cisplatin

KW - coordination compound

KW - guanine

KW - organometallic compound

KW - osmium derivative

KW - picolinamide

KW - ruthenium derivative

KW - antineoplastic activity

KW - article

KW - cancer cell

KW - cancer cell culture

KW - cancer resistance

KW - colon cancer

KW - controlled study

KW - drug binding

KW - drug cytotoxicity

KW - drug hydrolysis

KW - dynamics

KW - female

KW - human

KW - human cell

KW - isomerism

KW - nuclear magnetic resonance

KW - ovary cancer

KW - pH

KW - temperature

KW - time

KW - Adenine

KW - Amides

KW - Antineoplastic Agents

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - DNA

KW - Guanine

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Hydrolysis

KW - Isomerism

KW - Kinetics

KW - Ligands

KW - Magnetic Resonance Spectroscopy

KW - Models, Molecular

KW - Molecular Conformation

KW - Organometallic Compounds

KW - Osmium

KW - Picolinic Acids

KW - Quantum Theory

KW - Ruthenium

KW - Thermodynamics

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DO - 10.1021/jm900731j

M3 - Article

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SP - 7753

EP - 7764

JO - Journal of Medicinal Chemistry

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JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -