Inhibition of cancer cell growth by ruthenium(II) arene complexes

Robert E. Morris, Rhona E. Aird, Piedad del Socorro Murdoch, Haimei Chen, Jeffrey Cummings, Nathan D. Hughes, Simon Parsons, Andrew Parkin, Gary Boyd, Duncan I. Jodrell, Peter J. Sadler

Research output: Contribution to journalArticle

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Abstract

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(η6-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(η6-p-cymene)Ru(en)Cl]PF6 (5), [(η6-p-cymene)RuCl2(isonicotinamide)] (7), and [(η6-biphenyl)Ru(en)Cl]PF6 (9) are reported. They have “piano stool” geometries with η6 coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru−Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.
Original languageEnglish
Pages (from-to)3616-3621
Number of pages6
JournalJournal of Medicinal Chemistry
Volume44
DOIs
Publication statusPublished - 2001
Externally publishedYes

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ethylenediamine
Ruthenium
Growth
Benzene
Neoplasms
Ligands
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Carboplatin
Oligonucleotides
Antineoplastic Agents
Ovarian Neoplasms
Chlorides
Hydrolysis
Metals
High Pressure Liquid Chromatography
X-Rays
Clinical Trials
Ions
Cell Line

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Morris, R. E., Aird, R. E., Murdoch, P. D. S., Chen, H., Cummings, J., Hughes, N. D., ... Sadler, P. J. (2001). Inhibition of cancer cell growth by ruthenium(II) arene complexes. Journal of Medicinal Chemistry, 44, 3616-3621. https://doi.org/10.1021/jm010051m
Morris, Robert E. ; Aird, Rhona E. ; Murdoch, Piedad del Socorro ; Chen, Haimei ; Cummings, Jeffrey ; Hughes, Nathan D. ; Parsons, Simon ; Parkin, Andrew ; Boyd, Gary ; Jodrell, Duncan I. ; Sadler, Peter J. / Inhibition of cancer cell growth by ruthenium(II) arene complexes. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44. pp. 3616-3621.
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abstract = "Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(η6-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(η6-p-cymene)Ru(en)Cl]PF6 (5), [(η6-p-cymene)RuCl2(isonicotinamide)] (7), and [(η6-biphenyl)Ru(en)Cl]PF6 (9) are reported. They have “piano stool” geometries with η6 coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru−Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.",
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Morris, RE, Aird, RE, Murdoch, PDS, Chen, H, Cummings, J, Hughes, ND, Parsons, S, Parkin, A, Boyd, G, Jodrell, DI & Sadler, PJ 2001, 'Inhibition of cancer cell growth by ruthenium(II) arene complexes', Journal of Medicinal Chemistry, vol. 44, pp. 3616-3621. https://doi.org/10.1021/jm010051m

Inhibition of cancer cell growth by ruthenium(II) arene complexes. / Morris, Robert E.; Aird, Rhona E.; Murdoch, Piedad del Socorro; Chen, Haimei; Cummings, Jeffrey; Hughes, Nathan D.; Parsons, Simon; Parkin, Andrew; Boyd, Gary; Jodrell, Duncan I.; Sadler, Peter J.

In: Journal of Medicinal Chemistry, Vol. 44, 2001, p. 3616-3621.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of cancer cell growth by ruthenium(II) arene complexes

AU - Morris, Robert E.

AU - Aird, Rhona E.

AU - Murdoch, Piedad del Socorro

AU - Chen, Haimei

AU - Cummings, Jeffrey

AU - Hughes, Nathan D.

AU - Parsons, Simon

AU - Parkin, Andrew

AU - Boyd, Gary

AU - Jodrell, Duncan I.

AU - Sadler, Peter J.

PY - 2001

Y1 - 2001

N2 - Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(η6-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(η6-p-cymene)Ru(en)Cl]PF6 (5), [(η6-p-cymene)RuCl2(isonicotinamide)] (7), and [(η6-biphenyl)Ru(en)Cl]PF6 (9) are reported. They have “piano stool” geometries with η6 coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru−Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

AB - Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(η6-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(η6-p-cymene)Ru(en)Cl]PF6 (5), [(η6-p-cymene)RuCl2(isonicotinamide)] (7), and [(η6-biphenyl)Ru(en)Cl]PF6 (9) are reported. They have “piano stool” geometries with η6 coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru−Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

U2 - 10.1021/jm010051m

DO - 10.1021/jm010051m

M3 - Article

VL - 44

SP - 3616

EP - 3621

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -

Morris RE, Aird RE, Murdoch PDS, Chen H, Cummings J, Hughes ND et al. Inhibition of cancer cell growth by ruthenium(II) arene complexes. Journal of Medicinal Chemistry. 2001;44:3616-3621. https://doi.org/10.1021/jm010051m