Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands

Abraha Habtemariam, Michael Melchart, Rafael Fernandez, Simon Parsons, Iain D. H. Oswald, Andrew Parkin, Francesca P. A. Fabbiani, James E. Davidson, Alice Dawson, Rhona E. Aird, Duncan I. Jodrell, Peter J. Sadler

Research output: Contribution to journalArticle

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Abstract

We report structure-activity relationships for organometallic Ru-II complexes of the type [( eta(6)-arene) Ru-( XY) Cl] Z, where XY is an N, N-( diamine), N, O-( e. g., amino acidate), or O,O- ( e. g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY) ethylenediamine ( en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY) bipyridyl derivatives exhibited reduced activity. The activity of the O, O- chelated complexes depended strongly on the substituents and on the arene. For arene) p-cymene, XY) amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY) en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

Original languageEnglish
Pages (from-to)6858-6868
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number23
Early online date14 Oct 2006
DOIs
Publication statusPublished - 16 Nov 2006

Fingerprint

ethylenediamine
Ruthenium
Structure-Activity Relationship
Cyclic Hydrocarbons
Benzene Derivatives
Ligands
2,2'-Dipyridyl
Diamines
Pancreatic Neoplasms
Ovarian Neoplasms
Doxorubicin
Colonic Neoplasms
Cisplatin
Lung Neoplasms
X-Rays

Keywords

  • anticancer complexes
  • organometallic complexes
  • titanocene dichloride
  • crystal-structures
  • in-vitro
  • DNA
  • chemistry
  • binding
  • cancer
  • recognition

Cite this

Habtemariam, Abraha ; Melchart, Michael ; Fernandez, Rafael ; Parsons, Simon ; Oswald, Iain D. H. ; Parkin, Andrew ; Fabbiani, Francesca P. A. ; Davidson, James E. ; Dawson, Alice ; Aird, Rhona E. ; Jodrell, Duncan I. ; Sadler, Peter J. / Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 23. pp. 6858-6868.
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abstract = "We report structure-activity relationships for organometallic Ru-II complexes of the type [( eta(6)-arene) Ru-( XY) Cl] Z, where XY is an N, N-( diamine), N, O-( e. g., amino acidate), or O,O- ( e. g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic {"}piano-stool{"} geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY) ethylenediamine ( en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY) bipyridyl derivatives exhibited reduced activity. The activity of the O, O- chelated complexes depended strongly on the substituents and on the arene. For arene) p-cymene, XY) amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY) en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.",
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author = "Abraha Habtemariam and Michael Melchart and Rafael Fernandez and Simon Parsons and Oswald, {Iain D. H.} and Andrew Parkin and Fabbiani, {Francesca P. A.} and Davidson, {James E.} and Alice Dawson and Aird, {Rhona E.} and Jodrell, {Duncan I.} and Sadler, {Peter J.}",
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Habtemariam, A, Melchart, M, Fernandez, R, Parsons, S, Oswald, IDH, Parkin, A, Fabbiani, FPA, Davidson, JE, Dawson, A, Aird, RE, Jodrell, DI & Sadler, PJ 2006, 'Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands', Journal of Medicinal Chemistry, vol. 49, no. 23, pp. 6858-6868. https://doi.org/10.1021/jm060596m

Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands. / Habtemariam, Abraha; Melchart, Michael; Fernandez, Rafael; Parsons, Simon; Oswald, Iain D. H.; Parkin, Andrew; Fabbiani, Francesca P. A.; Davidson, James E.; Dawson, Alice; Aird, Rhona E.; Jodrell, Duncan I.; Sadler, Peter J.

In: Journal of Medicinal Chemistry, Vol. 49, No. 23, 16.11.2006, p. 6858-6868.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands

AU - Habtemariam, Abraha

AU - Melchart, Michael

AU - Fernandez, Rafael

AU - Parsons, Simon

AU - Oswald, Iain D. H.

AU - Parkin, Andrew

AU - Fabbiani, Francesca P. A.

AU - Davidson, James E.

AU - Dawson, Alice

AU - Aird, Rhona E.

AU - Jodrell, Duncan I.

AU - Sadler, Peter J.

PY - 2006/11/16

Y1 - 2006/11/16

N2 - We report structure-activity relationships for organometallic Ru-II complexes of the type [( eta(6)-arene) Ru-( XY) Cl] Z, where XY is an N, N-( diamine), N, O-( e. g., amino acidate), or O,O- ( e. g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY) ethylenediamine ( en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY) bipyridyl derivatives exhibited reduced activity. The activity of the O, O- chelated complexes depended strongly on the substituents and on the arene. For arene) p-cymene, XY) amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY) en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

AB - We report structure-activity relationships for organometallic Ru-II complexes of the type [( eta(6)-arene) Ru-( XY) Cl] Z, where XY is an N, N-( diamine), N, O-( e. g., amino acidate), or O,O- ( e. g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY) ethylenediamine ( en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY) bipyridyl derivatives exhibited reduced activity. The activity of the O, O- chelated complexes depended strongly on the substituents and on the arene. For arene) p-cymene, XY) amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY) en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

KW - anticancer complexes

KW - organometallic complexes

KW - titanocene dichloride

KW - crystal-structures

KW - in-vitro

KW - DNA

KW - chemistry

KW - binding

KW - cancer

KW - recognition

U2 - 10.1021/jm060596m

DO - 10.1021/jm060596m

M3 - Article

VL - 49

SP - 6858

EP - 6868

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 23

ER -