Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts

Fuyi Wang, Haimei Chen, Simon Parsons, Iain D. H. Oswald, James E. Davidson, Peter J. Sadler

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

The aqua adducts of the anticancer complexes [(η 6-X)Ru(en)Cl] [PF6] (X=biphenyl (Bip) 1, X = 5,8,9,10-tetrahydroanthracene (THA) 2, X = 9,10-dihydroanthracene (DHA) 3; en = ethylenediamime) were separated by HPLC and characterised by mass spectrometry as the products of hydrolysis in water. The X-ray structures of the aqua complexes [(η6-X)Ru(en)Y] [PF6]n, X = Bip, Y = 0.5 H2O/0.5 OH, n = 1.5 (4), X = THA, Y = 0.5 H2O/0.5 OH, n = 1.5 (5A), X = THA, Y = H2O, n = 2 (5B), and X = DHA, Y = H2O, n = 2 (6), are reported. In complex 4 there is a large propeller twist of 45° of the pendant phenyl ring with respect to the coordinated phenyl ring. Although the THA ligand in 5A and 5B is relatively flat, the DHA ring system in 6 is markedly bent (hinge bend ca. 35°) as in the chloro complex 3 (41°). The rates of aquation of 1-3 determined by UV/Vis spectroscopy at various ionic strengths and temperatures (1.23-2.59 × 10-3 s-1 at 298 K, I = 0.1 M) are >20× faster than that of cisplatin. The reverse, anation reactions were very rapid on addition of 100 mM NaCl (a similar concentration to that in blood plasma). The aquation and anation reactions were about two times faster for the DHA and THA complexes compared to the biphenyl complex. The hydrolysis reactions appear to occur by an associative pathway. The pKa values of the aqua adducts were determined by 1H NMR spectroscopy as 7.71 for 4, 8.01 for 5 and 7.89 for 6. At physiologically-relevant concentrations (0.5-5 μM) and temperature (310 K), the complexes will exist in blood plasma as >89% chloro complex, whereas in the cell nucleus significant amounts (45-65%) of the more reactive aqua adducts would be formed together with smaller amounts of the hydroxo complexes (9-25%, pH 7.4, [Cl-] = 4 mM).

LanguageEnglish
Pages5810-5820
Number of pages11
JournalChemistry - A European Journal
Volume9
Issue number23
DOIs
Publication statusPublished - 5 Dec 2003

Fingerprint

Ruthenium
Acidity
Hydrolysis
Blood
Plasmas
X rays
Kinetics
Propellers
Hinges
Ionic strength
Ultraviolet spectroscopy
Nuclear magnetic resonance spectroscopy
Mass spectrometry
Ligands
Cells
Temperature
Cisplatin
Water
diphenyl

Keywords

  • anticancer agents
  • hydrolysis
  • kinetics
  • organometallic compounds
  • ruthenium

Cite this

Wang, Fuyi ; Chen, Haimei ; Parsons, Simon ; Oswald, Iain D. H. ; Davidson, James E. ; Sadler, Peter J. / Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts. In: Chemistry - A European Journal . 2003 ; Vol. 9, No. 23. pp. 5810-5820.
@article{7afa385d3cf24f9bb9dfe2dda8903052,
title = "Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts",
abstract = "The aqua adducts of the anticancer complexes [(η 6-X)Ru(en)Cl] [PF6] (X=biphenyl (Bip) 1, X = 5,8,9,10-tetrahydroanthracene (THA) 2, X = 9,10-dihydroanthracene (DHA) 3; en = ethylenediamime) were separated by HPLC and characterised by mass spectrometry as the products of hydrolysis in water. The X-ray structures of the aqua complexes [(η6-X)Ru(en)Y] [PF6]n, X = Bip, Y = 0.5 H2O/0.5 OH, n = 1.5 (4), X = THA, Y = 0.5 H2O/0.5 OH, n = 1.5 (5A), X = THA, Y = H2O, n = 2 (5B), and X = DHA, Y = H2O, n = 2 (6), are reported. In complex 4 there is a large propeller twist of 45° of the pendant phenyl ring with respect to the coordinated phenyl ring. Although the THA ligand in 5A and 5B is relatively flat, the DHA ring system in 6 is markedly bent (hinge bend ca. 35°) as in the chloro complex 3 (41°). The rates of aquation of 1-3 determined by UV/Vis spectroscopy at various ionic strengths and temperatures (1.23-2.59 × 10-3 s-1 at 298 K, I = 0.1 M) are >20× faster than that of cisplatin. The reverse, anation reactions were very rapid on addition of 100 mM NaCl (a similar concentration to that in blood plasma). The aquation and anation reactions were about two times faster for the DHA and THA complexes compared to the biphenyl complex. The hydrolysis reactions appear to occur by an associative pathway. The pKa values of the aqua adducts were determined by 1H NMR spectroscopy as 7.71 for 4, 8.01 for 5 and 7.89 for 6. At physiologically-relevant concentrations (0.5-5 μM) and temperature (310 K), the complexes will exist in blood plasma as >89{\%} chloro complex, whereas in the cell nucleus significant amounts (45-65{\%}) of the more reactive aqua adducts would be formed together with smaller amounts of the hydroxo complexes (9-25{\%}, pH 7.4, [Cl-] = 4 mM).",
keywords = "anticancer agents, hydrolysis, kinetics, organometallic compounds, ruthenium",
author = "Fuyi Wang and Haimei Chen and Simon Parsons and Oswald, {Iain D. H.} and Davidson, {James E.} and Sadler, {Peter J.}",
year = "2003",
month = "12",
day = "5",
doi = "10.1002/chem.200304724",
language = "English",
volume = "9",
pages = "5810--5820",
journal = "Chemistry - A European Journal",
issn = "0947-6539",
number = "23",

}

Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts. / Wang, Fuyi; Chen, Haimei; Parsons, Simon; Oswald, Iain D. H.; Davidson, James E.; Sadler, Peter J.

In: Chemistry - A European Journal , Vol. 9, No. 23, 05.12.2003, p. 5810-5820.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts

AU - Wang, Fuyi

AU - Chen, Haimei

AU - Parsons, Simon

AU - Oswald, Iain D. H.

AU - Davidson, James E.

AU - Sadler, Peter J.

PY - 2003/12/5

Y1 - 2003/12/5

N2 - The aqua adducts of the anticancer complexes [(η 6-X)Ru(en)Cl] [PF6] (X=biphenyl (Bip) 1, X = 5,8,9,10-tetrahydroanthracene (THA) 2, X = 9,10-dihydroanthracene (DHA) 3; en = ethylenediamime) were separated by HPLC and characterised by mass spectrometry as the products of hydrolysis in water. The X-ray structures of the aqua complexes [(η6-X)Ru(en)Y] [PF6]n, X = Bip, Y = 0.5 H2O/0.5 OH, n = 1.5 (4), X = THA, Y = 0.5 H2O/0.5 OH, n = 1.5 (5A), X = THA, Y = H2O, n = 2 (5B), and X = DHA, Y = H2O, n = 2 (6), are reported. In complex 4 there is a large propeller twist of 45° of the pendant phenyl ring with respect to the coordinated phenyl ring. Although the THA ligand in 5A and 5B is relatively flat, the DHA ring system in 6 is markedly bent (hinge bend ca. 35°) as in the chloro complex 3 (41°). The rates of aquation of 1-3 determined by UV/Vis spectroscopy at various ionic strengths and temperatures (1.23-2.59 × 10-3 s-1 at 298 K, I = 0.1 M) are >20× faster than that of cisplatin. The reverse, anation reactions were very rapid on addition of 100 mM NaCl (a similar concentration to that in blood plasma). The aquation and anation reactions were about two times faster for the DHA and THA complexes compared to the biphenyl complex. The hydrolysis reactions appear to occur by an associative pathway. The pKa values of the aqua adducts were determined by 1H NMR spectroscopy as 7.71 for 4, 8.01 for 5 and 7.89 for 6. At physiologically-relevant concentrations (0.5-5 μM) and temperature (310 K), the complexes will exist in blood plasma as >89% chloro complex, whereas in the cell nucleus significant amounts (45-65%) of the more reactive aqua adducts would be formed together with smaller amounts of the hydroxo complexes (9-25%, pH 7.4, [Cl-] = 4 mM).

AB - The aqua adducts of the anticancer complexes [(η 6-X)Ru(en)Cl] [PF6] (X=biphenyl (Bip) 1, X = 5,8,9,10-tetrahydroanthracene (THA) 2, X = 9,10-dihydroanthracene (DHA) 3; en = ethylenediamime) were separated by HPLC and characterised by mass spectrometry as the products of hydrolysis in water. The X-ray structures of the aqua complexes [(η6-X)Ru(en)Y] [PF6]n, X = Bip, Y = 0.5 H2O/0.5 OH, n = 1.5 (4), X = THA, Y = 0.5 H2O/0.5 OH, n = 1.5 (5A), X = THA, Y = H2O, n = 2 (5B), and X = DHA, Y = H2O, n = 2 (6), are reported. In complex 4 there is a large propeller twist of 45° of the pendant phenyl ring with respect to the coordinated phenyl ring. Although the THA ligand in 5A and 5B is relatively flat, the DHA ring system in 6 is markedly bent (hinge bend ca. 35°) as in the chloro complex 3 (41°). The rates of aquation of 1-3 determined by UV/Vis spectroscopy at various ionic strengths and temperatures (1.23-2.59 × 10-3 s-1 at 298 K, I = 0.1 M) are >20× faster than that of cisplatin. The reverse, anation reactions were very rapid on addition of 100 mM NaCl (a similar concentration to that in blood plasma). The aquation and anation reactions were about two times faster for the DHA and THA complexes compared to the biphenyl complex. The hydrolysis reactions appear to occur by an associative pathway. The pKa values of the aqua adducts were determined by 1H NMR spectroscopy as 7.71 for 4, 8.01 for 5 and 7.89 for 6. At physiologically-relevant concentrations (0.5-5 μM) and temperature (310 K), the complexes will exist in blood plasma as >89% chloro complex, whereas in the cell nucleus significant amounts (45-65%) of the more reactive aqua adducts would be formed together with smaller amounts of the hydroxo complexes (9-25%, pH 7.4, [Cl-] = 4 mM).

KW - anticancer agents

KW - hydrolysis

KW - kinetics

KW - organometallic compounds

KW - ruthenium

UR - http://www.scopus.com/inward/record.url?scp=0347624091&partnerID=8YFLogxK

UR - https://onlinelibrary.wiley.com/journal/15213765

U2 - 10.1002/chem.200304724

DO - 10.1002/chem.200304724

M3 - Article

VL - 9

SP - 5810

EP - 5820

JO - Chemistry - A European Journal

T2 - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

IS - 23

ER -