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Kinetics and mechanism for reduction of anticancer active tetrachloroam(m)ine platinum(IV) compounds by glutathione

Lemma, Kelemu LU ; Berglund, Johan; Farrell, Nicholas and Elding, Lars Ivar LU (2000) In Journal of Biological Inorganic Chemistry 5(3). p.300-306
Abstract
Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 °C in a 1.0 M aqueous medium at pH 2.0–5.0 (1) and 4.5–6.8 (2–4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH] tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH] tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic... (More)
Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 °C in a 1.0 M aqueous medium at pH 2.0–5.0 (1) and 4.5–6.8 (2–4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH] tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH] tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS− is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1–4 by GS− are (1.43±0.01)×107, (3.86±0.03)×106, (1.83±0.01)×106, and (1.18±0.01)×106 M−1 s−1, respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-Cl axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anti cancer active compounds, Platinum(IV), Glutathione, Reduction, Reaction mechanism
in
Journal of Biological Inorganic Chemistry
volume
5
issue
3
pages
7 pages
publisher
Springer
external identifiers
  • scopus:0034124164
ISSN
1432-1327
DOI
10.1007/PL00010658
language
English
LU publication?
yes
id
658495e6-df93-43b5-97a0-a45b36b5868f
date added to LUP
2016-12-16 19:29:58
date last changed
2017-08-13 05:02:03
@article{658495e6-df93-43b5-97a0-a45b36b5868f,
  abstract     = {Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 °C in a 1.0 M aqueous medium at pH 2.0–5.0 (1) and 4.5–6.8 (2–4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH] tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH] tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS− is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1–4 by GS− are (1.43±0.01)×107, (3.86±0.03)×106, (1.83±0.01)×106, and (1.18±0.01)×106 M−1 s−1, respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-Cl axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds.},
  author       = {Lemma, Kelemu and Berglund, Johan and Farrell, Nicholas and Elding, Lars Ivar},
  issn         = {1432-1327},
  keyword      = {Anti cancer active compounds,Platinum(IV),Glutathione,Reduction,Reaction mechanism},
  language     = {eng},
  month        = {11},
  number       = {3},
  pages        = {300--306},
  publisher    = {Springer},
  series       = {Journal of Biological Inorganic Chemistry},
  title        = {Kinetics and mechanism for reduction of anticancer active tetrachloroam(m)ine platinum(IV) compounds by glutathione},
  url          = {http://dx.doi.org/10.1007/PL00010658},
  volume       = {5},
  year         = {2000},
}