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Kinetics and Mechanism for Reduction of the Anticancer Prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM 335) by Thiols

Lemma, Kelemu LU ; Shi, Tiesheng LU and Elding, Lars Ivar LU (2000) In Inorganic Chemistry 39(8). p.1728-1734
Abstract

Reduction of the anticancer trans platinum(IV) prodrug JM335 by thiols in a moderately alkaline aqueous perchlorate medium is quite rapid and yields trans-[Pt(OH)2(c-C6H11NH2)(NH3)] as the reaction product. The mechanism of reduction involves reductive attack by thiol or thiolate on one of the mutually trans chloride ligands, leading to the formation of a chloride-bridged activated complex.

The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by l-cysteine, dl-penicillamine, dl-homocysteine, N-acetyl-l-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, and glutathione has been investigated at 25 °C in a 1.0 M aqueous perchlorate medium with 6.8 ≤ pH ≤ 11.2 using... (More)

Reduction of the anticancer trans platinum(IV) prodrug JM335 by thiols in a moderately alkaline aqueous perchlorate medium is quite rapid and yields trans-[Pt(OH)2(c-C6H11NH2)(NH3)] as the reaction product. The mechanism of reduction involves reductive attack by thiol or thiolate on one of the mutually trans chloride ligands, leading to the formation of a chloride-bridged activated complex.

The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by l-cysteine, dl-penicillamine, dl-homocysteine, N-acetyl-l-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, and glutathione has been investigated at 25 °C in a 1.0 M aqueous perchlorate medium with 6.8 ≤ pH ≤ 11.2 using stopped-flow spectrophotometry. The stoichiometry of Pt(IV):thiol is 1:2, and the redox reactions follow the second-order rate law −d[Pt(IV)]/dt = k[Pt(IV)][RSH]tot, where k denotes the pH-dependent second-order rate constant and [RSH]tot the total concentration of thiol. The pH dependence of k is ascribed to parallel reductions of JM335 by the various protolytic species of the thiols, the relative contributions of which change with pH. Electron transfer from thiol (RSH) or thiolate (RS-) to JM335 is suggested to take place as a reductive elimination process through an attack by sulfur at one of the mutually trans chloride ligands, yielding trans-[Pt(OH)2(c-C6H11NH2)(NH3)] and RSSR as the reaction products, as confirmed by 1H NMR. Second-order rate constants for the reduction of JM335 by the various protolytic species of the thiols span more than 3 orders of magnitude. Reduction with RS- is ∼30−2000 times faster than with RSH. The linear correlation log(kRS-) = (0.52 ± 0.06)pKRSH − (2.8 ± 0.5) is observed, where kRS- denotes the second-order rate constant for reduction of JM335 by a particular thiolate RS- and KRSH is the acid dissociation constant for the corresponding thiol RSH. The slope of the linear correlation indicates that the reactivity of the various thiolate species is governed by their proton basicity, and no significant steric effects are observed. The half-life for reduction of JM335 by 6 mM glutathione (40-fold excess) at physiologically relevant conditions of 37 °C and pH 7.30 is 23 s. This implies that JM335, in clinical use, is likely to undergo in vivo reduction by intracellular reducing agents such as glutathione prior to binding to DNA. Reduction results in the immediate formation of a highly reactive platinum(II) species, i.e., the bishydroxo complex in rapid protolytic equilibrium with its aqua form. (Less)
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publication status
published
subject
keywords
Anticancer active Pt(IV) compounds, Prodrug, Thiol, Reduction, Kiinetics and Mechanism
in
Inorganic Chemistry
volume
39
issue
8
pages
7 pages
publisher
The American Chemical Society
external identifiers
  • scopus:0034678254
ISSN
1520-510X
DOI
10.1021/ic991351l
language
English
LU publication?
yes
id
47b800fd-d0b2-4f27-8d8a-d58049328d6d
date added to LUP
2016-12-16 19:47:08
date last changed
2017-03-26 04:48:08
@article{47b800fd-d0b2-4f27-8d8a-d58049328d6d,
  abstract     = {<br/>Reduction of the anticancer trans platinum(IV) prodrug JM335 by thiols in a moderately alkaline aqueous perchlorate medium is quite rapid and yields trans-[Pt(OH)2(c-C6H11NH2)(NH3)] as the reaction product. The mechanism of reduction involves reductive attack by thiol or thiolate on one of the mutually trans chloride ligands, leading to the formation of a chloride-bridged activated complex.<br/><br/>The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by l-cysteine, dl-penicillamine, dl-homocysteine, N-acetyl-l-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, and glutathione has been investigated at 25 °C in a 1.0 M aqueous perchlorate medium with 6.8 ≤ pH ≤ 11.2 using stopped-flow spectrophotometry. The stoichiometry of Pt(IV):thiol is 1:2, and the redox reactions follow the second-order rate law −d[Pt(IV)]/dt = k[Pt(IV)][RSH]tot, where k denotes the pH-dependent second-order rate constant and [RSH]tot the total concentration of thiol. The pH dependence of k is ascribed to parallel reductions of JM335 by the various protolytic species of the thiols, the relative contributions of which change with pH. Electron transfer from thiol (RSH) or thiolate (RS-) to JM335 is suggested to take place as a reductive elimination process through an attack by sulfur at one of the mutually trans chloride ligands, yielding trans-[Pt(OH)2(c-C6H11NH2)(NH3)] and RSSR as the reaction products, as confirmed by 1H NMR. Second-order rate constants for the reduction of JM335 by the various protolytic species of the thiols span more than 3 orders of magnitude. Reduction with RS- is ∼30−2000 times faster than with RSH. The linear correlation log(kRS-) = (0.52 ± 0.06)pKRSH − (2.8 ± 0.5) is observed, where kRS- denotes the second-order rate constant for reduction of JM335 by a particular thiolate RS- and KRSH is the acid dissociation constant for the corresponding thiol RSH. The slope of the linear correlation indicates that the reactivity of the various thiolate species is governed by their proton basicity, and no significant steric effects are observed. The half-life for reduction of JM335 by 6 mM glutathione (40-fold excess) at physiologically relevant conditions of 37 °C and pH 7.30 is 23 s. This implies that JM335, in clinical use, is likely to undergo in vivo reduction by intracellular reducing agents such as glutathione prior to binding to DNA. Reduction results in the immediate formation of a highly reactive platinum(II) species, i.e., the bishydroxo complex in rapid protolytic equilibrium with its aqua form.},
  author       = {Lemma, Kelemu and Shi, Tiesheng and Elding, Lars Ivar},
  issn         = {1520-510X},
  keyword      = {Anticancer active Pt(IV) compounds,Prodrug,Thiol,Reduction,Kiinetics and Mechanism},
  language     = {eng},
  month        = {03},
  number       = {8},
  pages        = {1728--1734},
  publisher    = {The American Chemical Society},
  series       = {Inorganic Chemistry},
  title        = {Kinetics and Mechanism for Reduction of the Anticancer Prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)]  (JM 335)  by Thiols},
  url          = {http://dx.doi.org/10.1021/ic991351l},
  volume       = {39},
  year         = {2000},
}