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Kinetics and Mechanism for Reduction of Oral Anticancer Platinum(IV) Dicarboxylate Compounds by L-Ascorbate Ions

Lemma, Kelemu LU ; Sargeson, Alan M. and Elding, Lars Ivar LU (2000) In Journal of the Chemical Society, Dalton Transactions 2000(7). p.1167-1172
Abstract
Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis,trans,cis-[PtCl2(OAc)2(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)2(cha)(NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: −d[Pt(IV)]/dt = k [Pt(IV)] [Asc]tot where k is a pH... (More)
Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis,trans,cis-[PtCl2(OAc)2(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)2(cha)(NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: −d[Pt(IV)]/dt = k [Pt(IV)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2−] + [HAsc−] + [H2Asc]. Reduction of JM216 and JM221 is slow (overall rate constants k298 = 5.08 ± 10−2 and 3.25 × 10−2 mol−1 dm3 s−1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster (k298 = 230 ± 6 mol−1 dm3 s−1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2− and less efficiently by HAsc− leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc− and Asc2− at 25 °C are 0.548 ± 0.004 and (4.46 ± 0.01) × 106 mol−1 dm3 s−1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2− at 25 °C are calculated to be 672 ± 15 and 428 ± 10 mol−1 dm3 s−1, respectively and reduction by HAsc− was not observed under these conditions. Thus, Asc2− is up to 7 orders of magnitude more efficient as a reductant than HAsc−. H2Asc is virtually inactive. The activation parameters ΔH ‡ and ΔS‡ for reduction of JM216, JM221, JM394, and JM576 by Asc2− are 52 ± 1, 46 ± 1, 56.2 ± 0.5, and 63 ± 2 kJ mol−1 and −97 ± 4, −120 ± 4, −24 ± 2, and −8 ± 5 J K−1 mol−1, respectively. An isokinetic relationship gives further support to the mechanistic assignments. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Platinum(IV), Ascorbate, Reduction, Pro-drug, Anti-cancer drug, Reaction mechanism
in
Journal of the Chemical Society, Dalton Transactions
volume
2000
issue
7
pages
7 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:0000886006
ISSN
1472-7773
DOI
10.1039/a909484i
language
English
LU publication?
yes
id
da0c9c94-82af-4f97-a0bf-e8862ce15232
date added to LUP
2016-12-16 19:39:46
date last changed
2017-11-14 09:52:25
@article{da0c9c94-82af-4f97-a0bf-e8862ce15232,
  abstract     = { Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis,trans,cis-[PtCl2(OAc)2(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)2(cha)(NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: −d[Pt(IV)]/dt = k [Pt(IV)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2−] + [HAsc−] + [H2Asc]. Reduction of JM216 and JM221 is slow (overall rate constants k298 = 5.08 ± 10−2 and 3.25 × 10−2 mol−1 dm3 s−1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster (k298 = 230 ± 6 mol−1 dm3 s−1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2− and less efficiently by HAsc− leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc− and Asc2− at 25 °C are 0.548 ± 0.004 and (4.46 ± 0.01) × 106 mol−1 dm3 s−1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2− at 25 °C are calculated to be 672 ± 15 and 428 ± 10 mol−1 dm3 s−1, respectively and reduction by HAsc− was not observed under these conditions. Thus, Asc2− is up to 7 orders of magnitude more efficient as a reductant than HAsc−. H2Asc is virtually inactive. The activation parameters ΔH ‡ and ΔS‡ for reduction of JM216, JM221, JM394, and JM576 by Asc2− are 52 ± 1, 46 ± 1, 56.2 ± 0.5, and 63 ± 2 kJ mol−1 and −97 ± 4, −120 ± 4, −24 ± 2, and −8 ± 5 J K−1 mol−1, respectively. An isokinetic relationship gives further support to the mechanistic assignments.},
  author       = {Lemma, Kelemu and Sargeson, Alan M. and Elding, Lars Ivar},
  issn         = {1472-7773},
  keyword      = {Platinum(IV),Ascorbate,Reduction,Pro-drug,Anti-cancer drug,Reaction mechanism},
  language     = {eng},
  number       = {7},
  pages        = {1167--1172},
  publisher    = {Royal Society of Chemistry},
  series       = {Journal of the Chemical Society, Dalton Transactions},
  title        = {Kinetics and Mechanism for Reduction of Oral Anticancer Platinum(IV) Dicarboxylate Compounds by L-Ascorbate Ions},
  url          = {http://dx.doi.org/10.1039/a909484i},
  volume       = {2000},
  year         = {2000},
}