Kinetics and mechanism for reduction of oral anticancer platinum(IV) dicarboxylate compounds by L-ascorbate ions †

Autor: Alan M. Sargeson, Lars Ivar Elding, Kelemu Lemma
Rok vydání: 2000
Předmět:
Zdroj: Journal of the Chemical Society, Dalton Transactions. :1167-1172
ISSN: 1364-5447
1470-479X
DOI: 10.1039/a909484i
Popis: 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.
Databáze: OpenAIRE
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