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

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.