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() prodrugs cis,trans,cis-[PtCl 2 (OAc) 2 (cha)(NH 3 )] (JM216) and cis,trans,cis-[PtCl 2 (OCOC 3 H 7 ) 2 (cha)(NH 3 )] (JM221) and of the isomers of JM216, viz. trans,cis,cis-[PtCl 2 (OAc) 2 (cha)(NH 3 )] (JM394) and trans,trans,trans-[PtCl 2 (OAc) 2 (cha)(NH 3 )] (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-[PtCl 2 (cha)(NH 3 )] (JM118) and JM394 and 576 to cis-and trans-[Pt(OAc) 2 (cha)(NH 3 )], respectively. The redox reactions follow the second-order rate law:where k is a pH dependent second-order overall rate constant andReduction of JM216 and JM221 is slow (overall rate constants k 298 = 5.08 ± 10 Ϫ2 and 3.25 × 10 Ϫ2 mol Ϫ1 dm 3 s Ϫ1 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 (k 298 = 230 ± 6 mol Ϫ1 dm 3 s Ϫ1 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 Asc 2Ϫ and less efficiently by HAsc Ϫ leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc Ϫ and Asc 2Ϫ at 25 ЊC are 0.548 ± 0.004 and (4.46 ± 0.01) × 10 6 mol Ϫ1 dm 3 s Ϫ1 , respectively. The rate constants for reduction of JM216 and JM221 by Asc 2Ϫ at 25 ЊC are calculated to be 672 ± 15 and 428 ± 10 mol Ϫ1 dm 3 s Ϫ1 , respectively and reduction by HAsc Ϫ was not observed under these conditions. Thus, Asc 2Ϫ is up to 7 orders of magnitude more efficient as a reductant than HAsc Ϫ . H 2 Asc is virtually inactive. The activation parameters ∆H ‡ and ∆S ‡ for reduction of JM216, JM221, JM394, and JM576 by Asc 2Ϫ are 52 ± 1, 46 ± 1, 56.2 ± 0.5, and 63 ± 2 kJ mol Ϫ1 and Ϫ97 ± 4, Ϫ120 ± 4, Ϫ24 ± 2, and Ϫ8 ± 5 J K Ϫ1 mol Ϫ1 , respectively. An isokinetic relationship gives further support to the mechanistic assignments.

Kinetics and Mechanism of Oxidation of L-Ascorbic Acid by Pt(IV)(aq) in Aqueous Hydrochloric Acid Medium

“…In this redox process, octahedral Pt(IV) is reduced to square plannar Pt(II). Therefore this reaction is better classified as reductive elimination reaction [19]. IR and 1 H NMR spectra showed the formation of dehydroascorbate along with Pt(II).…”

A Comparative Kinetic Study of Silver(I)-Catalyzed Oxidations of Alanine and Valine by Platinum (IV) in Perchloric and Sulfuric Acids Solutions

“…[25,26]. Because platinum (IV) complexes are generally substitution-inert [37], initial complex formation between platinum (IV) and reductant prior to electron transfer can be excluded in reductive-elimination reactions.…”

“…Platinum (IV) in Perchloric and Sulfuric Acids Solutions It has been noted that transition metal ions in the higher oxidation state can usually be stabilized by chelation with suitable complex agents, so that metal complexes formed would be good oxidants in acidic or alkaline media under appropriate conditions. Platinum (IV) complexes have increased interest in the last decades due to their remarkable anticancer properties [24][25][26][27]. Kinetic studies on the oxidation of inorganic and organic substrates using one of the platinum (IV) complexes such as hexachloroplatinate (IV) complex, [PtCl 6 ] 2-, are scarce and limited to a few cases [15][16][17][18][19][20][21][28][29][30][31], in which [PtCl 6 ] 2-may behave as one or two electron oxidant, depending upon the substrate and experimental conditions.…”

Ruthenium(III)-Catalyzed Oxidation of Vanillin by Anticancer Hexachloroplatinate(IV) Complex in Perchloric Acid Solutions: A Kinetic Study

“…In this reduction process, octahedral Pt(IV) is reduced to square planar Pt(II) with release of two Cl -ions. Therefore, this reaction is better classified as a reductive-elimination reaction [9,11]. Because platinum(IV) complexes are generally substitution-inert [39], initial complex formation between platinum(IV) and reductant prior to electron transfer can be excluded in reductive-elimination reactions.…”

“…However, oxidation capacity depends on the redox potential of the metal ion and the latter depends on the pH of the medium. The chemistry of biologically active Pt(IV) complexes has become increasingly important over the last few decades due to their anticancer properties [8][9][10][11]. They have become attractive because they are usually substitution-inert, hence requiring reduction to Pt(II) species before they can act as potential anticancer drugs.…”