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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.

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Reduction of trans-[Pt(CN)4Cl2]2- (as a model compound for antitumor-active platinum(IV) complexes) by thiols, RSH (thioglycolic acid, l-cysteine, dl-penicillamine, and glutathione), has been studied in a 1.00 M aqueous perchlorate medium by use of stopped-flow spectrophotometry at 25 °C in the interval 7.08 × 10-6 ≤ [H+] ≤ 1.00 M. Time-resolved spectra show that redox takes place directly without initial substitution at Pt(IV). The stoichiometry is [RSH]:[Pt(IV)] = 2:1. Reduction is first-order with respect to [Pt(IV)] and the total concentration of thiol [RSH]tot. The bromide complex trans-[Pt(CN)4Br2]2- is reduced 47 times faster than trans-[Pt(CN)4Cl2]2- by cysteine. The [H+]-dependence of the observed kinetics can be rationalized by a reaction mechanism in which the platinum(IV) complex is reduced in parallel reactions by the various protolytic species present in rapid equilibria with each other, via halide-bridged electron transfer. Second-order rate constants for a particular reductant derived from the pH-dependence of the overall kinetics increase several orders of magnitude when the molecular forms of the reductants are deprotonated. For instance, no reduction of platinum(IV) by the fully protonated cation of glutathione can be observed, whereas the various deprotonated forms reduce the complex with second-order rate constants of 23.4 ± 0.3, 655 ± 4, and (1.10 ± 0.01) × 108 M-1 s-1, respectively. Thiolate anions reduce the platinum(IV) complex (1.7−19) × 105 times faster than the corresponding vicinal thiol forms. The second-order rate constants k RS − for reaction of thiolate anions RS- with [Pt(CN)4Cl2]2- are described by the Brønsted correlation log k RS − = (0.82 ± 0.08)pK RSH + (1.1 ± 0.7). The slope of 0.82 indicates that the basicity of RS- is a predominant factor in determining the reactivity toward the Pt(IV) complex. Reduction of Pt(IV) antitumor drugs by thiol-containing molecules before interaction between Pt(II) and DNA may take place via similar reaction mechanisms.

Density functional theory is applied to modeling the exchange in aqueous solution of H(2)O on [Pd(H(2)O)(4)](2+), [Pt(H(2)O)(4)](2+), and trans-[PtCl(2)(H(2)O)(2)]. Optimized structures for the starting molecules are reported together with trigonal bipyramidal (tbp) systems relevant to an associative mechanism. While a rigorous tbp geometry cannot by symmetry be the actual transition state, it appears that the energy differences between model tbp structures and the actual transition states are small. Ground state geometries calculated via the local density approximation (LDA) for [Pd(H(2)O)(4)](2+) and relativistically corrected LDA for the Pt complexes are in good agreement with available experimental data. Nonlocal gradient corrections to the LDA lead to relatively inferior structures. The computed structures for analogous Pd and Pt species are very similar. The equatorial M-OH(2) bonds of all the LDA-optimized tbp structures are predicted to expand by 0.25-0.30 Å, while the axial bonds change little relative to the planar precursors. This bond stretching in the transition state counteracts the decrease in partial molar volume caused by coordination of the entering water molecule and can explain qualitatively the small and closely similar volumes of activation observed. The relatively higher activation enthalpies of the Pt species can be traced to the relativistic correction of the total energies while the absolute DeltaH() values for exchange on [Pd(H(2)O)(4)](2+) and [Pt(H(2)O)(4)](2+) are reproduced using relativistically corrected LDA energies and a simple Born model for hydration. The validity of the latter is confirmed via some simple atomistic molecular mechanics estimates of the relative hydration enthalpies of [Pd(H(2)O)(4)](2+) and [Pd(H(2)O)(5)](2+). The computed DeltaH() values are 57, 92, and 103 kJ/mol compared to experimental values of 50(2), 90(2), and 100(2) kJ/mol for [Pd(H(2)O)(4)](2+), [Pt(H(2)O)(4)](2+), and trans-[PtCl(2)(H(2)O)(2)], respectively. The calculated activation enthalpy for a hypothetical dissociative water exchange at [Pd(H(2)O)(4)](2+) is 199 kJ/mol. A qualitative analysis of the modeling procedure, the relative hydration enthalpies, and the zero-point and finite temperature corrections yields an estimated uncertainty for the theoretical activation enthalpies of about 15 kJ/mol.

Visible and UV aqueous solution spectra for the square-planar complexes PtCl"(H20)4-."2™'\ PdCln(H20)4-"2"n, and PdBrn(H20)4-"2"n ( = 0,1, 2, 3, 4) have been recorded and calculated. The difference in blue shift within each family of spectra when halide is substituted by water is two to three times smaller for the d-d bands than for the symmetry-allowed high-intensity bands. This vatiation of blue shift and the variation of band intensity due to the different symmetry of the complexes within each series together with previous magnetic circular dichroism and polarized crystal spectra have made possible unambigous assignments of the bands in the MX42™ spectra (X = Cl, Br). Thus, the shoulders at 3.79 µ 1 (PtCl42™) and 3.03 µ 1 (PtBr42™) are probably due to 2a2u «-2b2g and the shoulders at 2.9 µ 1 (PdCl42™) and 2.35 µ 1 (PdBr42) to 3blg *-a2g, i.e., these shoulders are probably not associated with d-d transitions as often previously assumed. The symmetry-allowed high-intensity bands in the UV PtCl42™ spectrum at 4.65 and 4.34 µ 1 (3.73 and 3.37 µ 1 for PtBr42") are described as metal-to-ligand charge transfer transitions 2a2u 3alg and 2a2u *-2eg whereas the symmetry-allowed bands in the PdCl42™ spectrum at 4.50 and 3.74 µ 1 (4.05 and 3.02 µ 1 for PdBr42~) are described as ligand-to-metal charge transfer 3blg <-2eu and 3big *-b2u, 3eu. The results also suggest that the xBlg xAlg and xEg *-xAlg transitions overlap both in the platinum and palladium complexes, i.e., the d22 metal orbital is probably very close in energy to the degenerate dxz and dyz orbitals. These conclusions are summarized in the simplified energy level diagrams in Figure 8.

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 degrees C in a 1.0 M aqueous perchlorate medium with 6.8 < or = pH < or = 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 approximately 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 degrees 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.

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