Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione

Abstract

Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 degrees C in a 1.0 M aqueous medium at pH 2.0-5.0 (1) and 4.5-6.8 (2-4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH]tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH]tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1-4 by GS- are (1.43 +/- 0.01) x 10(7), (3.86 +/- 0.03) x 10(6), (1.83 +/- 0.01) x 10(6), and (1.18 +/- 0.01) x 10(6) M(-1)s(-1), respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-C1 axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds.

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

“…Therefore, these compounds are prodrugs that have to undergo extracellular or preferably intracellular reduction by agents like ascorbic acid, glutathione, or high molecular weight biomolecules, thereby resulting in the antitumor active square-planar platinum(II) metabolites. [24][25][26][27][28] Thus, the activity of these complexes depends on a range of bioinorganic and pharmacological attributes like the reduction potential, lipophilicity and solubility, binding behavior to biomolecules, and inertness with regard to ligand exchange reactions. [29][30][31] Several studies show that the type of axial ligands has an exceptionally high influence on the reduction potential and consequently on the cytotoxicity (chlorido ligands, high reduction potential and high cytotoxicity; hydroxido ligands, low reduction potential and low cytotoxicity).…”

Quantum chemical modeling of the reduction of cis‐diammineplatinum(IV) tetrachloride [Pt(NH3)2Cl4] by methyl thiolate anion

“…In this article quantum-chemical methods as well as a hybrid QM/MM approach are used to simulate the reaction of cis-[Pt(NH 3 ) 2 Cl 4 ] with methyl thiolate anion in aqueous medium. According to the experimental results of Lemma et al, 5 only one molecule of glutathione is involved in the rate-determining step of the reaction with platinum complexes, and the thiolate anion is the major reductant under the experimental conditions. Consequently, the methyl thiolate anion SCH 3 Ϫ is used as a model for glutathione in simulations.…”

“…5 The result of the reaction is the reduction of the Pt(IV) complex, (a) on Figure 2, into the uncharged Pt(II) complex (b), and formation of the ClSCH 3 species, which instantly undergoes the hydrolysis. The electronic distribution study of the neutral and charged Pt(IV) complex (a) has been done to achieve better understanding of the reaction mechanism.…”

“…6 The assumed mechanism involves an attack by the reducing agent on a halide, coordinated trans to a leaving group, and it is formally equivalent to a Cl ϩ transfer from the Pt(IV) center to the incoming nucleophile (thiolate ion). 5 To the best of our knowledge, such structure of the assumed activated complex (or transition state) has not been examined by theoretical methods. Quantum-chemical modeling of reactions of biochemical significance is becoming a powerful tool in elucidating details of reaction mechanisms.…”

“…For cis-[Pt(NH 3 ) 2 Cl 4 ] reduction the rate constant was determined to be (1.18 Ϯ 0.01) ϫ 10 6 M Ϫ1 s Ϫ1 (25°C in a 1.0-M aqueous solution at pH 4.5-6.8). 5 No stable intermediates were found in reactions of various Pt(IV) complexes with glutathione. Reductive elimination reactions of platinum(IV) halide complexes have been interpreted in terms of a halide-bridged activated complex.…”