Glutathione readily replaces the thioether on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylated glutathione); a model study for cisplatin–protein interactions

Abstract

As models for cis-[PtCl₂(NH₃)₂] (cisplatin)–protein interactions, the reactions of [Pt(dien)Cl]⁻ with the tripeptides GSMe (S-methylated glutathione) and GSH (glutathione, γ-glutamylcysteinylglycine) have been studied. The substitution reaction of the platinum–methionine model adduct [Pt(dien)(GSMe)]²⁺ with GSH has been investigated using ¹H and ¹⁹⁵Pt NMR. It was found that GSH substitutes GSMe in [Pt(dien)(GSMe)]²⁺, readily forming [{Pt(dien)}₂GS]³⁺. At pD ≥ 7.0 the intermediate [Pt(dien)(GS)]⁺ was observed. Kinetic and thermodynamic parameters of this reaction were determined at pD 3.2: k = 1.1 × 10⁻³ M⁻¹ s⁻¹, t_1/2 = 24.7 h, ΔH^‡ = 1.5 ± 0.3 kJ mol⁻¹, ΔS^‡ = 5 ± 1 J K⁻¹ mol⁻¹ at 298 K; and k = 28.5 × 10⁻³ M⁻¹ s⁻¹, t_1/2 = 0.97 h, ΔH^‡ = 1.5 ± 0.3 kJ mol⁻¹, ΔS^‡ = 4 ± 1 J K⁻¹ mol⁻¹ at 316 K. At alkaline pH the substitution reaction occurs within 5 min, illustrating the dramatic influence of the pH on this reaction. These parameters are discussed in relation to the competition between GSMe and the N7 atom of guanosine monophosphate. The intermolecular substitution of GSMe by GSH is much faster than the substitution by guanine N7, even under acidic conditions. This platinum–thioether to –thiolate substitution can play a significant role in the cellular processing of platinum–protein adducts, and is an important mechanism in the circumvention of cisplatin induced toxicity by thiol-containing protective agents.