Kinetics and mechanism for reduction of Pt(IV) anticancer model compounds by Se-methyl L-selenocysteine. Comparison with L-selenomethionine

Abstract

Se-methyl L-selenocysteine (MeSeCys) is one of the major organic selenium compounds acquired from the diet by human beings. It has been shown to have anticancer activity and cancer prevention functions. However, its antioxidant activity, largely related to its biological function, has not been well characterized so far. We here report a stopped-flow kinetic study of the reduction of the Pt(IV) anticancer model compounds trans-[PtX 2 (CN) 4 ] 2− (X = Cl; Br) by MeSeCys in a wide pH range. Overall second-order kinetics is established for the redox reactions, and spectrophotometric titrations indicate a 1:1 reaction stoichiometry. The MeSeCys is oxidized to its selenoxide form, as identified by high-resolution mass spectra. The proposed reaction mechanism involves parallel attack on one of the trans-coordinated halides of the Pt(IV) complexes by the selenium atom of the various MeSeCys protolytic species. Rate constants for the rate determining steps as well as the pK a values of the various protolytic species of MeSeCys have been determined at 25.0°C and 1.0 M ionic strength. A bridged twoelectron transfer mechanism for the rate-determining steps is supported by rapid-scan spectra, activation parameters, and by the much larger reaction rate of [PtBr 2 (CN) 4 ] 2− compared to [PtCl 2 (CN) 4 ] 2− . The experiments indicate that the reduction of [PtX 2 (CN) 4 ] 2− by MeSeCys proceeds via a similar reaction mechanism as Lselenomethionine (SeMet) studied previously. However, there is a large reactivity difference between these two selenium compounds, as a matter of fact the largest one observed so far when compared to other redox systems. It differs between the various protolytic species of MeSeCys and SeMet. The different reactivity of MeSeCys and SeMet in the reduction of various biologically relevant oxidants might account for their disparate efficacies as anticancer agents.

Mechanistic scrutiny of the oxidations of thiol‐containing drugs cysteamine and d‐penicillamine by cis‐diamminetetrachloroplatinum(IV)

“…Our , respectively, are reduced much faster. 17,32 Hence, our earlier findings are against the reaction mechanism illustrated in Figure S8. 17,32…”

“…A spectrophotometric titration approach was opted to study the reaction stoichiometry of the present redox processes. [32][33][34] was estimated from the intersection point. Essentially, the estimated ratio is very close to a theoretical stoichiometry of 1:2 if CA was assumed to be oxidized to CA disulfide (H 2 NCH 2 CH 2 SSCH 2 CH 2 NH 2 or CA-disulfide) as expressed by Equation 3:…”

Investigations of the Kinetics and Mechanism of Reduction of a Carboplatin Pt(IV) Prodrug by the Major Small-Molecule Reductants in Human Plasma

“…The stoichiometry of the reaction between [Pt(cdbca)(NH 3 ) 2 Cl 2 ] and ascorbate was studied by the spectrophotometric titration method described earlier [23,37,38,39]. A series of reaction mixtures were prepared in a phosphate buffer at pH 7.40 with [Asc] tot = 0.10 mM kept constant, whereas [Pt(IV)] was varied between 0 and 0.30 mM.…”

“…The excellent agreement between experimental data and theoretical simulations shown in Figure 5 and Figure 6 bolsters the validity of the reaction mechanisms given in Figure 7 and Figure S3. By use of the obtained rate constants in Table 2 and the p K a values for the various protolytic species [54,56], the reactivity of the various Cys and GSH species in the reduction of cis,trans -[Pt(cbdca)(NH 3 ) 2 Cl 2 ] was analyzed in terms of reactivity versus pH distribution diagrams [38,39]. These are shown in Figure S5 for Cys and in Figure S6 for GSH in Supplementary Material.…”

Deciphering the role of selenium‐enriched rice protein hydrolysates in the regulation of Pb2+‐induced cytotoxicity: an in vitro Caco‐2 cell model study

“…Considering SeMet in the existing species of organic Se, they have negative charges and provide the electrostatic interactions, facilitating the combination with positive charged Pb 2+ . However, Se IV is always positive charge and generates repulsion with Pb 2+ , resulting in a decrease in the content of Pb 2+ (Liu et al ., 2018). It indicated that SPHs‐2 has a better availability to chelate Pb 2+ , and SeMet plays an important role in reducing Pb 2+ penetration.…”