Reactivity of the glutathione species towards the reduction of ormaplatin (or tetraplatin)

et al. 2019

IJMS

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The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k′ followed the order Asc << Cys–Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (−SCH2CH(NH3+)COO−) and species IV of GSH (−OOCCH(NH3+)CH2CH2CONHCH(CH2S−)- CONHCH2COO−) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.

Section: Resultssupporting

confidence: 80%

Section: Resultssupporting

confidence: 74%

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

Liu

et al. 2019

IJMS

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“…A straightforward way of examining the reactivity of the Hcy species under the physiological pH (7.4) is to construct the reactivity versus pH distribution diagram . The Hcy species versus pH distribution diagram is displayed in Fig.…”

Section: Resultsmentioning

confidence: 99%

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Dong

Chi

et al. 2017

Int. J. Chem. Kinet.

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Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis-[Pt(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans-[Pt(cbdca)(NH 3 ) 2 Cl 2 ] by DL-homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second-order kinetics: −d[Pt(IV)]/dt = k [Hcy] tot [Pt(IV)], where [Hcy] tot stands for the total concentration of Hcy and k pertains to the observed second-order rate constants. The k versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of [Pt(IV)]: [Hcy] tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate-determining steps, resulting in a Cl + transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants An Accumet Basic AB15 Plus pH meter, equipped with an Accumet AccutupH R combination pH electrode (Fisher Scientific, Pittsburgh, PA), was used to measure the pH values of buffer solutions. Each time, the electrode was calibrated using the standard buffers

“…The reaction stoichiometry was investigated by spectrophotometric titrations as we have used recently . The measured absorption values for the series of reaction mixtures as a function of [HONH 2 ] tot are shown in Figure .…”

Section: Resultsmentioning

confidence: 99%

New kinetic and mechanistic findings in the oxidation of hydroxylamine by Cerium(IV) in perchloric acid media

Int J of Chemical Kinetics

Yao

et al. 2018

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The oxidation of hydroxylamine (HONH 2 ) by Ce(IV) in perchloric acid media took place fast and was followed by a stopped-flow spectrometer. A rate law of −d[Ce(IV)] tot /dt = k ′ [HONH 2 ] tot [Ce(IV)] tot was proved, where k ′ stands for the observed second-order rate constant and [Ce(IV)] tot and [HONH 2 ] tot represent the total concentrations of Ce(IV) and HONH 2 , respectively. The dependencies of k ′ on [H + ] and on ionic strength were investigated. Rapid scan spectra recorded for a typical reaction course and a stoichiometric measurement unraveled several additional characters for the redox reaction. Based on experimental results, a reaction mechanism is proposed, which involves Ce 4+ , Ce(OH) 3+ , and Ce(OH) 2 2+ attacking on HONH 3 + in parallel. Moreover, these parallel attacking reactions are the ratedetermining steps, generating free radicals • ONH 2 , which are rapidly oxidized to nitrate by Ce(IV). Rate constants of these rate-determining steps have been evaluated; a reactivity trend of Ce 4+ > Ce(OH) 3+ > Ce(OH) 2 2+ is disclosed, but the reactivity differences among them are very small. The rate-determining steps are rationalized in terms of an outer-sphere electron transfer, and possible transition states are proposed in the cases of Ce(OH) 3+ and Ce(OH) 2 2+ to account for the small reactivity differences. The obtained kinetic and mechanistic results in the present work are compared with those acquired previously for the same reaction but in sulfuric acid and nitric media. It is concluded that the reaction media can play a dominant role in determining the reaction kinetics, mechanisms, and the product(s) in the oxidation of hydroxylamine by Ce(IV). K E Y W O R D SCe(IV), hydroxylamine, kinetic mechanism, oxidation 856