Abstract
Although Mesna is an FDA-approved chemotherapeutic adjuvant and an antioxidant based largely on its antioxidative properties, kinetic and mechanistic studies of its redox reactions are limited. A kinetic analysis of the reduction processes of cis-diamminetetrachloroplatinum(IV) (cis-[Pt(NH3)2Cl4], a cisplatin Pt(IV) prodrug) by thiol-containing compounds Mesna, thioglycolic acid (TGA), and DL-thiolactic acid (TLA) was carried out in this work at 25.0°C and 1.0 M ionic strength. The reduction processes were followed under pseudo-first-order conditions and were found to strictly obey overall second-order kinetics; the observed second-order rate constant k′ versus pH profiles were established in a wide pH range. A general reaction stoichiometry of Δ[Pt(IV)] : Δ[Thiol]tot = 1 : 2 was revealed for all the thiols; the thiols were oxidized to their corresponding disulfides which were identified by mass spectrometry. Reaction mechanisms are proposed which involves all the prololytic species of the thiols attacking the Pt(IV) prodrug in parallel, designating as the rate-determining steps. Transient species chlorothiol and/or chlorothiolate are formed in these steps; for each particular thiol, these transient species can be trapped rapidly by another thiol molecule which is in excess in the reaction mixture, giving rise to a disulfide as the oxidation product. The rate constants of the rate-determining steps were elucidated, revealing reactivity enhancements of (1.4–8.9) × 105 times when the thiols become thiolates. The species versus pH and reactivity of species versus pH distribution diagrams were constructed, demonstrating that the species ‒SCH2CH2SO3‒ of Mesna largely governs the total reactivity when pH > 5; in contrast, the form of Mesna per se (mainly as HSCH2CH2SO3‒) makes a negligible contribution. In addition, a well-determined dissociation constant for the Mesna thiol group (pKa2 = 8.85 ± 0.05 at 25.0°C and μ = 1.0 M) is offered in this work, which was determined by both kinetic approach and spectrophotometic titration method.
Highlights
Mesna is an FDA-approved drug which has been used to reduce the risk of hemorrhagic cystitis in people who receive ifosfamide or cyclophosphamide for cancer treatments [1,2,3]. ese two anticancer drugs in vivo may be converted to urotoxic metabolites such as acrolein.e protecting mechanism of Mesna is assisting to detoxify these metabolites by reaction of its thiol group with the α,β-unsaturated carbonyl containing compounds including acrolein. us, Mesna is a chemotherapeutic adjuvant [1,2,3]
UV-Vis and Rapid-Scan Spectra. e UV-Vis spectra for the compounds employed in this work were recorded by use of their solutions freshly prepared in a buffer of pH 4.42. e obtained spectra for 0.20 mM cis-[Pt(NH3)2Cl4], 0.20 mM cis-[Pt(NH3)2Cl2], 1.0 mM Mesna, 1.0 mM thioglycolic acid (TGA), and 1.0 mM thiolactic acid (TLA) are shown in the upper panel of Figure S1
The absorption band around 236 nm and absorption shoulder round 265 nm decreased concertedly as the reaction proceeded, and no new absorption bands emerged. e absorbance readings at 236 and 266 nm as a function of time are shown in Figure 2(b). e absorbance versus time curves or kinetic traces were fit by equation (1) [34], where kobsd represents of pseudo-first-order rate constant and
Summary
Mesna (namely, sodium 2-mercaptoethanesulfonate) is an FDA-approved drug which has been used to reduce the risk of hemorrhagic cystitis (a condition that causes inflammation of the bladder and can result in serious bleeding) in people who receive ifosfamide or cyclophosphamide for cancer treatments [1,2,3]. ese two anticancer drugs in vivo may be converted to urotoxic metabolites such as acrolein.e protecting mechanism of Mesna is assisting to detoxify these metabolites by reaction of its thiol group with the α,β-unsaturated carbonyl containing compounds including acrolein. us, Mesna is a chemotherapeutic adjuvant [1,2,3]. E observed second-order rate constants k′ increase several orders of magnitude (Table S1–S3 and Figures 4 and 5) when the reaction media are changed from acidic via neutral to basic for the three thiols, unveiling that the thiolate species of TGA, TLA, and Mesna are much more reactive than their corresponding thiol forms.
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