The reductions of Pt(iv) anticancer prodrugs [Pt(dach)Cl4] (ormaplatin/tetraplatin), cis-[Pt(NH3)2Cl4], and cis,cis,trans-[Pt(NH3)2Cl2Br2] by the several dominant reductants in human plasma have been characterized kinetically in this work, including l-ascorbic acid (Asc), l-glutathione (GSH), l-cysteine (Cys), dl-homocysteine (Hcy), and a dipeptide Gly-Cys. All the reductions follow an overall second-order kinetics, being first-order each in [Pt(iv)] and in the [reductant]. A general reactivity trend of Asc < Hcy < Cys-Gly < GSH < Cys is clearly revealed for the reductions of [Pt(dach)Cl4] and [Pt(NH3)2Cl4] at 37.0 °C and pH 7.40. Analysis of the observed second-order rate constants k' implies that these Pt(iv) prodrugs have a very short lifetime (less than a minute) in human plasma and can hardly enter into cells before reduction and that Asc might not play a dominant role in the reduction process among the reductants. The reductions of [Pt(dach)Cl4] and [Pt(NH3)2Cl4] by Asc have been studied in a wide pH range, and a reaction mechanism has been proposed involving parallel reductions of the Pt(iv) complexes by the Asc protolytic species. Moreover, a halide-bridged (inner-sphere) electron transfer mode for the rate-determining steps is discussed in detail; several lines of evidence strongly bolster this type of electron transfer. Furthermore, the observed activation parameters corresponding to k' have been measured around pH 7.40. Analysis of the established k'-pH profiles indicates that k' is a composite of at least three parameters in the pH range of 5.74-7.40 and the measured activation parameters in this range do not correspond to a single rate-determining step. Consequently, the isokinetic relationship reported previously using the measured ΔH(‡) and ΔS(‡) in the above pH range might be an artifact since the relationship is not justified anymore when our new data are added.

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A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl] as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl] and hydrazide, and the observed second-order rate constants k' have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(iv)] : [hydrazide] = 4 : 1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved spectra and stoichiometry, involves parallel attacks by [IrCl] on all four protolytic species of INH and NH as rate-determining steps, depending on pH. These steps are proposed to generate two types of hydrazyl free radicals. These radicals react further in three rapid consecutive processes, leading to the final oxidation products. Rate constants for the rate-determining steps have been determined for all protolytic species I-IV of INH and NH. They are used to calculate reactivity-pH diagrams. These diagrams demonstrate that for both systems, species IV is ca. 10 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4. Thus, species IV will be the main reactant, in spite of the fact that its concentration at this pH is extremely low, a fact that has not been considered in previous work. The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also, and that in such systems this process most likely is more complicated than previously assumed.