Reduction of ormaplatin and cis-diamminetetrachloroplatinum(IV) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

摘要

The reductions of Pt(IV) anticancer prodrugs [Pt(dach)Cl-4] (ormaplatin/tetraplatin), cis-[Pt(NH3)(2)Cl-4], and cis, cis, trans-[Pt(NH3)(2)Cl2Br2] 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)Cl-4] and [Pt(NH3)(2)Cl-4] at 37.0 degrees 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)Cl-4] and [Pt(NH3)(2)Cl-4] 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 Delta H-double dagger and Delta S-double dagger in the above pH range might be an artifact since the relationship is not justified anymore when our new data are added.