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Reduction of Ormaplatin and Cis-Diamminetetrachloroplatinum(iv) by Ascorbic Acid and Dominant Thiols in Human Plasma: Kinetic and Mechanistic Analyses

Reduction of Ormaplatin and Cis-Diamminetetrachloroplatinum(iv) by Ascorbic Acid and Dominant Thiols in Human Plasma: Kinetic and Mechanistic Analyses

Jingran Dong, Yanli Ren, Shuying Huo, Shigang Shen, Jianzhong Xu, Hongwu Tian, Tiesheng Shi

Dalton Trans. 2016 Jul 28;45(28):11326-37.

PMID: 27327648

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP16893053	cis-Diamminetetrachloroplatinum(IV)		16893-05-3	Price

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