Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses.
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.
College of Chemistry and Environmental Science, and the MOE Key Laboratory of Medicinal Chemistry and Molecular Diagnostics, Hebei University, Baoding 071002, Hebei Province, People's Republic of China. shensg@hbu.edu.cn xjz8112@sina.com rock@hbu.edu.cn.
Jingran
J
Dong
Yanli
Y
Ren
Shuying
S
Huo
Shigang
S
Shen
Jianzhong
J
Xu
Hongwu
H
Tian
Tiesheng
T
Shi
D001205:Ascorbic Acid / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009944:Organoplatinum Compounds / Q000378:metabolism*; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000097:blood* / Q000493:pharmacokinetics
D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D001205:Ascorbic Acid; D002945:Cisplatin; C049777:ormaplatin