Some Pt(IV) anticancer active complexes, possibly forming the new generationplatinum anticancer drugs, have some advantages including substitution inertness, lowside effects and no cross resistance to cisplatin. Pt(IV) anticancer drugs are oftenregarded as prodrugs, since they could be reduced to Pt(II) complexes beforeinteractions with DNA.In this work,3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a modelcompound for the active sites of thioredoxins and its reactions with cis-[Pt(NH3)2Cl4]and trans-[PtCl2(CN)4]2-(cisplatin prodrug and a model complex) were studied. ThepKavalues for the dithiol were characterized to be8.7±0.2and9.6±0.2at25.0oCand ionic strength of1.0M. The reaction kinetics was followed by a stopped-flowspectrophotometer over a wide pH range. An overall second-order rate law wasestablished:-d[Pt(IV)]/dt=k′[Pt(IV)][dithiol], where k′stands for the observedsecond-order rate constants. Values of k′increased several orders of magnitude whenthe solution pH was increased from3to9. Dithiol was oxidized to form anintramolecular disulfide, coinciding with the nature of thioredoxin proteins. Rateconstants for the rate-determining steps were evaluated.The reactions of tiopronin, captopril, N-acetyl-L-cysteine with cis-[Pt(NH3)2Cl4]and trans-[PtCl2(CN)4]2-were studied in the present work. The oxidation kinetics wasfollowed by a stopped-flow spectrophotometer. Time-resolved spectra were alsorecorded for both Pt(IV) complexes, enabling us to establish an overall second-orderrate law:-d[Pt(IV]/dt=k′[RSH][Pt(IV)], where k′pertains to observed second-orderrate constants. A reaction mechanism was proposed, involving parallel reductions ofthe Pt(IV) complexes by the three protolytic tiopronin species as rate-determiningsteps. The rate constants for the rate-determining steps were derived.Kinetics and mechanism for reduction of model compounds of Pt(IV) anticancerdrugs, trans-[PtCl2(CN)4]2-and trans-[PtBr2(CN)4]2-, by SeMet were studied in thepresent work. It was found that the reduction is first-order with respect to SeMet, andto [Pt(CN)4Cl22-]/[Pt(CN)4Br22-], respectively. An overall second-order rate law,-d[Pt(IV)]/dt=k′[Pt(IV)][SeMet], was established, where k′denotes thepH-dependent second-order rate constants. k′increases only slightly when pH isincreased. A reaction mechanism was proposed, involving parallel reductions of the Pt(IV) complexes by the three protolytic SeMet species as rate-determining steps. Therate constants for the rate-determining steps were derived. The activation parameterswere determined through the temperature-dependence study for reactions ofMeSe(CH2)2CH(NH3+)CO2-with the two Pt(IV) complexes. It can be concluded thatSeMet-containing proteins may also play some roles in the reduction processes ofPt(IV) anticancer prodrugs. |