Kinetic And Mechanistic Investigations Of Activation Processes Of Three Pt(?) Anticancer Prodrugs

Pt???anticancer active complexes are commonly regarded as prodrugs,and the reduction of the prodrugs to their Pt???analogs is the activation process.The reduction of a cisplatin prodrug cis-[Pt?NH₃?₂Cl₄]and a carboplatin prodrug cis,trans-[Pt?cbdca??NH₃?₂Cl₂]by DL-homocysteine?Hcy?has been investigated kinetically in a wide pH range in this work.The reduction processes follow overall second-order kinetics:-d[Pt???]/dt=k'[Hcy]_tot[Pt???],where[Hcy]_totot stands for the total concentration of Hcy and k'pertains to the observed second-order rate constants.The k'versus pH profiles have been established for both prodrugs.Spectrohotometric titrations reveal a stoichiometry of[Pt???]:[Hcy]_tot=1:2;homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry.A reaction mechanism has been proposed,which involves all the four protolysis species of Hcy attacking the Pt???prodrugs in parallel.Moreover,these parallel attacks are the rate-determining steps,resulting in a Cl⁺transfer from the Pt???prodrugs to the attacking sulfur atom.Rate constants of the rate-determining steps have been derived,indicating that the two prodrugs are reduced with a very similar rate in spite of the difference between the coordination ligands in their equatorial positions.The reactivity analysis in the case of cis,trans-[Pt?cbdca??NH₃?₂Cl₂]unravels that one species of Hcy?form ?I?is almost exclusively responsible for the reductions at the physiological pH?7.4?,although it is existing only 5.2%of the total Hcy population.On the other hand,the dominant existing form ? of Hcy virtually does not make a contribution to the overall reactivity at pH 7.4A stopped-flow kinetic and mechanistic analysis of the reduction of ormaplatin by DL-homocysteine?Hcy?and L-cysteine?Cys?has been carried out in a wide pH range at 25.0 ? and1.0 M ionic strength.A common rate law is established and a reaction mechanism is proposed which involves all the four protolytic species of Hcy/Cys attacking the Pt???prodrugs in parallel.The thiolate species ?I of Cys is predominant in the total reactivity from pH of 4 to 7.4,highlighting that species ?I plays a pivotal role in the reduction of ormpaplatin in the physiological matrix,although its population is very low in this pH region.This is owing to the big ratio of k₃/k₂=2.7 x 10⁵ for Cys.