| Prodrugs provide the possibility of overcoming various barriers in pharmaceutical preparations.The proportion of prodrugs is increasing among the newly approved drugs world-widely.The activation processes of Pt???anticancer prodrugs and an antitubercular prodrug have been analyzed kinetically in this thesis.The first part concerns the investigation of the activation processes of Pt???anticancer prodrugs.Several representative Pt???anticancer prodrugs including ormaplatin?[Pt?dach?Cl4]?and cisplatin prodrugs cis-[Pt?NH3?2Cl4],and cis,cis,trans-[Pt?NH3?2Cl2Br2]were chosen for the investigation.Their reductions by the several dominant reductants in human plasma?L-ascorbic acid?Asc?,L-glutathione?GSH?,L-cysteine?Cys?,DL-homocysteine?Hcy?,and a dipeptide Gly-Cys?have been characterized.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???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.Moreover,in the reduction reactions of[Pt?dach?Cl4]and[Pt?NH3?2Cl4]by Asc,the isokinetic relationship previously reported in the literature was re-examined and found to be an artificial one.We further carried out a careful study on the reduction of ormaplatin by GSH in a wide pH range,and proposed the reaction mechanism involving parallel attacks by all the GSH protolysis species on the Pt???prodrug as rate-determining steps.All rate constants for the rate-determining steps have been derived for the first time,enabling the construction of the reactivity of GSH species versus their pH distribution diagram.The diagram clearly displays that one of the five GSH species is mainly responsible for the reduction of ormaplatin at the physiological pH of 7.4.Thus,the activation of Pt???anticancer prodrugs is not only affected by biological reducing molecules,but also by the protolysis species of the reducing compounds under the physiological conditions.Subsequently,we analyzed the reduction reactions of ormaplatin by an extended series of thiols with large variations in structures.For each thiol,the second-order rate constants of the rate-determining steps for all the protolysis species have been determined.A novel and remarkable correlation between logkRS-and pKRSH is disclosed by these experiments:logkRS-=?0.50±0.02?p KRSH+?0.68±0.13?.This linear free-energy correlation implicates that when ormaplatin is exposed to a pool of thiols with varying p KRSH in the physiological matrix,the reactivity of each thiolate species towards the reduction of ormaplatin is predictable as long as its pKRSH is known.The second part of work was the study the activation process of anti-tubercular prodrugs.A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid?isonicotinic hydrazide,INH?by[IrCl6]2-as a model for redox processes of such drugs in biological systems has been investigated in aqueous solution as a function of pH between 0and 8.5.All reactions are overall second-order,first-order in[IrCl6]2-and hydrazide,and the observed second-order rate constants k'have been determined as a function of pH.Spectrophotometric titrations indicate a stoichiometry of[Ir???]:[hydrazide]=4:1.HPLC analysis shows that the oxidation product of INH is isonicotinic acid.The derived reaction mechanism,based on rate law,time-resolved spectra and stoichiometry,involves parallel attacks by[IrCl6]2-on all four protolytic species of INH and NH as rate-determining steps,depending on pH.These steps are proposed to generate two types of hydrazyl free radicals.These radicals react further in three rapid consecutive processes,leading to the final oxidation products.Rate constants for the rate-determining steps have been determined for all protolytic species I-? of INH and NH.They are used to calculate reactivity–pH diagrams.These diagrams demonstrate that for both systems,species ? is ca.105 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4.Thus,species ? will be the main reactant,in spite of the fact that its concentration at this pH is extremely low,a fact that has not been considered in previous work.The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also,and that in such systems this process most likely is more complicated than previously assumed. |
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