Abstract
Knowledge of the mechanisms for the reduction of Pt-IV anticancer prodrugs is of great importance, since the reduction process is considered as a necessary step for their activation. Therefore, in this study, we investigate the reduction of satraplatin {JM216, cis,trans,cis-[PtCl2(OAc)(2)(cha)(NH3)], cha = cyclohexylamine} by ascorbic acid (AA) where proton-assisted electron-transfer and outer-sphere electron-transfer mechanisms are employed.
Also, the presence of an additional base, which should increase the concentration of the deprotonated AA(2-) form, is discussed. Structures are optimized at the B3LYP-GD3BJ/6-31+G(d)/MWB60/C-PCM/Klamt level and single-point calculations are performed in the larger 6-311++G(2df,2pd)/MWB60 basis set, together with the better implicit solvation model - IEF-PCM/scaled-UAKS.
All three protonation states of ascorbic acid are taken into consideration. An effective rate constant of 2.6x10(-3) m(-1)s(-1) is obtained from the kinetic formalism for side reactions, as described recently.
For the reduction of satraplatin by fully deprotonated ascorbic acid, changes of the electron-density distribution along the reaction coordinate are further investigated using NPA, QTAIM, and reaction electronic-flux analysis. Both electron-transfer mechanisms are also explored for the satraplatin trans analog JM576 {trans,trans,trans-[PtCl2(OAc)(2)(cha)(NH3)]}.
The resulting effective rate constant of 5.1x10(-2) m(-1)s(-1) is compared with available experimental data.