Side Reactions with an Equilibrium Constraint: Detailed Mechanism of the Substitution Reaction of Tetraplatin with dGMP as a Starting Step of the Platinum(IV) Reduction Process

Abstract

Two possible pathways of the substitution reaction within the reduction process of the Pt(DACH)Cl by dGMP are compared: associative reaction course and autocatalytic Basolo-Pearson mechanisms. Since two forms: single-protonated and fully deprotonated phosphate group of dGMP are present in equilibrium at neutral and mildly acidic solutions, consideration of a side reactions scheme with acido-basic equilibrium-constraint is a very important model for obtaining reliable results. The examined complexes are optimized at the B3LYP-GD3BJ/6-31G(d) level with the COSMO implicit solvation model and Klamt's radii used for cavity construction. Energy characteristics and thermodynamics for all reaction branches are determined using the B3LYP-GD3BJ/6-311++G(2df,2pd)/IEF-PCM/scaled-UAKS level with Wertz's entropy corrections. Rate constants are estimated for each individual branch according to Eyring's transition state theory (TST), averaged according to equilibrium constraint and compared with available experimental data. The determined reaction barriers of the autocatalytic pathway fairly correspond with experimental values. Furthermore, autocatalytic reaction of tetraplatin and its two analogues complexes [Pt(en)Cl and Pt(NH)Cl] are explored and compared with measured data in order to examined general reaction descriptors.

Insight into the Electrochemical Reduction Mechanism of Pt(IV) Anticancer Complexes

“…Optimizations were carried out in gas phase using the density functional theory (DFT) with the B3LYP hybrid functional, , which is known to give a good description of geometries and reaction profiles for transition-metal-containing compounds , including platinum­(II) − and a few platinum­(IV) , based anticancer compounds. Other latest-generation functionals explicitly developed for systems with long-range electron correlations were used for benchmarking such as M06, M06-2X, as well as the dispersion-corrected M06-D3 and the long-range-corrected version of B3LYP using the Coulomb-attenuating method CAM-B3LYP-D3 with Grimme’s dispersion correction .…”

Interactions of Ascorbic Acid with Satraplatin and its trans Analog JM576: DFT Computational Study

“…Since satraplatin can interact with all three forms of AA, the reduction process must be described from the perspective of side reactions with a fast acid–base equilibrium condition to get results comparable with the experimental studies of Lemma and Dong . In this case, an effective rate constant k eff can be determined as a weighted average of the calculated rate constants, k 1 , k 2 , and k 3 , for the individual branches (side reactions), where the weightings are given by the molar fractions of the AA forms: where [ S ] represents concentration of satraplatin. According to this relationship, the rate constants k 1 or k 3 should be considered only if they are substantially higher (by several orders of magnitude) than k 2 , due to the dominant abundance of the AAH – protonation state at neutral pH.…”

“…However, the “direct” substitution by the S N 2 mechanism in the initial step is characterized by too‐high activation barriers. They are more than 32 kcal mol –1 high, in the case of tetraplatin [tetrachloro(D,L‐trans)l,2‐diaminocyclohexane‐platinum(IV)] and dGMP as a reducing agent ,. [6c], In fact, a preferred pathway for the initial substitution of one of the axial ligands is represented by an autocatalytic mechanism proposed by Basolo and Pearson .…”

“…All three protonation states of ascorbic acid are taken into consideration. An effective rate constant of 2.6 × 10 –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.…”