Reduction Process of Tetraplatin in the Presence of Deoxyguanosine Monophosphate (dGMP): A Computational DFT Study
Abstrakt
The reduction mechanism of [Pt-IV(dach)Cl-4] (dach=diaminocyclohexyl) in the presence of dGMP was studied. The first step is substitution of a chloro ligand by dGMP, followed by nucleophilic attack of a phosphate or sugar oxygen atom to the C8-position of guanine.
Subsequent reduction forms the [Pt-II(dach)Cl-2] complex. The whole process is completed by a hydrolysis.
Two different pathways for the substitution reaction were examined: a direct associative and a Basolo-Pearson autocatalytic mechanism. All the explored structures were optimized at the B3LYP-D3/6-31G(d) level and by using the COSMO solvation model with Klamt's radii.
Single-point energetics was determined at the B3LYP-GD3BJ/6-311+ +G(2df,2pd)/PCM/scaled-UAKS level. Activation barriers were used for an estimation of the rate constants and these were compared with experimental values.
It was found that the rate-determining step is the nucleophilic attack with a slightly faster performance in the 3'-dGMP branch than in the case of 5'-dGMP with activation barriers of 21.1 and 20.4 kcal mol(-1) (experimental: 23.8 and 23.2 kcal mol(-1)). The reduction reaction is connected with an electron flow from guanine.
The product of the reduction reaction is a chelate structure, which dissociates within the last reaction step, that is, a hydrolysis reaction. The whole redox process (substitution, reduction, and hydrolysis) is exergonic by 34 and 28 kcal mol(-1) for 5'-dGMP and 3'-dGMP, respectively.