Hydrolysis and binding mechanism of AMD473 (cis-[PtCl2(NH3)(2-picoline)]) with guanine: A quantum mechanical study

Hydrolysis of cisplatin analogue cis-[PtCl2(NH3)(2-pic)] (AMD473) has been investigated using Hartree-Fock and density functional methods. Four different paths of hydrolysis are studied by replacing two Cl atoms trans to NH3 and 2-picoline ligands and then subsequent addition of guanine ligand. The geometries of different reactant and product complexes are confirmed by IRC calculations from the transition state structures for each reaction. The rate of hydrolysis of chloride ligand trans to 2-picoline group is higher than that of chloride ligand cis to 2-picoline group due to steric effect experienced by the axial picoline ligand. The rate constants calculated in gas phase for the first steps of hydrolysis reactions are in close agreement with the experimental values. However, the gas phase values for the second steps differ significantly from the experimental data. An improvement of these values is made by incorporating solvent medium in our calculations. Monofunctional binding of the obtained aquo species with guanine provides a detailed understanding of binding mechanism of this anticancer drug. The geometrical parameters of all stationary points obtained for each guanine substitution reaction are comparable with that of the parent compound, cisplatin. Formation of the reactant complexes is stabilized by mainly hydrogen bond connecting amine group and O6 atom of guanine. The HF/6-31G∗ calculated rate constants, k3 = 1.43 × 10−3 s−1 M−1 and k3′ = 5.42 × 10−3 s−1 M−1 are in good agreement with the experimental values, 6.67 × 10−3 s−1 M−1 and 7.97 × 10−3 s−1 M−1, respectively.