Hydrolysis theory for cisplatin and its analogues based on density functional studies

Area of Science:

• Computational Chemistry
• Medicinal Chemistry
• Quantum Chemistry

Background:

• Cisplatin is a widely used anticancer drug, and its hydrolysis is considered a critical activation step.
• Accurate theoretical models are needed to understand the hydrolysis mechanism of square-planar Pt(II) complexes.
• Previous studies lacked a comprehensive understanding of the hydrolysis pathway, especially considering solvent effects.

Purpose of the Study:

• To elucidate the detailed hydrolysis mechanism of cisplatin and related Pt(II) complexes.
• To investigate the influence of solvent effects on the hydrolysis pathway and reaction energetics.
• To provide theoretical guidance for the design of novel platinum-based anticancer agents.

Main Methods:

• Comprehensive theoretical study using DFT methods (mPW1PW91/SDD) with various basis sets.
• Characterization of five stationary states (R, I1, TS, I2, P) in the S(N)2 hydrolysis pathway.
• Analysis of structural and atomic charge variations, Gibbs free energy, enthalpy, and entropy changes.

Main Results:

• The first theoretical characterization of all five stationary states in the hydrolysis S(N)2 pathway.
• Significant structural and charge variations were observed in the equatorial plane of trigonal-bipyramidal intermediates.
• Calculated reaction parameters (enthalpy, entropy) show good agreement with experimental data; solvent effects are crucial for accuracy.

Conclusions:

• The hydrolysis of cisplatin follows a typical S(N)2 mechanism with identifiable intermediates and transition states.
• Solvent effects significantly impact the hydrolysis mechanism and molecular geometry, particularly in the equatorial plane.
• These findings offer valuable theoretical insights for developing more effective platinum-based anticancer drugs.