S-Se oxidative addition to auranofin derivatives: a DFT study

Area of Science:

• Inorganic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Auranofin (AF) and its analogues are gold(I) complexes with demonstrated anticancer properties.
• These compounds exert their therapeutic effects by inhibiting the thioredoxin reductase (TrxR) enzyme.
• The S-Se bond oxidative addition to Au(I) is generally a slow reaction with a high activation barrier.

Purpose of the Study:

• To investigate the oxidative addition of the S-Se bond to a series of 26 auranofin derivatives.
• To explore how modifications in AF ligands affect the reaction's activation barrier and feasibility.
• To elucidate the electronic and steric factors governing the reaction mechanism and its correlation with biological activity.

Main Methods:

• Computational analysis of the oxidative addition reaction for 26 auranofin derivatives.
• Calculation of activation barriers (ΔH‡) and reaction energies (ΔH°).
• Analysis of charge transfer processes and strain energy at the transition state.

Main Results:

• The reaction of auranofin with the S-Se bond has a high activation barrier (33.0 kcal mol⁻¹).
• Ligand modifications, such as replacing -PEt₃ with -P(Et₂)(OEt), significantly reduced the activation barrier to 17.1 kcal mol⁻¹.
• Substitution of the -SAtg ligand with -Cl⁻ resulted in an activation barrier of 22.5 kcal mol⁻¹.
• The reaction is primarily driven by nucleophilic attack of the S-Se bond on the Au(I) center via charge transfer.
• Strain energy in the transition state geometry also plays a crucial role in the activation barrier trends.
• A correlation between activation barrier and reaction energy suggests a product-like transition state.

Conclusions:

• Subtle ligand modifications can render the oxidative addition reaction feasible under mild conditions.
• Understanding these reaction dynamics provides insights into the interaction of AF derivatives with TrxR.
• This research may pave the way for developing novel AF-based anticancer agents with improved efficacy.