Ligand Exchange Reaction of Au(I) R-N-Heterocyclic Carbene Complexes with Cysteine

Area of Science:

• Organometallic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Gold complexes, like auranofin, have a history in chemotherapy.
• Organometallic compounds, particularly those with N-heterocyclic carbene (NHC) ligands, are emerging as promising anticancer agents.

Purpose of the Study:

• To perform a kinetic analysis of the reaction between six alkyl-substituted NHC-gold complexes and cysteine (Cys).
• To elucidate the mechanism and energy profiles of the ligand exchange processes.
• To understand the structure-reactivity relationships governing these reactions.

Main Methods:

• Kinetic analysis of ligand exchange reactions.
• Computational modeling to determine reaction mechanisms and energy profiles.
• Calculation of activation enthalpy and correlation with steric and electronic properties.

Main Results:

• The first ligand exchange step, the rate-limiting step, shows an activation enthalpy order influenced by NHC substituents.
• Steric effects, indicated by Au-S bond lengths in transition states, correlate with reactivity.
• Electronic effects, related to the HOMO orbital eigenvalue of NHC ligands, also impact activation barriers, with stronger donating NHCs leading to higher barriers.

Conclusions:

• Steric bulk and electronic properties of NHC ligands significantly influence the reactivity of gold complexes with cysteine.
• Understanding these structure-reactivity relationships is crucial for designing effective NHC-gold anticancer agents.
• The findings provide insights into the mechanism of action for potential gold-based cancer therapies.