Gold N-heterocyclic carbene complexes as anti-cancer agents : Au-Se interactions and solubility

[摘要] ENGLISH ABSTRACT: A theoretical study of a series of Au(I) complexes was performed in order to evaluate their suitability as anti-cancer prodrugs targeting the mitochondria and the TrxR enzyme. The complexes studied comprise a range of cationic Au(I) complexes bearing different N-heterocyclic carbene (NHC) and phosphine ligands, and form part of a class of compounds known as delocalised lipophilic cations (DLCs).To reduce the complexity of calculations, two small model Se anions were chosen to represent the Se in the TrxR active site. In order to assess their appropriateness as models, these compounds were compared to compounds of larger size with greater resemblance to the enzyme active site. Optimised geometries of several of the Au complexes were compared to crystal structure data to evaluate the chosen model chemistry (PBE0-D3/TZVP). Good agreement was observed and a rationale for differences could be provided.Lipophilicity has been identified as an important variable affecting the performance of Au(I) anti-cancer drugs, and the octanol-water partition coefficients (Log P) of a range of Au complexes were therefore calculated. The lipophilicities of NHC complexes were found to be very similar to that of phosphine complexes, confirming that NHCs can serve as a replacement for phosphine ligands in DLCs. A strong correlation between both molecular volume and average electrostatic potential with Log P was identified, indicating that these properties may be useful in the prediction of lipophilicity of similar compounds, and that the size of the N-substituent of an NHC can be varied to obtain Au complexes of predictable relative lipophilicity.Ligand exchange reactions of Au(I) compounds are thought to occur via an associative mechanism in which a three-coordinate transition state is formed. The reactant van der Waals (vdW) complex may provide hints as to the ease of forming the transition state, which occurs subsequently along the reaction path. To estimate the propensity of a series of Au-NHC complexes to form vdW complexes with the TrxR active site Se, the geometries of vdW complexes of these coordination complexes and model Se fragments were optimised and the free energies of association were calculated. Complexes bearing benzimidazolylidene-type NHC ligands were found to interact more strongly than those bearing imidazolylidene NHC ligands, and more sterically demanding N-substituents on the NHC ligands were found to hinder the formation of close Au⋯Se contacts.The energetics of ligand exchange of a variety of Au-NHC and Au-phosphine complexes were also investigated. The N-substituent of an NHC ligand was found not to meaningfully affect the strength of the Au-NHC bond, indicating that the N-substituent could be varied to tune the lipophilicity without affecting the lability of the ligand. NHC ligands were found to be more strongly bound to Au than phosphine ligands, suggesting that phosphine ligands are more suitable as exchangeable ligands than NHCs.

[发布机构] Stellenbosch University