Browsing by Author "De Kock, Sunel"
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- ItemGold N-heterocyclic carbene complexes as anti-cancer agents : Au-Se interactions and solubility(Stellenbosch : Stellenbosch University, 2016-12) De Kock, Sunel; Esterhuysen, Catharine; Dillen, Jan; Stellenbosch University. Faculty of Engineering. Dept. of Chemistry and Polymer Science.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.
- ItemSteric and electronic effects in gold N-heterocyclic carbene complexes revealed by computational analysis(Wiley, 2019-04-29) Dillen, Jan; Esterhuysen, Catharine; De Kock, Sunel; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.A computational analysis of a series of cationic and neutral gold imidazolylidene and benzimidizolylidene complexes is reported. The Bond Dissociation Energies of the various ligands in the complexes calculated at the PBE0-D3/def2-TZVP level of theory increase with increasing ligand volume, except for those of complexes containing t-butyl-substituted ligands, which are anomalously low particularly for the benzimidazolylidene species. Atoms in Molecules studies show the presence of a variety of weak intramolecular interactions, characterised by the presence of bond critical points with a range of different properties. Energy Decomposition Analysis and calculation of Electrostatic Surface Potentials indicate that some interactions are weakly attractive dispersion-type interactions, while others are repulsive. The octanol/water partition coefficients (log P values) were calculated as a measure of the lipophilicities of the complexes and were found to increase with increasing volume.