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

De Kock, Sunel (2016-12)

Thesis (MSc)--Stellenbosch University, 2016.

Thesis

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.

AFRIKAANSE OPSOMMING: ‘n Teoretiese studie van ‘n reeks Au(I) komplekse is uitgevoer om hul bruikbaarheid as antikanker progeneesmiddels wat die mitochondrieë en TrxR ensiem teiken te evalueer. Die bestudeerde komplekse beslaan ‘n reeks kationiese Au(I) komplekse met verskillende N-heterosikliese karbeen (NHC) en fosfien-ligande, en vorm deel van ‘n groep chemiese stowwe wat bekend staan as gedelokaliseerde lipofiliese katione (DLCs). Om die kompleksiteit van die berekeninge te verminder is twee klein model Se anione gekies om die Se in die aktiewe setel van TrxR te verteenwoordig. Hierdie chemiese verbindings is met groter verbindings met ‘n hoër ooreenkoms tot die ensiem se aktiewe setel vergelyk om hul toepaslikheid as modelle te evalueer. Om die teoretiese model (PBE0-D3/TZVP) te beoordeel is die geoptimiseerde structure vergelyk met kristalstruktuur data. ‘n Goeie ooreenkoms tussen die structure is waargeneem en ‘n rasionaal vir die verskille was gebied. Lipofilisiteit is geïdentifiseer as ‘n belangrike veranderlike wat die prestasie van Au(I) antikankermiddele beïnvloed, dus was die oktanol-water verdelingskoëffisiënte (Log P) van ‘n reeks Au komplekse bereken. Dit is gevind dat die lipofilisiteit van NHC komplekse baie soortgelyk is aan die van fosfien komplekse, wat bevestig dat NHCs as vervangers van fosfien ligande in DLCs kan dien. ‘n Sterk korrelasie tussen beide molekulêre volume en die gemiddelde elektrostatiese potensiaal met Log P is geïdentifiseer, wat aandui dat die eienskap bruikbaar mag wees in die voorspelling van lipofilisiteit van soortgelyke komplekse, en dat die grootte van die N-substituent van ‘n NHC gewissel kan word om Au komplekse van voorspelbare relatiewe lipofilisiteit te verkry. Ligand uitruilings reaksies van Au(I) verbindings gebeur vermoedelik via ‘n assosiatiewe meganisme waarin ‘n drie-koördinaat oorgangstoestand gevorm word. Die van der Waals (vdW) kompleks wat gevorm word voor die ontstaan van die oorgangstoestand kan leidrade bied oor die gemak van oorgangstoestandformasie. Om die geneigdheid waarmee ‘n reeks Au-NHC komplekse vdW komplekse met die TrxR aktiewe setel Se vorm te skat is die strukture van vdW komplekse tussen hierdie koördinasie komplekse en model Se fragmente geoptimiseer en die vrye energieë van assosiasie bereken. Dit is gevind dat komplekse met benzimidazolielideen ligande sterker interaksies vorm as komplekse met imidazolielideen ligande, terwyl steriesveeleisende N-substituente op die NHC ligande gevind is om die vorming van kort Au⋯Se kontakte te verhinder. Die energetika van ligandverruilling van ‘n verskeidenheid Au-NHC en Au-fosfien komplekse is ook ondersoek. Die N-substituent van ‘n NHC ligand het nie ‘n betekenisvolle effek op die sterkte van die Au-NHC verbinding nie, wat aandui dat die N-substituent gewissel kan word om die lipofilisiteit te verstel sonder om die labiliteit van die ligand te beïnvloed. NHC ligande vorm sterker verbindings met Au as die fosfien ligande, wat daarop dui dat fosfien ligande meer gepas is as uitruilbare ligande as NHCs.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/100374
This item appears in the following collections: