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Catalysis in cells for therapeutic applications

Thomas, Sophie 2021. Catalysis in cells for therapeutic applications. PhD Thesis, Cardiff University.
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Abstract

Bioorthogonal reactions templated by metal complexes is a thriving area in medicinal bioinorganic chemistry for applications in therapy and/or imaging. These reactions are commonly catalytic transformations mediated by metal complexes in organic solvents and cannot proceed naturally. However, applying these reactions in physiological conditions is not facile due to the presence of endogenous nucleophiles, e.g. thiols. Palladium complexes have been widely investigated to mediate bioorthogonal reactions; however, they often suffer from lack of chemoselectivity and are limited to certain experimental conditions (e.g. pH and incubation time). Thus, gold complexes have also been considered due to their greater tolerance to aqueous conditions and chemoselectivity. Therefore, this research aims to explore gold-based catalysts to mediate bioorthogonal reactions using two different approaches. The first part of this thesis investigates the ability of cyclometalated Au(III) C^N complexes to mediate C-S crosscoupling reactions via reductive elimination of cysteine residues in different peptides, including pharmacologically relevant zinc finger domains. Following this work, other cross-coupling reactions have been explored in water and/or generally mild reaction conditions, namely C-P and C-C bond formation with different substrates. For example, silver phenylacetylide and vinyl-tri(n-butyl)stannane were used as coupling partners to form C(sp2 )-C(sp) and C(sp2 )-C(sp2 ) products, respectively. Mechanistic insights into the different cross-coupling reactions were achieved using an integrated investigational approach, including spectroscopic and analytical methods as well as computational studies. The second part of this thesis incorporates a heterogeneous approach to bioorthogonal reactions by the synthesis and characterisation of water-soluble gold nanoparticles stabilised by N-heterocyclic carbene ligands (NHC@AuNPs) featuring imidazolium scaffolds with sulfonate groups. Gold nanoparticles are widely known for their applications in catalysis. Therefore, we envisaged their use as catalysts in living cells for bioorthogonal reactions, e.g., activating a pro-drug in situ. Two types of NHC@AuNPs were synthesised by a bottom-up approach using Au bis-NHC complexes and reducing them with sodium borohydride. Afterwards, the obtained AuNPs were characterised by different methods, including transmission electron microscopy (TEM), which was used to observe the small size of the NPs (ca. 2 nm). The catalytic performance of the nanoparticles was assessed using the model 4-nitrophenol reduction to 4-aminophenol in water, with more biocompatible reactions envisaged in future studies. Moreover, the same NHC@AuNPs can be used in other biomedical applications, including photothermal therapy (PTT) and photoacoustic imaging (PAI).

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Chemistry
Date of First Compliant Deposit: 30 November 2021
Last Modified: 01 Dec 2021 14:44
URI: https://orca.cardiff.ac.uk/id/eprint/145833

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