Synthesis and investigation of artificial metallonucleases

The aim of this work is the synthesis and investigation of artificial metallonucleases. In the first part of this work a simple model system was used allowing for the quantification of the artificial nucleases ability. In the second part of the work the synthesis of artificial metallonucleases with the ability to target specific cells was explored. In the first part the synthesis of three dinucleating ligands, which structurally consist of a 4- methyl phenol 'body' and two mononucleating ligand 'arms' are described. This 'body' allowed for the generation of dinuclear complexes with both metal atoms in close contact. Using a DNA and RNA analogue the nuclease ability of the complexes was quantified. It was found that complexes of the unsymmetrical ligand were more reactive and had higher optimum pH than the corresponding symmetrical complexes. Using both pH rate profiles and solution behaviour a mechanism of action based on an aqua hydroxo species was proposed. The metals investigated were copper due to its Lewis acidity, gallium due to its potential to mimic the more biologically relevant Fe 3+ and magnesium due to its involvement in nucleases. In the second part the synthesis of a mononucleating ligand with an amine moiety is described, to allow for greater synthetic versatility this was further derivatized with a carboxylic acid moiety. Using the amine moiety the mononucleating ligand was linked to cholic acid and TSPO ligands generating 4 novel mononucleating ligands. Monocopper complexes of these ligands were synthesised using 1,10 phenanthroline as a co ligand the synthesis of which is described. These novel complexes combine both an artificial nuclease and a targeting unit, potentially allowing for the selective targeting of tumour cells.

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IRCSET

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Attribution-NonCommercial-NoDerivs 3.0 Ireland

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University of Galway Theses (PhD Theses)