Abstract
This thesis consists of four chapters.
Chapter 1 gives a brief overview of bacteria and the threat they pose to the human population, before detailing the discovery of antibacterial agents and our subpar use that has led to the rise of antibacterial resistance. The first uses of metal antibacterials are outlined, before segueing into the three main approaches used to generate metallosupramolecular architectures; the ligand directed approach, the symmetry interaction approach, and the weak link approach. The application of these architectures is discussed, with respect to the inherent cavity of these architectures and/or their structural design. The promising biological properties of platinum(II) architectures for antibacterial/anticancer avenues are then introduced and the inherent difficulty in acquiring these structures discussed. This leads directly into the overall aims of this thesis whereby a new approach to platinum(II) architectures and the biological properties of a family of pyridyl-triazole (pytri) architectures were investigated.
Chapter 2 details the beginning of the field of [M2L4] cage architectures and the difficulties faced by the formation of [Pt2L4] cages due to the relative stability of platinum. The few [Pt2L4] cages known are presented before the dynamic covalent approach to [M2L4] cages using the reversible formation of imine bonds by Chand and co-workers is introduced. The first heterometallic [PtPdL4] architectures acquired by the Crowley group are discussed and the utilisation of the preformed [Pt(3-pyridinecarboxaldehyde)4]2+ complex with the dynamic covalent approach to acquire a homometallic [Pt2L4]4+ cage architecture is proposed. The generation of a family of platinum(II) architectures using this dynamic approach is detailed, whereby the nucleophilicity of the amine and the resulting coordination angle play roles in the formation of the architectures. Attempts to increase the stability of the architectures to water by performing a post-assembly reduction of the imine bonds proved unsuccessful. This led to the generation of a homometallic hydrazone [Pt2L4]4+ cage which provided more water stability.
Chapter 3 covers the use of pytri complexes as antibacterial agents, outlining previous work that has been done within the Crowley group using ruthenium(II) and related osmium(II) complexes by others. While there exist many related platinum(II) pytri complexes, with varying uses from catalysis to cytotoxic activity, there is a lack of investigation into the antibacterial properties of these complexes. The work in this chapter builds on the previous work from within the Crowley group for the generation of a family of homoleptic platinum(II) pytri complexes as well as a series of neutral and palladium(II) variants to act as controls for the family. Most of the complexes were synthesised with an aliphatic chain as this had been previously shown to lead to the best activity for this type of ligand system. Inspiration was take from others who had worked on related systems to functionalise the core of the complex system with either a triphenylamine or isoquinoline moiety to potentially track the complexes in situ or increase their activity respectively.
Chapter 4 begins by giving a brief outline of cancer and the damage it can cause. The water stability of the platinum(II) pytri complexes and architectures synthesised herein is examined and the lack of stability by the imine based architectures is observed, while the hydrazone based [PtL4]4+ cage and the platinum(II) pyridyl-triazole complexes proved stable in the presence of water. Stability studies with the biologically relevant nucleophile chloride anions indicated that only the platinum(II) pytri complexes were stable in the presence of them, while Cpxy was the only imine based architecture that remained partially intact after 24 h. Host guest studies indicated none of the imine based architectures possessed any notable binding, but the a [Pt(pytri)2]2+ complex expressed an interaction with the antibacterial 3,6-diaminoacridine in solution. Select [Pt(pytri)2]2+ complexes and select imine based architectures were shown to generate reactive oxygen species in solution. [Pt(heptyl)2]2+ is the most active antibacterial complex from all of the structures synthesised in this thesis at 1 μg mL-1 and 2 μg mL-1 against S. aureus and E. coli, while Cpxy was the only imine based architecture to express any form of bacterial activity at 12 μg mL-1 against both strains. Transmission electron microscopy indicated that the [Pt(pytri)2]2+ complexes expressed a different mode of action to the parent ruthenium(II) families. However they retained the same dependence on lipophilicity for the activity of the complexes, where [Pt(heptyl)2]2+ existed at the bottom of a well for the structure-activity relationship. Unfortunately the [Pt(pytri)2]2+ complexes were equally as active against cancerous and healthy cell lines with very little selectivity. An approach to generating a platinum(II) pytri based macrocycle is presented, with the design of potentially increasing the strength of the 3,6-diaminoacridine interaction for the purpose of duel drug delivery.