Synthesis and biomedical applications of fluorescent organophosphorus compounds

Abstract

An important and ongoing area of research is the treatment and imaging of diseases such as cancer and heart disease, as these are two of the leading causes of death worldwide. Prior research in this area has led to the development of effective agents such as the chemotherapeutic agent, cisplatin, and Myoview, a cardiac perfusion imaging agent. However, with the number of cases of cancer and heart disease continuing to rise, there is still an urgent requirement for further development of these agents. Thus, the synthesis of effective imaging agents and, in particular, probes with multiple modalities which can harness the benefits of multiple imaging techniques are of interest. Organophosphorus compounds provide a versatile platform to build such probes that could be applied in fluorescence imaging, SPECT, PET and MRS. Therefore, this thesis explores the functionalisation of organophosphorus compounds to afford a range of novel, fluorescent, phosphine probes with potential medicinal applications. Auranofin is a triethylphosphine containing, FDA approved therapeutic agent that has recently shown potential for its repurposing in new areas including neurodegenerative disorders, parasitic infections, HIV and cancers. Thus, Chapter 2 explores the synthesis of a series of analogues of auranofin by altering the triethylphosphine ligand. A series of fluorescent analogues of auranofin are also introduced which may hold potential as theranostic agents and perhaps aid in the derivation or elucidation of the mechanism of action of the pharmaceutical. Azacycles are nitrogen containing cyclic compounds which are commonly found in natural products and bioactive compounds. Chapter 3 introduces three novel fluorescent phosphacycles which are far less studied than their nitrogen derivatives. We investigate a highly strained three-membered cycle, a phosphirane, where we explore its air- and thermalstability and its coordination to group 6 metal carbonyl complexes. The methylation of the phosphirane to afford a phosphiranium salt is detailed for which the product has potential application as a dual optical and magnetic resonance imaging agent. We also look briefly at two six-membered 1,3,5-diazaphosphinanes, which were synthesised in collaboration with Dr Randolf Köhn, at the University of Bath are detailed. Coordination of one of the diazaphosphinanes to chromium(III) centres and the subsequent preliminary experiments to test for its application in catalytic 1-hexene trimerization will then be described. A short collaborative project with Professor Bill Henderson at the University of Waikato is introduced to detail how one of the fluorescent phosphines can be applied in the fluorescent labelling of amine modified surfaces. The final phosphacycles introduced are the seven-membered phosphacycles, the phosphepines. The synthesis of two group 6 phosphepine complexes will be described followed by a study of their electronic properties. Preliminary experiments were then carried out in an effort to afford the free ligand which would allow for its further functionalisation. Chapter 4 describes the synthesis of BodP3, a fluorescent tridentate phosphine, via a platinumcatalysed hydrophosphination of the fluorescent primary phosphine. Exploration into its coordination to group 10 metals will be detailed, with particular attention focused on the square planar platinum complexes as potential theranostic agents. Combined imaging agents are becoming increasingly popular in order to harness the benefits of multiple imaging techniques, such as optical imaging and radioimaging, to overcome the limitations of the individual techniques. Thus, Chapter 5 introduces a series of phosphonium salts which have potential as trifunctional imaging agents. These novel phosphonium salts contain i) a fluorescent Bodipy backbone suitable for in vitro fluorescence imaging, ii) a positively charged phosphonium centre to enable specific localisation within the mitochondria, and iii) an alkyne functional group to enable radiolabelling by click chemistry to facilitate in vivo PET imaging. Finally, preliminary click chemistry reactions will be described to demonstrate the synthesis of a cold standard of this trifunctional imaging agent.