Synthesis and Characterisation of Fluorescent Phosphorus Compounds and their Applications in Medical Imaging

Abstract

A significant and continuous field of study is the therapy and imaging of diseases like ovarian cancer. A lot of research has been done in this area, which led to the discovery of the chemotherapeutic agent Taxol, which is made from organic molecules, and the development of useful drugs like cisplatin and RAPTA-C, inorganic agents for cancer treatment. However, considering the high incidence of cancer cases, there is still a pressing need to further develop these agents. Developing effective imaging agents, particularly probes with multimodalities that use the advantages of various imaging techniques, is intriguing. Organophosphorus chemicals can be used to make a wide range of probes for fluorescence imaging, SPECT, and PET. This thesis investigates the functionalisation of organophosphorus chemicals to produce a variety of novel fluorescent phosphine probes with potential medical applications. For the first step, fluorescent organophosphorus ligands had to be made. In Chapter 2, four fluorescent Bodipy-based tertiary phosphine ligands were synthesised. Changing the substituents on tertiary phosphine changes its steric and electronic properties. This leads to changes in how it reacts, how it can make different isomer compounds, and how it glows. This thesis necessitated an exploration of the electronic characteristics and steric hindrance in the structures of the four fluorescent tertiary phosphine ligands. In Chapter 3, the phosphorus ligands were coordinated with molybdenum (Mo) and tungsten (W), transition metals from Group 6, to synthesise complexes for infrared (IR) analysis of electronic properties. Additionally, platinum (Pt), a transition metal from Group 10, was utilised to clarify the steric hindrance and electronic behaviour of fluorescent tertiary phosphine ligands in cis and/or trans complexes. RAPTA-C, a ruthenium complex, functions as an alternative to platinum-based chemotherapeutics in cancer treatment. It is less toxic than cisplatin. This thesis aimed to improve RAPTA-C's function as a multimodal system that utilises the advantages of imaging techniques. In Chapter 3, the four fluorescent Bodipy-based tertiary phosphine ligands were coordinated with ruthenium (Ru), a transition metal from group 8. Four ruthenium dimers, namely [RuCl(-Cl)(p-cymene)], [RuCl(-Cl)(benzene)], [RuI(-I)(p-cymene)], and [RuI(- I)(benzene)], were employed to synthesise a fluorescent analogue of RAPTA-C. The novel fluorescent ruthenium complexes (fluorescent analogues of RAPTA-C) have been sent to our collaborator, Professor Paul Dyson (ETH university) in Switzerland, where they will be tested in ovarian cancer cells. If successful, this would provide a multimodal-imaging agent that (i) has a fluorescent Bodipy core to enable fluorescence imaging and (ii) anticancer potential based on the known properties of RAPTA-C Mitochondrial malfunction has been associated with multiple disorders, including Parkinson's, Alzheimer's, diabetes, and various cancers. The membrane has a negative membrane potential, which lets phosphonium salts, which are attracted to fats, pass through and build up in the matrix. So, attaching a bioactive chemical to the cationic species and putting it into the matrix could lead to more therapeutic options. Neamati et al. documented the manufacture and efficacy of triphenyl-based phosphonium salts, which they used on diverse cancer cell lines and a human breast cancer mouse model. In Chapter 4, there are two goals. The first goal is making Bodipy-based methyl phosphonium salts, which might be useful for imaging atherosclerotic plaques. This would make a multimodal imaging agent that (i) has a fluorescent Bodipy core for fluorescence imaging; (ii) targets mitochondria through the phosphonium cation; (iii) might have an 11C radiolabel for PET imaging. The second goal is to make fluorescent alkynyl phosphonium salts that can be used to image breast cancer cells. Also, this would make a multimodal imaging agent that (i) targets mitochondria with a phosphonium cation; (ii) has a fluorescent Bodipy core for fluorescence imaging; (iii) can be labelled with 18F through click chemistry via a triple bond; (iv) binds to the antibody trastuzumab through click chemistry via a triple bond. The novel fluorescent phosphonium salt 54c has been sent to our collaborator, Professor Steve Archibald's group at Hull University, for labelling with 18F using a click chemical reaction and evaluation as a mitochondrial imaging agent. Three fluorescent alkynyl phosphonium salts, 54a, 54b, and 54c, have been sent to Dr. James Knight at Newcastle University. They conducted antibody labelling tests using trastuzumab and utilised the resultant antibody probes for imaging breast cancer cells in vitro. 54b demonstrates effective antibody labelling. Chapter 5 aimed to illustrate the production fluorescent phosphonium salt conjugated to a cyclen chelator via a xylenyl linker, with the ability to bind radionuclides including copper-64, gallium-67 and -68, actinium-225 and lutetium-177. [InCl2(cyclen)]Cl 67 was prepared and characterised by X-ray spectroscopy. This indium complex was subsequently reacted with BodPCy2-phosphonium-xylenyl bromide, 61 and a new fluorescent phosphonium-xylenyl bromide, 70, replacing the cyclohexyl groups with p-methoxybenzene, in an attempted conjugation reaction to produce indium complex 68 and 72. NMR for both suggests the reaction may have been successful, but X-ray crystallography and mass spectrometry still need to confirm this.