Chemical tools for understanding the biological activity of platinum anticancer agents

Platinum-based chemotherapeutics are widely used for chemotherapy, but their continued use is restricted by patient side effects and resistance. To maximise efficacy and minimise side effects, there is a need to personalise the treatment to the patient and their cancer, which requires a better understanding of the biological interactions of platinum complexes. This thesis has investigated these interactions through new strategies and techniques. Novel monofunctional platinum complexes were investigated in order to distinguish how these complexes differ from clinical agents. Two members of the series had a dramatic divergence in cytotoxicity which was ascribed to their cellular accumulation. Their protein binding profiles were characterised by SEC-ICP-MS for the first time, indicating that the monofunctional complexes react with unique intracellular protein targets. Fluorogenic probes were recognised as tools that would help to unravel further information on biological platinum interactions. With no fluorogenic naphthalimide tetrazines reported to date, a novel series of compounds were synthesised. These compounds exhibited a strong fluorogenic response in vitro and in vivo. Their versatility was demonstrated by labelling of insulin fibrils for high-resolution imaging. Based on this scaffold, probes that monitor organelle health were developed. The first probe reported on the distribution of lysosomes within cells. The second probe had a fluorescent response that was sensitive to the mitochondrial membrane potential, which is an indicator of cellular health. Both probes were used in preliminary studies with platinum complexes, revealing that the mitochondria are disrupted and that the lysosomes do not change after 1 h of treatment. The tools developed in this work have revealed insights about how platinum complexes interact with cells. It highlights the importance of studying these interactions and their translation to the clinic to improve patient outcomes