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Influencing the chemistry and biochemistry of electron-deficient organometallics

Faculty of Life Sciences

About the Project

In 2012, 14 million new cases of cancer were diagnosed worldwide, while 8.2 million people died due to cancer or related illnesses. In 2015, the number of cancer related deaths increased to 8.8 million people and it is expected to increase to 23.6 million by 2030. Many efforts have been focused on the development of chemotherapeutics (drugs) capable of fighting cancers. However, drug resistance and toxicity (due to lack of selectivity) are major drawbacks of chemotherapy. New anti-cancer drugs which are more selective, less toxic and with new mechanisms of action are therefore urgently needed.

Conventional anti-cancer drugs are mostly organic molecules, but structures where inorganic metals are incorporated in the form of metal coordination complexes offer potentially unique biological and chemical diversity which are quite distinct from that of the more conventional organic drugs. This arises not only from the choice of the metal itself and its oxidation state, but also from the types and numbers of coordinated ligands and the coordination geometry of the complex. We have recently developed a particular type of coordination complexes, so called electron-deficient half-sandwich complexes, which possess remarkably high cytotoxicity and selectivity towards a range of cancer cell lines (colon, ovarian, lung). One complex in particular was found to be 70 x more potent than the clinically used cisplatin drug against ovarian cancer cells, whilst exhibiting an in vitro >50 x selectivity against normal cells. Their outstanding capabilities to preferentially kill cancer cells over normal cells stem from the oxidative stress which those compounds induce in cancer cells (related to the unusual redox activity of these complexes).

In this research programme, the doctoral candidate will undertake a thorough investigation of the structure–activity relationship of such compounds. A variety of organic ligands will be synthesised and coordinated to the metal ions in order to tune the biological activity of the resulting complexes. In vitro screening will be carried out by the doctoral candidate and the biological results will inform the chemical design. The subsequent elucidation of the metallodrug mechanism of action will inform further molecule synthesis and design. As such, this proposal includes elements of underpinning concept which will ultimately lead to the identification of novel metal-based lead molecules that will be strong candidates for pre-clinical research.

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee may also apply to this project, in addition to the tuition fees. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support.

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