Novel design of metallodrugs by mechanochemistry: towards a greener future

As a result of their important biological properties, metal complexes have been used in medicine for centuries. Whilst our understanding of their design and mechanism of action has significantly improved since the Roman era, most metal complexes are prepared using copious amounts of very toxic solvents, involve long reaction times, with only moderate yields being obtained.

In line with the UK’s 25 Year Environment Plan, this PhD project seeks to develop novel ‘greener’ strategies to synthesise discrete metal complexes, and their precursors, in a sustainable and efficient manner. Mechanochemistry, which involves the grinding of two or more reagents, in the absence of solvent, can be used to instigate chemical reactions. As a result, reaction times are reduced from days to minutes, and qualitative yields are obtainable. Complexes of interest are the chemotherapeutic agents, Cu(II) casiopeínas, picoplatin and Cu(II) diacetyl-bis(N-methylthiosemicarbazone), all of which are currently undergoing Phase II clinical trials. Once a proof of concept is established, with an in-depth understanding of the reaction mechanisms, scale-up of the solvent-free synthesis into a multi-gram (and potentially kghr^-1) continuous process will be conducted.

The bioactivity of these metal complexes, particularly towards cancer cells lines, will be investigated and compared with those obtained via conventional synthesis. We have recently reported the enhanced cytotoxicity, towards ovarian cancer cells, of mechanochemically prepared Cu(II) complexes. Promising metallodrug candidates will undergo formulation studies, producing a fully functioning manufacturing process which is expected to generate interest from the pharmaceutical industry.

This highly interdisciplinary project will explore the extremely promising area of novel technologies for designing a better world, through easier access to active pharmaceutical ingredients and/or the discovery of novel drugs. This project fits well within the 2020 list of urgent, global health challenges that the World Health Organisation has released.