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University of Reading Featured PhD Programmes

Synthetic transition metal catalysts for the treatment of cancer


   School of Pharmacy

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Working the interfaces of chemical catalysis, analytical chemistry, cellular biology, pharmacology and medicine, this project provides unique interdisciplinary training in the skills required for the development of a pre-clinical metal-based therapy.

Catalysts facilitate reactions that would otherwise not occur. In nature, enzymes carry out processes such as oxidation, reduction and hydrolysis, while in chemical synthesis, transition metal catalysts are often employed to enable similar transformations. We recently reported the first example of using synthetic metal catalysts to carry out an enantioselective reduction (pyruvate to D-lactate) inside cells, using sodium formate as a source of hydride in a similar way in which an enzyme might utilise a cofactor such as NADH. This project will explore new subcellular targets and transformations that can be achieved with transition metal catalysts, and will work to develop new bio-analytical techniques, including single-cell elemental analysis, to produce a quantitative framework of metal speciation. The project will investigate why bio-orthogonal catalysis, as a novel cellular mechanism appears to generate antiproliferative selectivity for cancer cells over non-cancerous cells, and consider how catalytic therapies may influence the next generation of chemotherapeutics.

We have previously reported the synthesis and chemical characterisation of a new class of osmium(II) reduction catalysts, providing the first example of in-cell asymmetric transfer hydrogenation carried out by a synthetic catalyst; converting intracellular pyruvate to D-lactate. Complementary investigations into the cellular accumulation and subcellular distribution of the catalysts demonstrated potential deactivation pathways and cellular efflux mechanisms. Chemical model systems have highlighted that the catalysts may also achieve the reduction of quinones in biological systems (which are involved in the mitochondrial electron transport chain) however this has never been investigated at cellular level. Studies of extracellular interactions are limited, and much work is still to be done to better understand the consequences of intracellular catalysis, and how a catalytic mechanism of action generates antiproliferative selectivity for cancer cells over non-cancerous cells.

This exciting interdisciplinary project will explore the use of novel analytical techniques, including ICP-MS and ICP-OES in conjunction with chromatographic techniques (e.g. chromatography) with full training provided. The project has potential engagement with industrial bodies who are very interested in the applications of such techniques. In addition, the postgraduate researcher will be fully trained to work autonomously in human tissue culture, so as to work independently in a multi-disciplinary environment. 

 Person Specification

Applicants should have a strong background in medicinal and analytical chemistry. This project will involve various analytical instrumentation (e.g. HPLC, ICP-MS, NMR) so relevant laboratory experience is desirable, but not essential. A good understanding of inorganic chemistry is crucial. Applicants should have a commitment to medicinal chemistry research and hold (or realistically expect to obtain) at least an Upper Second Class Honours Degree in Pharmacy, Chemistry or a closely related subject.   

 How to apply

Informal enquiries should be directed to Dr James Coverdale ()

To be considered for this studentship, please send the following documents to Dr James Coverdale ()

•             A detailed CV, including your nationality and country of birth;

•             Names and addresses of two referees;

•             A covering letter highlighting your research experience/capabilities;

•             Copies of your degree certificates with transcripts;

•             Evidence of your proficiency in the English language, if applicable.

 


Funding Notes

Self-funded PhD students only

References

• J. P. C. Coverdale, I. Romero-Canelon, A. Habtemariam, M. Wills, P. J. Sadler, Nature Chemistry, 2018
• E. M. Bolitho, J. P. C. Coverdale et al., Angewandte Chemie International Edition, 2021, 15, 60, 12, 6462-6472
• J. P. C. Coverdale, H. E. Bridgewater J. I. Song, N. A. Smith, N. P. E. Barry, I. Bagley, P. J. Sadler, I. Romero-Canelon, Journal of Medicinal Chemistry, 2018, 61, 20, 9246-9255
• Z. Fan, J. Huang, H. Huang, S. Banerjee, ChemMedChem, 2021, 16, 2480-2486
• J. J. Soldevila-Barreda, N. Metzler-Nolte, Chemistry Reviews, 2019, 119, 2, 829-869

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