Design and synthesis of stable Nicotinamide Riboside analogues with potential therapeutic application
This PhD project will focus on the design, synthesis and evaluation of novel Nicotinamide Riboside analogues that are processed by tumour cells into inhibitors of key NAD-utilising enzymes.
Tumour metabolism is an increasingly attractive target for the design of novel pharmacological agents due to its relative specificity and ubiquity across numerous cancer types. Most of the major cellular metabolic pathways, including glycolysis, utilise redox potential to shift the equilibrium of reactions, the most common of which are nicotinamide adenine dinucleotide (NAD)-linked. Indeed, the NAD-linked reactions catalysed by glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDHA/B) are central to the high glycolytic rate in cancer cells, leading to the hypothesis that targeting these may represent an efficacious approach to the treatment of cancer.
We have collaborations with experts in cancer metabolism who are able to detect the uptake/transformation of our compounds and monitor their effects on cells using advanced NMR-based metabolomic analysis, supporting the design of new tools with improved specificity.
Aims of this project
1) Structure-based design and synthesis of targeted NR analogues: utilising public-domain structural data to optimise towards pre-cursors of specific inhibitors of glycolytic enzymes (e.g. GAPDH, LDHA).
2) Utilise our NMR based techniques for metabolomic profiling in tumour cells to assess the effects of known (tiazofurin, benzamide riboside) and novel NR analogues on glycolysis in tumour cells.
3) To develop NMR-labelled probes to examine environment-specific NAD synthetic pathways in tumour cells.
The project will be suitable for a student with a strong background in synthetic chemistry who wishes to pursue a synthetic PhD whilst developing their knowledge of Medicinal Chemistry from a supervisor with a background in the pharmaceutical industry and a proven track record in the design of clinically active drug molecules.
For more information about Sam Butterworth please visit http://www.birmingham.ac.uk/schools/cem/staff/profile.aspx?ReferenceId=57497.
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FTE Category A staff submitted: 28.00
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