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Using catalysis and synthesis to drive the hyperpolarization of pyruvate for transforming the monitoring of reactivity.


   Department of Chemistry

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  Prof S Duckett, Dr A Kennerley, Dr Peter Rayner  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

This interdisciplinary Ph.D. project lies at the boundary between inorganic and organic chemistry with applications in chemical analysis and cellular biology. 

Background: Nuclear magnetic resonance spectroscopic is a powerful analytical technique used widely in Chemistry. It also provides both spatial and dynamic information on molecular processes through MRI. As such, it finds important industrial and medical applications in reaction monitoring. However, normally the signals these instruments produce are very weak. In this project, a process known as hyperpolarisation will be used to dramatically increase the sensitivity of NMR and MRI through the use of catalysis and chemical synthesis/engineering. This will involve taking small organic esters and functionalising them through a hydrogenation step prior to releasing the desired probe, such as pyruvate, through ester hydrolysis. Biphasic catalysis will enable the released pyruvate to become available for subsequent addition to biological systems. The yield and rate of the hydrogenation reaction will be optimised through the synthesis of novel catalysts and ligands and the preparation of a range of unsaturated ester derivatives. Expanding the reaction scope beyond pyruvate (e.g. acetate, glucose, vitamin C) will ensure that the student becomes fully adept at a range of synthetic organic techniques. The hydrolysis process will be monitored in real time by UV spectroscopy and by traditional MRI methods before reactivity, studies are undertaken.

Scheme 1: The proposed hydrogenation and hydrolysis of an unsaturated ester can lead to a hyperpolarised biomolecule in aqueous solution via biphasic catalysis.

 The project objectives are therefore: 

●      Synthesis: Inorganic synthesis of hydrogenation catalysts alongside the preparation of a range of unsaturated precursors for screening (Scheme 1, step 1)

●      Catalysis: Optimization of the hydrogenation and hydrolysis steps using in-situ methods such as UV spectroscopy or MRI (Scheme 1, steps 2 and 3)

●      Analysis: Detection and evaluation of the hyperpolarized hydrolysis products by NMR. Collection of hyperpolarized NMR and MRI data (Scheme 1, step 3)

●      Reactivity: Use of suitable organic synthons to probe hydrolyzed product reactivity. Extension to in-vitro studies of enzyme derived reactions and cellular processes.

●      Compare to other parahydrogen based approaches

 Experimental Approach: This project is based in the multimillion-pound Centre for Hyperpolarisation in Magnetic Resonance (CHyM) which is part of the Department of Chemistry at the University of York. Since its opening in 2012, CHyM has achieved global impact in the fields of catalysis, the synthesis of labelled compounds and magnetic resonance methods for analysis, being recognised through prizes, patents and >90 scientific manuscripts since 2012. You will therefore join a vibrant research team, and use high field 400 MHz NMR and MRI in CHyM to test and verify in-house synthesised catalysts for hyperpolarization with access to world leading facilities for magnetisation transfer optimisation. You will also have access to the expertise necessary to showcase the methods applications.

Novelty: Our overall goal is to improve the diagnostic capability of MRI by increasing its sensitivity to biomolecule detection so that diseases can be readily monitored. This goal will be facilitated by harnessing novel aspects of synthesis, catalysis to improve analysis by NMR and MRI. The ‘hyperpolarised’ agents that are output will lead to high impact studies relevant to a range of disciplines. 

Training: You will follow our innovative Doctoral Training in Chemistry (iDTC) which provides a level of cohort-based training to support the development of scientific, transferable and employability skills. In conjunction with this core training, you will select additional training related to your area of their research. You will also gain advanced training in catalysis, aspects of organic synthesis, NMR spectroscopy, magnetic resonance imaging, and kinetic modelling. CHyM based research students receive wide-ranging data analysis support as they learn to interpret their own data (programming in EXCEL or MATLAB) and communicate their results through group presentations, visits, conferences and scientific manuscripts. All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/cdts/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.

For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution

This PhD will formally start on 1 October 2022. Induction activities may start a few days earlier.

To apply for this project, submit an online PhD in Chemistry application:

https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. 


Funding Notes

Fully funded for 3 years by the Department of Chemistry and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,609 for 2021-22), (ii) tuition fees at the Home rate, (iii) funding for consumables. See guidance for further details: https://www.york.ac.uk/chemistry/postgraduate/research/dept-stud/
Studentships are available to any student who is eligible to pay tuition fees at the home rate: https://www.york.ac.uk/study/postgraduate-research/fees/status/
Not all projects will be funded; candidates will be appointed via a competitive process.

References

Candidate selection process:
• You should hold or expect to receive at least an upper second class degree in chemistry or a chemical sciences related subject
• Applicants should submit a PhD application to the University of York by 28 February 2022
• Supervisors may contact candidates either by email, telephone or web-chat
• Supervisors can nominate up to 2 candidates to be interviewed for the project
• The interview panel will shortlist candidates for interview from all those nominated
• Shortlisted candidates will be invited to a panel interview on 30th or 31st March or 1stApril
• The awarding committee will award studentships following the panel interviews
• Candidates will be notified of the outcome of the panel’s decision by email

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