Catalysis and synthesis

Pure & Applied Chemistry PhD opportunities

Dr Colin Gibson, Dr Paul Coats, Professor Colin Suckling

Activators of nitric oxide synthase

Duration

36 months

Eligibility criteria

2.1 degree in chemistry

The Project

Nitric oxide is a key signalling agent in the body and is generated from arginine by nitric oxide synthase (NOS).  One NOS isoform, endothelial NOS (eNOS) is responsible for relaxation of the blood vessels in the body.  Various disease states result from a malfunction of this enzyme and we have previously reported the preparation of stable analogues of the NOS coenzyme, tetrahydrobiopterin.  These analogues result in the relaxation of eNOS under disease state models and have potential in the treatment of atherosclerosis.  Despite current drug therapies (aspirin, ACE inhibitors, beta blockers and statins) there is still an unmet need for further novel drug therapies.

This project will seek to prepare new analogues of oxidatively stable blocked dihydropterins as activators of nitric oxide synthase with potential as treatments of atheroscrelosis.  The project is mainly synthetic but will involve collaboration with international experts in the field of NOS to measure various enzyme kinetic parameters.  It will also involve collaboration with pharmacologists to establish biological activities of the new synthetic entities.

Contact

Professor John Murphy, Dr Tell Tuttle

Light-Activated Approaches to Organic Electron Transfer Reactions

Duration

42 months

Eligibility criteria

Candidates with a 1st class or Upper 2nd class degree in Chemistry or equivalent

The project

We have recently developed a family of simple novel organic reducing agents (Super Electron Donors) comprising simply carbon, hydrogen and nitrogen that have record strengths. They can achieve unique and novel transformations that are useful for synthesis, and can also replace transition metal (e.g. palladium) catalysts in key coupling reactions. They become even more powerful when activated by visible light. Now we want to make them catalytic and that is a major focus of this PhD project. This will provide a new direction to photoactivated organocatalysis, targeting reactions that have never been achieved with organic reagents. Our research is undertaken in collaboration with Dr Tell Tuttle.

The project will provide an excellent training both in forefront synthetic organic chemistry and in computational chemistry, which assumes an ever greater importance in the training of synthetic chemists.

Contact

Reference:

J. A. Murphy, J. Org. Chem.2014, 79, 3731-3746. DOI: 10.1021/jo500071u

Understanding and Mimicking the Conversion of CO2 to Methane in Methanogens

Duration

36 months

Funding

To be obtained

Eligibility

1st of upper 2nd class honours degree in Chemistry or equivalent

The project

These days, the creation of new roles for carbon dioxide waste assumes a high priority, so that ‘Carbon Dioxide’ is on the Grand Challenges posed to chemistry by the Research Council, EPSRC. Nature reduces carbon dioxide:

  • by photosynthesis in plants
  • by conversion to methane in methanogens. 
The chemistry carried out by the methanogens is not well understood and is unique. Our aim is to understand these transformations in order to develop alternative catalysts that can be more easily applied, for example, to CO2 arising from point sources such as coal-burning power stations.

The project uses synthetic organic chemistry to address a pressing environmental need. Besides equipping the Ph.D. student with experience in environmentally relevant perspective on chemistry, it will provide an excellent training both in forefront synthetic organic chemistry and in computational chemistry, which assumes an ever greater importance in the training of synthetic chemists.

A recent reference: MJ Corrand, JA Murphy, Chem. Soc. Rev. 2011,  40, 2279-2292. DOI:10.1039/C0CS00150C

Contact

Dr Glenn Burley, Dr Hing Leung

A new synthetic biological tool in RNA research: expanding nature’s genetic repertoire for site-specific incorporation of functional groups in RNA to study alternative RNA splicing

Background - Prostate cancer (PC) is the second commonest cause of cancer deaths in British males with nearly 10,000 deaths per annum. There are 36,000 new cases reported every year and this figure is predicted to double over the next 20 years, placing considerable strain on our healthcare sector. This problem is further exacerbated by the ineffectual androgen deprivation therapy (ADT) currently available for the treatment of locally advanced PC, which inevitably progresses to castrate-resistant prostate cancer (CRPC). Chemotherapy with docetaxol or carbazitaxol only prolongs life in CRPC patients by weeks, thus a platform technology that can selectively deliver therapeutic payloads more effectively to target CRPC tumours is urgently needed. 

Project Objective - The principal objective of this studentship is to develop a new platform technology for the efficient delivery of a chemotherapeutic payload to prostate cancer cells. This will involve the synthesis of a trimodal delivery system comprising a targeting group, a cell uptake enhancing module linked to a chemotherapeutic. This is a collaborative Chemical Biology project that will involve extensive interaction between Glenn Burley’s synthetic group and Hing Leung’s oncology group based at the Beatson Institute for Cancer Research. 

Academic Environment - The student undertaking this project will receive unparalleled experience in all aspects of modern chemical biology within our industrially-facing interdisciplinary collaboration. Dr Glenn Burley has extensive experience in small molecule synthesis, solid phase peptide/nucleic acid synthesis and microfluidic device fabrication to culture prostate cancer cells. Cell-based experiments will be conducted n the synthetic biology laboratory of Dr Michele Zagnoni whose group has developed a high-throughput microfluidic platform to analyse cell uptake and cytotoxicity. Tissue and in vivo work will be conducted in the world-leading oncology group of Prof. Hing Leung (Beatson Institute). Prof. Leung has access to state-of-the-art facilities and expertise to assess and quantify the selectivity of cell uptake and the efficiency of the dose and toxicity in castrate-resistant mouse models. In addition, the student will collaborate with Chemical Biology groups based at GlaxoSmithKline’s (GSK) Stevenage site. 

Funding Notes

This EPSRC Industrial CASE studentship (4 years) is open to Home/EU students. The student will spend at least 3 months in GSK's state of the art laboratories in Stevenage learning cutting edge techniques related to medicinal chemistry and chemical biology. 

Candidates should have a strong background in Synthetic Organic or Medicinal Chemistry/Chemical Biology and have obtained a (i) or 2(i) [or equivalent for EU students] degree. 

Candidates who are interested in this position are encouraged to send their CV and contact details of two referees to glenn.burley@strath.ac.uk before 31st January, 2016. 

References

1. Smith, L.D., Dickinson, R.L, Lucas,C.M., Cousins, A., Malygin, A.A., Weldon, C., Perrett, A.J., Bottrill, A.R., Searle, M.S., Burley, G.A., Eperon, I.C. "A targeted oligonucleotide enhancer of SMN2 exon 7 splicing forms competing quadruplex and protein complexes in functional conditions" Cell Reports, 2014, 9, 193-205 . 

2. Fallows, A.J., Singh, I., Dondi, R., Cullis, P.M. Burley, G.A. "Highly efficient synthesis of DNA-binding polyamides using a convergent fragment-based approach" Organic Letters, 2014, 16, 4654-4657. 

3. Singh, I., Wendeln, C., Clarke, A.W., Cooper, J.M., Ravoo B.J., Burley, G.A. "Sequence-selective detection of double-stranded DNA sequences using pyrrole-imidazole polyamide microarrays" Journal of the American Chemical Society, 2013, 135, 3449-3457. 

4. Rajan, P.; Sudbery, I. M.; Villasevil, M. E. M.; Mui, E.; Fleming, J.; Davis, M.; Ahmad, I.; Edwards, J.; Sansom, O. J.; Sims, D.; Ponting, C. P.; Heger, A.; McMenemin, R. M.; Pedley, I. D.; Leung, H. Y. Next-generation Sequencing of Advanced Prostate Cancer Treated with Androgen-deprivation Therapy. Eur. Urology 2014, 66, 32-39. 

5. Ahmad I, Patel R, Singh LB, Nixon C, Seywright M, Barnetson RJ, Brunton V, Muller WJ, Edwards J, Sansom OJ, Leung, H. Y. HER2 overcomes PTEN (loss) induced Senescence to cause Aggressive Prostate Cancer. Proc. Natl. Acad. Sci., 2011, 108, 16392.


Professor Nick Tomkinson

Organocatalytic alkene bis-functionalisation

Duration

3 years

Eligibility criteria

EU National or self-funding

The project

A new project recently initiated within the group is concerned with the organocatalytic bis-functionalisation of alkenes, with the ultimate aim of delivering a simple and effective metal-free methods for alkene substitution.

Contact

New Catalyst Scaffolds

Duration

3 years

Eligibility criteria

EU National or self-funding

The project

In a mature collaborative project with Dr. Jamie Platts at Cardiff University we are unraveling the catalytic cycle of secondary amine catalysed activation of carbonyl compounds through a combination of synthetic, structural, mechanistic, and computational approaches, with the ultimate goal of developing the bench-mark catalysts for this important class of reaction.

Contact

Professor William Kerr

Enhanced Homogeneous Iridium Complexes for Widespread Application in Synthetic Organic Procedures

Duration

3.5 years

Eligibility

1st or Upper Second MChem/MSci undergraduate degree

Aims of the project

  • to refine emerging iridium catalyst systems by the interdisciplinary combination of preparative organometallic chemistry and theoretical chemistry methods, for the wider application of these modified catalyst species in hydrogen-isotope exchange processes;
  • to apply the developed catalyst species in mild and selective hydrogenation reactions of direct relevance to the pharmaceutical, agrochemical, and fine chemicals industries; and
  • to develop new and strategic applications for the new catalyst systems in a series of novel organic bond forming processes.

Contact

New Metal-catalysed Cyclisation Methods, Strategic Applications in the Synthesis of Novel Steroidal Natural Products of Medicinal Importance

Duration

3.5 years

Eligibility criteria

1st or Upper Second MChem/MSci undergraduate degree

The aims of the project

  • develop and strategically employ catalytic cobalt-mediated cyclisation chemistry to allow synthetic access to the key structural features of the Agariblazeispirol C natural product system
  • establish new asymmetric palladium-catalysed methods for the construction of the A-B ring system of Agariblazeispirol C
  • synthesise Agariblazeispirol C and prepare a series of medicinally-important analogue systems

Contact

Synthetically Useful Cyclopentenones via the Pauson-Khand Reaction

Duration

3.5 years

Eligibility

1st or Upper Second MChem/MSci undergraduate degree

Aims of the project

  • investigate the applicability of novel heteroatom containing substrates such as enol ethers, and other more functionalised derivatives, as alkene partners within the Pauson-Khand annulation process
  • develop a general and practically efficient reaction protocol that will deliver a range of pharmaceutically important cyclised scaffolds, with potential sites for further elaboration
  • strategically employ the newly developed methodology in the total synthesis of Xeromphalinones C and D and prepare a series of medicinally-important analogue systems

Contact

Professor Duncan Graham

Synthesis of functionalised nanoparticles for imaging biological interactions relating to cancer

Duration

42 months

Eligibility Criteria

UK national or relevant UK connection plus 2.1 minimum

Funding

Funding has been secured for this project

The project

We've recently been able to show that nanoparticles functionalised with a specific lectin which binds to sialic acid on the surface of cells can be used to quantify the numbers of normal cells and cancer tumour cells from a single patients sample.

In this preliminary example we were able to detect prostate cancer cells. The measurement is based on surface enhanced Raman scattering coding from specific nanoparticles which can be functionalised to interact with different cell surface moieties in a quantitative and multiplexed fashion. In order to extend this preliminary data we would propose to investigate the functionalization of metallic nanoparticles with specific receptor systems to bind to lung cancer cells to aid in the diagnosis of lung cancer through a collaborative effort involving scientists in Edinburgh and also Japan.

DDR2 is a protein involved in the signalling pathway for many cancers and the grouping of Professor Kimura at Saga University in Japan have recently discovered a new mutation which appears to be unique to lung cancer populations. This is a very exciting discovery in terms of the potential for both diagnosis and therapy. However there's a bottleneck in terms of being able to identify the cancerous cells containing this mutation. At present, quantitative QPCR methods are required which are time consuming and look at the DNA sequence rather than the proteins actually present. We are looking to develop a new methodology which will report on the effects of this mutation through imaging of the mutated proteins directly using these functionalised nanoparticles. In order to achieve this we are proposing to develop a new monoclonal antibody or peptide aptamer which will bind specifically to these cancer cells. This aspect of the training will be conducted in collaboration with Professor Ted Hupp at the University of Edinburgh.

We've already successfully co-supervised a PhD student and this is a logical expansion of our growing activities. Professor Kimura has sent one of his PhD students to spend 6 months in our laboratory which is seeding this work indicating the collaborations are in place to provide an excellent research training opportunity for the successful student.

The main aim of this project is to create new functional nanoparticles for use in lung cancer cell diagnosis. The specific objectives are:

  • identify the appropriate receptor moiety for functionalization of the nanoparticles in relation to the new mutation identified by the group in Japan.
  • investigate the specificity of these nanoparticles against different cell types and cancer mutations with a view to providing quantitative and selective analysis.
  • investigate the use of this Raman based analysis of lung cancer cells in aiding clinical diagnosis and hence treatment of lung cancer patients.
  • create an international collaboration based on this research methodology.

 

Contact 

Investigation into new chemistries for stabilisation and functionalization of gold and silver nanoparticles

Duration

38 Months

Start date

Available to start now

Eligibility Criteria

UK national or relevant UK connection plus 2.1 minimum

The project

Functionalised gold and silver nanoparticles are gaining in use and interest in both the commercial and academic sectors. Their use is based predominantly on their optical brightness and the most obvious use of gold nanoparticles is in home pregnancy testing. As ever, there is room for improvement in the chemistry associated with the linkage and stability of the nanoparticles when functionalised with the targeting species e.g. an antibody. This collaborative, industry supported studentship has been constructed to investigate the opportunities for new linkage chemistry to functionalise gold and silver nanoparticles in a more robust way than is currently possible.  We have excellent background expertise on nanoparticle functionalisations through our last 15 years of research and propose to utilise this along with some innovative new ideas to tackle the problem set by our industrial partner. Our first objective is to produce gold nanoparticles that are extraordinary stable. To do this, we will investigate the nature of the bond to the metal surface, the stabilising linkage which forms a stable shell around the nanoparticle and then the outer functionality which can be used for attachment of biologically active molecules. We will also investigate new approaches for the addition of functionality that haven’t been used before to broaden the scientific approach. Stability testing will be done in common buffers and also in harder conditions such as strong acids. We have a range of known chemistries available to us for these studies and have also designed some new approaches which would generate IP in the sector if successful. The objectives set out for this studentship are:

 

  • investigate new linkage chemistries onto gold nanoparticles. This will include conventional thiol based linkages but also alternative multi-dentate ligands and lesser used lewis bases.  We will also design a series of linkers that go with the actual surface chemistry to provide further stabilisation via hydrophobic interactions, hydrogen bonding or both.
  • assess the stability of these functionalised gold nanoparticles. This is critical to the outcome of the project and the conditions and performance criteria will be set and agreed in advance.
  • functionalise the nanoparticles with active species and investigate the issue of non-specific adhesion to non-target species. We will use protein based species such as antibodies and engineered fragments which is in line with the end use requirements of these species. 

 

This is an industrially led PhD programme which has been designed around fundamental science with a highly applied aspect. The area is highly topical and opportunities for further funding based on the outcomes from the research are significant.

Contact

Duncan Graham