A 700 MHz broadband cryoprobe and NMR spectrometer at UCL Chemistry
Lead Research Organisation:
University College London
Department Name: Chemistry
Abstract
There are different types of scientific equipment in each university. But one type which is most widely used by hundreds, from undergraduate students to emeritus staff, is nuclear magnetic resonance (NMR) spectroscopy. The advantage of NMR relies on its versatility and applicability to nearly any kind of material. The NMR of a liquid, mainly a solution of a material in a solvent, is particularly widespread due to the ease of use and the rich information content provided by well-resolved signals. The major problem in NMR, however, is sensitivity: we usually need milligrams of a sample to collect an NMR signal. Sensitivity is measured as a signal-to-noise ratio on a standard sample. One way to improve it is to increase the magnetic field strength. After about 25 years of magnet developments, a saturated state was approached. A breakthrough came in 1999 when the temperature of the probe coil and other parts was dropped drastically giving a >4-fold increase in sensitivity. This translates into a >16-fold reduction in time. The introduction of cryoprobes in NMR can be compared to the implementation of fast processors in computers. The increase in sensitivity means that we can now measure not only 1H or 31P with nearly 100% natural abundance but also 13C or 15N of small amounts of sample.
The main objective of this proposal is to introduce the first broadband cryoprobe at the highest 1H frequency of 700 MHz into a daily research of a diverse range of materials and drugs in Physical and Life sciences. To give a few examples, the new equipment will be used in such studies as the origin of life, drug discovery, cancer research, metabonomics, batteries, polymers and catalysis. The equipment will be installed in UCL, which has a £385M total EPSRC support. It will become part of the existing NMR facility in UCL Chemistry, with 4 solution and 1 solid-state NMRs. The 700 MHz instrument will be the highest field instrument at UCL Chemistry and will underpin both chemical biology and materials research.
In recent years, several new appointments have been made, many of which actively use NMR, including Prof Battaglia - the chemistry of biological polymers, Dr Powner - origins of life via chemical pathways leading to biological form and function, multicomponent reactions, sulphur and phosphorus chemistry, Dr Chudasama (named by Forbes magazine as one of the world's top scientists under the age of 30) - novel biotechnology drugs for selective delivery of chemotherapy to tumour cells via combinations with antibodies, Dr Bronstein - conjugated fused aromatic small molecules and polymers for use in optoelectronics. Within a short time, Dr Powner has become our leading NMR user, running >35% of the total number of NMR spectra. His research will gain considerably from the multinuclear and improved signal dispersion capabilities of the new instrument.
In addition to addressing the increased demand within UCL Chemistry, the new equipment will be used by >15 other UCL departments, which have joint EPSRC supported research projects with Chemistry, including Biochemical Engineering, Chemical Engineering, Eastman Dental Institute, School of Pharmacy, Wolfson Institute and others.
As this is a unique facility with the first helium-cooled broadband cryoprobe in the UK, the use of the new equipment will be extended to include other UK universities and research institutions in order to address their need in NMR of less studied nuclei. The operation of the facility will be fully automated to provide high throughput. Remote access will also be enabled for users from outside UCL Chemistry.
It is expected that the new facility will provide more comprehensive structural information by expanding NMR to nearly all atoms present in a molecule, not just 1H and 13C. This will enable drawing detailed structure-property relationships, which in turn will enhance our ability to design new advanced materials and drugs with desired properties and functions.
The main objective of this proposal is to introduce the first broadband cryoprobe at the highest 1H frequency of 700 MHz into a daily research of a diverse range of materials and drugs in Physical and Life sciences. To give a few examples, the new equipment will be used in such studies as the origin of life, drug discovery, cancer research, metabonomics, batteries, polymers and catalysis. The equipment will be installed in UCL, which has a £385M total EPSRC support. It will become part of the existing NMR facility in UCL Chemistry, with 4 solution and 1 solid-state NMRs. The 700 MHz instrument will be the highest field instrument at UCL Chemistry and will underpin both chemical biology and materials research.
In recent years, several new appointments have been made, many of which actively use NMR, including Prof Battaglia - the chemistry of biological polymers, Dr Powner - origins of life via chemical pathways leading to biological form and function, multicomponent reactions, sulphur and phosphorus chemistry, Dr Chudasama (named by Forbes magazine as one of the world's top scientists under the age of 30) - novel biotechnology drugs for selective delivery of chemotherapy to tumour cells via combinations with antibodies, Dr Bronstein - conjugated fused aromatic small molecules and polymers for use in optoelectronics. Within a short time, Dr Powner has become our leading NMR user, running >35% of the total number of NMR spectra. His research will gain considerably from the multinuclear and improved signal dispersion capabilities of the new instrument.
In addition to addressing the increased demand within UCL Chemistry, the new equipment will be used by >15 other UCL departments, which have joint EPSRC supported research projects with Chemistry, including Biochemical Engineering, Chemical Engineering, Eastman Dental Institute, School of Pharmacy, Wolfson Institute and others.
As this is a unique facility with the first helium-cooled broadband cryoprobe in the UK, the use of the new equipment will be extended to include other UK universities and research institutions in order to address their need in NMR of less studied nuclei. The operation of the facility will be fully automated to provide high throughput. Remote access will also be enabled for users from outside UCL Chemistry.
It is expected that the new facility will provide more comprehensive structural information by expanding NMR to nearly all atoms present in a molecule, not just 1H and 13C. This will enable drawing detailed structure-property relationships, which in turn will enhance our ability to design new advanced materials and drugs with desired properties and functions.
Planned Impact
Development of new materials and drugs with desired properties relies on our knowledge of their structure and dynamics. The most versatile technique in this regard is NMR spectroscopy. Applied separately on each type of nucleus present in a material NMR provides much-needed selectivity for structure and dynamics studies, which in turn advances our ability to design new materials and drugs.
The major problem of NMR, however, is its sensitivity, requiring larger quantities of samples than other methods. The objective of this proposal is to establish a 700 MHz NMR facility with a helium-cooled broadband cryoprobe. The proposed facility will be unique in the sense that it will combine multiple cutting-edge NMR technologies into a single all-in-one instrument dedicated to comprehensive studies of materials at the atomistic level. It will provide record levels of sensitivity for NMR measurements enabling experiments considered as unfeasible until recently, such as 19F NMR detections at micromolar concentrations or natural abundance NMR of 15N in the absence of nearby protons.
To our knowledge, there is no such facility in the world, making this instrument unique as multinuclear NMR equipment at the internationally leading level. Therefore, the requested equipment meets national needs by establishing a unique world-leading research activity. As such, it will be available to students and staff from UK academia and industry.
The immediate beneficiaries will include the EPSRC funded projects. Researchers from London and other UK universities will be provided with the full walk-up access to the new facility. In UCL Chemistry alone, the facility will have a direct impact on the research of >20 groups. The highest sensitivity of multinuclear NMR facility combined with fully automated and remote operation will satisfy requests from hundreds of users promptly, expediting wide impact of the facility.
The impact of the proposed facility on fundamental and applied sciences spans Chemistry, Materials Science, Biology, Physics, Medicine, Healthcare, Engineering, Geology and others. The research enabled by the new equipment is relevant to the strategic EPSRC themes:
1. Energy (EP/K014714 £3.7M, EP/N009533 £1.3M, EP/L017091 £840K)
2. Healthcare Technologies (EP/K031953 £11M, EP/M01732X £564K)
3. Manufacturing the Future (EP/L017709 £2.3M, EP/K014897 £1.9M, EP/N01572X £778K)
4. Physical Sciences (EP/K004980 £970K, EP/M02220X £345K)
5. Research Infrastructure (CRUK&EPSRC Cancer Imaging Centre at KCL&UCL)
The new equipment will benefit research falling within the four Grand Challenges of Chemical Sciences and Engineering:
(i) Dial-a-Molecule - 100% efficient synthesis
(ii) Directed Assembly of Extended Structures with Targeted Properties
(iii) Systems Chemistry: Exploring the Chemical Roots of Biological Organisation
(iv) Utilising CO2 in Synthesis and Transforming the Chemicals Industry
The research benefiting from the new facility is also relevant to 2 out of 4 Grand Challenges in Physics:
(i) Nanoscale Design of Functional Materials and
(ii) Understanding the Physics of Life,
as well as in Healthcare Technologies:
(i) Developing Future Therapies and
(ii) Optimising Treatment.
Thus, the new equipment will contribute towards addressing long-term public expectations and industrial needs identified by EPSRC. For example, the amidation reaction by Dr Sheppard will be crucial for direct amide synthesis, the most commonly used reaction in the pharmaceutical industry, which is a sector of huge importance to the UK economy.
The principal and substantial impacts will come from the work done by many groups using the new facility, which will affect lives of broader social groups through developments of, e.g., new batteries, solar panels, drugs and healthcare products. The new facility will also impact research into diagnostics and therapy of such diseases as cancer, liver cirrhosis and multiple sclerosis.
The major problem of NMR, however, is its sensitivity, requiring larger quantities of samples than other methods. The objective of this proposal is to establish a 700 MHz NMR facility with a helium-cooled broadband cryoprobe. The proposed facility will be unique in the sense that it will combine multiple cutting-edge NMR technologies into a single all-in-one instrument dedicated to comprehensive studies of materials at the atomistic level. It will provide record levels of sensitivity for NMR measurements enabling experiments considered as unfeasible until recently, such as 19F NMR detections at micromolar concentrations or natural abundance NMR of 15N in the absence of nearby protons.
To our knowledge, there is no such facility in the world, making this instrument unique as multinuclear NMR equipment at the internationally leading level. Therefore, the requested equipment meets national needs by establishing a unique world-leading research activity. As such, it will be available to students and staff from UK academia and industry.
The immediate beneficiaries will include the EPSRC funded projects. Researchers from London and other UK universities will be provided with the full walk-up access to the new facility. In UCL Chemistry alone, the facility will have a direct impact on the research of >20 groups. The highest sensitivity of multinuclear NMR facility combined with fully automated and remote operation will satisfy requests from hundreds of users promptly, expediting wide impact of the facility.
The impact of the proposed facility on fundamental and applied sciences spans Chemistry, Materials Science, Biology, Physics, Medicine, Healthcare, Engineering, Geology and others. The research enabled by the new equipment is relevant to the strategic EPSRC themes:
1. Energy (EP/K014714 £3.7M, EP/N009533 £1.3M, EP/L017091 £840K)
2. Healthcare Technologies (EP/K031953 £11M, EP/M01732X £564K)
3. Manufacturing the Future (EP/L017709 £2.3M, EP/K014897 £1.9M, EP/N01572X £778K)
4. Physical Sciences (EP/K004980 £970K, EP/M02220X £345K)
5. Research Infrastructure (CRUK&EPSRC Cancer Imaging Centre at KCL&UCL)
The new equipment will benefit research falling within the four Grand Challenges of Chemical Sciences and Engineering:
(i) Dial-a-Molecule - 100% efficient synthesis
(ii) Directed Assembly of Extended Structures with Targeted Properties
(iii) Systems Chemistry: Exploring the Chemical Roots of Biological Organisation
(iv) Utilising CO2 in Synthesis and Transforming the Chemicals Industry
The research benefiting from the new facility is also relevant to 2 out of 4 Grand Challenges in Physics:
(i) Nanoscale Design of Functional Materials and
(ii) Understanding the Physics of Life,
as well as in Healthcare Technologies:
(i) Developing Future Therapies and
(ii) Optimising Treatment.
Thus, the new equipment will contribute towards addressing long-term public expectations and industrial needs identified by EPSRC. For example, the amidation reaction by Dr Sheppard will be crucial for direct amide synthesis, the most commonly used reaction in the pharmaceutical industry, which is a sector of huge importance to the UK economy.
The principal and substantial impacts will come from the work done by many groups using the new facility, which will affect lives of broader social groups through developments of, e.g., new batteries, solar panels, drugs and healthcare products. The new facility will also impact research into diagnostics and therapy of such diseases as cancer, liver cirrhosis and multiple sclerosis.
Organisations
- University College London (Lead Research Organisation)
- Francis Crick Institute (Collaboration)
- National Aeronautics and Space Administration (NASA) (Collaboration)
- University College London (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- QUEEN MARY UNIVERSITY OF LONDON (Collaboration)
- AstraZeneca (United Kingdom) (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Dementia Discovery Fund (Collaboration)
- Rutherford Appleton Laboratory (Collaboration)
- Simons Foundation (Collaboration, Project Partner)
- Ludwig Maximilian University of Munich (LMU Munich) (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Pilkington Glass (Collaboration)
- Sengenia Ltd (Collaboration)
- King Abdullah University of Science and Technology (KAUST) (Collaboration)
- Almac Group (Collaboration)
- UNIVERSITY OF SOUTHAMPTON (Collaboration)
Publications
Bahou C
(2023)
Hydrogel Cross-Linking via Thiol-Reactive Pyridazinediones.
in Biomacromolecules
Bahou C
(2022)
Correction: Use of pyridazinediones as extracellular cleavable linkers through reversible cysteine conjugation.
in Chemical communications (Cambridge, England)
Bahou C
(2021)
A Plug-and-Play Platform for the Formation of Trifunctional Cysteine Bioconjugates that also Offers Control over Thiol Cleavability.
in Bioconjugate chemistry
Bahou C
(2023)
Hydrogel crosslinking via thiol-reactive pyridazinediones
Barnett S
(2019)
Combined high-resolution x-ray and DFT Bader analysis to reveal a proposed Ru-H ··· Si interaction in Cp(IPr)Ru(H)2SiH(Ph)Cl
in Inorganica Chimica Acta
Barnett S
(2019)
Combined high resolution X-ray and DFT Bader analysis to reveal a proposed Ru-H?Si interaction in Cp(IPr)Ru(H)2SiH(Ph)Cl
in Inorganica Chimica Acta
Bayle ED
(2021)
Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling.
in Journal of medicinal chemistry
Benhamou L
(2019)
Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass
in Green Chemistry
Bertram L
(2022)
Photochemistry of 2-thiooxazole: a plausible prebiotic precursor to RNA nucleotides.
in Physical chemistry chemical physics : PCCP
Briston T
(2019)
Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets.
in Trends in pharmacological sciences
| Description | There are various wide-ranging impacts associated with the research work of the users of the multinuclear 700 MHz NMR facility at UCL/Chemistry. Below we list some of them received from research groups using the spectrometer in response to our request to contribute to this report: Prof Ivan Parkin (Department of Chemistry, UCL): The research undertaken is expected to be of interest to healthcare professionals. Prof David Selwood "Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFß) Production in Regulatory T-Cells" (PMID: 29648813): Translational funding has been secured for this project going forward. Further non-academic impacts through commercial funding for the gene therapy applications are being sought. We were the first group to show that a host-directed PROTAC could have antiviral activity (PMID: 32539931). A series of compounds have also been developed with the potential to treat Fragile X disease (PMID: 34196695). Overall, our new bioactive compounds are discoveries that can be developed by other academic groups or by the pharma industry to produce new medicines. Dr Hien Nguyen (City University): We are working with several companies to commercialize what we have developed with the aim to provide a fast screening solution to yield new information on what is an important aspect of improving the environment. Dr Vijay Chudasama (Department of Chemistry, UCL) "A facile route to 1H- and 2H-indazoles from readily accessible acyl hydrazides by exploiting a novel aryne-based molecular rearrangement.": Potentially could contribute to the research in the area of new drug discovery. Several methodologies were developed for the synthesis of pharmaceutically-relevant indazoles, benzodiazepines and small molecule drug conjugate scaffolds. We envisage our findings would be particularly useful to those developing more efficient synthesis for pharmaceutically relevant molecules and therapeutics. Dr Salvador Tomas (Department of Biological Sciences, Birkbeck College): Our findings are relevant in abiogenesis. They, therefore, contribute to a better understanding of life's origin. Our research will boost the development of programmable drug delivery vehicles. The potential societal impact of such devices is difficult to overstate: they will decisively contribute to drastically reducing (and at the fullest of their development, eliminating) the scourge of cancer and infectious diseases. Finally, by developing mathematical tools that describe and allow us to predict the behaviour of smart nano-vesicles our research is contributing to the development of artificial protocells, the building blocks of soft-matter based robots inspired by the architecture of living organisms. The development of this new field of robotics is a medium-long term prospect but has the potential to revolutionise the manufacturing industry in the not-too-distant future. Our research is also of interest to those involved in the development of responsive nanomaterials and nanoreactors for sensing and drug delivery. Prof Helen Hailes: The findings are likely to have non-academic impacts in the longer term. They are relevant to new enzyme applications, anti-TB drugs and the synthesis of new tetrahydroisoquinolines. Fifteen papers have been published. Prof Tom Sheppard (Department of Chemistry, UCL): Twelve papers have already been published which are likely to have non-academic impacts in future. Our collaborations with AstraZeneca have been extended via two new 3-year collaborative PDRA projects on catalytic amidation (related to 3 in Findings) and C-H activation (related to 4 in Findings). Prof Alethea Tabor (Department of Chemistry, UCL): The findings of our research are likely to have non-academic impacts once the results have been published. Semiconducting polymer nanoparticles studied by us are used as novel contrast agents for photoacoustic and near infra-red imaging of tumours, which will allow for precision image-guided surgery of cancer patients. Dr Mukhlesur Rahman (School of Health, Sports and Bioscience, University of East London; Currently in Liverpool John Moores University): The research described in our publication titled "Terpenes from Zingiber montanum and Their Screening against Multi-Drug Resistant and Methicillin Resistant Staphylococcus aureus" will contribute towards the identification of lead anti-Staphylococcal compounds. Mr Ryan Trueman (School of Pharmacy, UCL) and Dr Bob Schroeder (Department of Chemistry, UCL) have used the 700 MHz NMR to study metabolites secreted by therapeutic cells under electrical stimulation. Fane F. K. Mensah, PhD Candidate, and Prof Geraldine Cambridge (Division of Medicine, Centre of Rheumatology Research, UCL): The condition Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been poorly studied. Nevertheless, various publications have pointed to abnormalities in the immune system as well as in the metabolism of the patients. Our paper titled "CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome" contributed to both of these findings and has been very well received by both the scientific and patient community. Funding for biomedical research in ME/CFS has been very limited in both the UK and outside of the UK. Scientific research and publications, such as our paper, contribute towards a better understanding of ME/CFS and other diseases. Prof Junwang Tang and Dr Christopher Windle (Department of Chemical Engineering, UCL): In the long term the catalyst developed by us may find use in industrial methane reforming. We have already discovered the structure of the reaction products using the 700MHz facility, e.g., isotopic ammonia and molecular catalysts. It is very important to identify the final isotopic products in order to avoid misunderstanding the underlying chemical processes. Dr Simoni Da Ros and Dr Katherine Curran (Bartlett School Env, Energy & Resources, Faculty of the Built Environment, UCL): For the project dealing with historic plastics of cultural heritage significance, the findings are contributing to the knowledge exchange between universities and museums. Our work has been disseminated through non-academic channels such as the Institute of Conservation (ICON) website and the ICON News Magazine, where an article piece about our work was published in the magazine in April 2021. It is relevant to museums which house historic plastic artefacts, for better planning of their care. Using the 700MHz facility, we have shown that NMR spectroscopy can be successfully used to analyse the composition and degradation of historic plastic artefacts. Drs Hannah Woodward, Dr Ben Atkinson, David Steadman, Paul Fish, Robert Lasniak and others (Alzheimer's Research UK UCL Drug Discovery Institute): A major impact was on the Notum research project, which enabled the development of compound ARUK3001185. Currently, this compound is being evaluated in animal models of Alzheimer's Disease with an eye to future clinical trials. The NMR facility was used to characterise compounds used in this and other projects carried out at UCL ARUK Drug Discovery Institute. Tool compounds discovered are relevant for understanding neurodegenerative diseases and disorders and will be used in the drug discovery process, including the exploration of third-party licensing opportunities. Additionally, the quality of the emerging molecules from UCL Drug Discovery Institute is having a great impact on the reputation of the institute in the scientific community and attracting potential collaborators. The existing collaborations with the Oxford and Cambridge ARUK drug discovery institutes and the Wellcome Centre for Human Genetics at the University of Oxford have already led to many publications. Dr Stefan Howorka (Department of Chemistry, UCL): The research results are of potential interest to bioimaging and small-molecule probe development in the chemical/biotech industry. Prof Erik Arstad, Dr Thibault Gendon, Dr iFath Srirndil and Dr Michael Porter (Institute of Nuclear Medicine, UCL and Department of Chemistry, UCL): We have developed a new type of leaving groups (dibenzothiophene sulfonium salts) for nucleophilic aromatic substitution, and have developed this as a platform for manufacturing of diagnostic positron emission tomography (PET) tracers. The chemistry is particularly relevant for PET chemistry, but we expect it will also find widespread use in synthetic chemistry as the leaving group we developed has been shown (by others) to be exceptionally well suited for Pd-couplings, i.e. allows coupling with 90% yield in the presence of aryl iodides Our findings have led to a £1.2 million grant from the MRC (subject to contract) for testing of a novel diagnostic tracer in humans for the first time. The 700MHz NMR instrument is used for recording quantitative 19F NMR spectra for the development of labelling chemistry of diagnostic tracers for imaging with PET. Dr Alistair Miller (Darr House and University of Exeter): The analysis carried out on the 700MHz NMR was used for the authentication of compounds for screening for insecticidal activity and is relevant to the agricultural section. Dr Abil Aliev and Prof William Motherwell (Department of Chemistry, UCL): The work on noncovalent interactions promotes our understanding and controlling of three-dimensional molecular recognition in chemical reactions and biological processes, as well as in supramolecular chemistry, pharmaceutical sciences, host-guest complexation and crystal engineering. Prof Matthew Powner (Department of Chemistry, UCL): Published research results in such high-impact journals as Nature and Science. Advanced our understanding of the origins of life. They are also relevant to the pharmaceutical and fine chemical industries. Awards including Blavatnik Honoree 2021 (http://blavatnikawards.org/honorees/profile/matthew-powner/) and RSC Harrison-Meldola Memorial Prize 2019 (https://www.rsc.org/prizes-funding/prizes/find-a-prize/harrison-meldola-memorial-prizes/previous-winners/). Our studies, which have used the 700MHz NMR facility and contributed significantly to the understanding of the emergence of life include: (1) We have reported the first prebiotic, chemoselective and stereospecific complete synthesis of (non-canonical) amino-nucleotide (See Whitaker & Powner Nat. Chem. 2022, accepted). Our results suggest that 3'-amino-threose nucleic acid (TNA) nucleosides may have been present on the early earth. (2) We have discovered a chemoselective peptide ligation in water (see Canavelli et al. Nature, 2019). (3) We have developed the first prebiotic synthesis of proteinogenic amino acid cysteine, via a novel nitrile mediated biomimetic reaction pathway (see Foden et al. Science, 2020). We have now shown that cysteine is a product of simple prebiotic chemistry. Our discovery supports the hypothesis that cysteine was simply a secondary product of serine chemistry at the origins of life. (4) We have discovered a novel protecting group-free, activating agent-free catalytic peptide ligation strategy that operates in neutral water (see Foden et al. published in Science, 2020). This work is relevant to green chemical strategies to synthesis and catalysis in water. (5) We have found that dipeptides derived from Ser, Thr and Asn undergo pronounced amidine hydrolysis to the corresponding peptides. Our data support a scenario in which nitriles served as an early energy currency on the primordial Earth, acting as a forerunner to ATP and thioesters that drive reactions in extant biology. (6) We have demonstrated diamidophosphate can be harnessed to achieve Strecker amino acid synthesis. The high yield of N-phosphoro-aminonitriles and their selective transformations provides new insights into prebiotic amino acid synthesis and activation. (7) We have developed a new method to achieve a divergent synthesis of purine and pyrimidine nucleotide with the for a common precursor (Roberts et al Nat. Commun 2018). (8) We have developed methods for the photochemical selection of nucleotide stereochemistry (Colville and Powner, under peer review). (9) We have developed a new prebiotic strategy to access nucleotide 5'-phosphates in water. The new strategy opens new pathways to explore nucleotide syntheses and activations, which are closely aligned with the biochemical strategies exploited by extant life. (10) We have demonstrated that N-phospho-aminonitriles can not only be highly efficiently synthesised in neutral water but the neutral phosphorostrecker reaction provide excellent selectivity for proteinogenic amino acid (see Ashe et al in Nature - Communications Chemistry, 2019). (11) We have developed new chiral aldehydes for analysis and as standards to use for investigating the chemical composition of meteorite samples in collaboration with scientists at the Solar System Exploration Division, NASA Goddard Space Flight Center, USA (see Aponte et al in ACS Earth Space and Chemistry, 2019). (12) We have investigated the origins of Life on other planets (including Mars and current NASA missions of sample return) and explored exoplanet atmosphere and astrochemistry, developing green chemical strategies to synthesis and catalysis in water. Prof Jamie Baker's (Department of Chemistry, UCL): The list of projects, which have made use of the 700MHz NMR, include: Mikesh Patel, PhD project: The development of nitrile reagents for antibody conjugation Charlie Bishop, PhD project: Investigating new mechanisms for cysteine-to-lysine transfer Yanbo Zhao, PhD project: Expanding the scope of Next Generation Maleimides for Antibody Conjugation Muhammed Haque, PhD project: Investigations into antibody conjugation by cysteine-to-lysine transfer Alina Chrzastek, PhD project: Dual reactivity disulfide bridging reagents for antibody bioconjugation Archie Wall, PhD project: Novel Approaches to Site-Selective Protein Modification Using Next-Generation Maleimides Luigia Salerno, PhD project: Active methylene compounds for homogeneous cysteine bioconjugation Nafsika Forte, PDRA on EPSRC grant: Site-selective antibody modification by cysteine-to-lysine transfer (CLT) Roshni Malde: PhD project: Development and Photophysical Investigations of Maleimide Chromophores for Applications in Photoactive Bioconjugates Dr Pooja Basnett (University of Westminster) has used the facility for the characterisation of sustainable polymers. Please note that there are also impacts and research results of a confidential nature, details of which cannot be revealed here at this time. |
| Sector | Agriculture, Food and Drink,Chemicals,Education,Electronics,Energy,Environment,Healthcare,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Cultural,Economic |
| Description | NMR Metabonomics for the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Researchers from UCL Centre of Rheumatology and New Zealand |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Title | Research Tools & Methods of Confidential Nature |
| Description | Research tools and methods of confidential nature are developed using the 700 MHz facility in collaboration with researchers from academic institutions and commercial companies. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | Due to the confidential nature, no details can be revealed at this stage. |
| Title | NMR Chemical shift anisotropy measurements |
| Description | Using 300 MHz and 700 MHz NMR instruments, it has been shown that static lineshape measurements are better suited for accurate measurements of the chemical shift anisotropy than those based on magic-angle spinning. |
| Type Of Material | Data analysis technique |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | Accurate measurements of chemical shift anisotropy is important for materials, chemistry and biological sciences. |
| URL | https://www.sciencedirect.com/science/article/pii/S0926204017301303?via%3Dihub |
| Description | Aliphatic Aldehydes and Ketones in Carbonaceous Chondrites (Matt Powner) |
| Organisation | Ludwig Maximilian University of Munich (LMU Munich) |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | NMR analysis. |
| Collaborator Contribution | Sample provision for analysis. |
| Impact | Publication: "Analyses of Aliphatic Aldehydes and Ketones in Carbonaceous Chondrites" José C. Aponte*, Daniel Whitaker, Matthew W. Powner, Jamie E. Elsila, and Jason P. Dworkin, ACS Earth Space Chem. 2019, 3, 3, 463-472 Publication Date:February 20, 2019. https://doi.org/10.1021/acsearthspacechem.9b00006 |
| Start Year | 2017 |
| Description | Aliphatic Aldehydes and Ketones in Carbonaceous Chondrites (Matt Powner) |
| Organisation | National Aeronautics and Space Administration (NASA) |
| Department | Goddard Space Flight Center |
| Country | United States |
| Sector | Public |
| PI Contribution | NMR analysis. |
| Collaborator Contribution | Sample provision for analysis. |
| Impact | Publication: "Analyses of Aliphatic Aldehydes and Ketones in Carbonaceous Chondrites" José C. Aponte*, Daniel Whitaker, Matthew W. Powner, Jamie E. Elsila, and Jason P. Dworkin, ACS Earth Space Chem. 2019, 3, 3, 463-472 Publication Date:February 20, 2019. https://doi.org/10.1021/acsearthspacechem.9b00006 |
| Start Year | 2017 |
| Description | Antiviral targets and gene therapy (David Selwood) |
| Organisation | University College London |
| Department | Division of Infection and Immunity |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | David Selwood: Working with Greg Towers (I&I, UCL) we have discovered that carefully optimised cyclosporine derivatives can block HIV and other viruses' replication. Gene delivery uses modified, safe HIV-vector based on the virus. HIV can efficiently deliver genes to target cells but unfortunately human stem cells are quite resistant to infection. Thus, a major hurdle in the clinical application of stem cell gene therapy is achieving sufficient modification to maximise clinical benefit. HIV-vector production costs ~£100,000's for a single trial. We have discovered that a significant block to stem cell infection can be circumvented using these derivatives and this is a focus of current research. We have achieved notable grant success for this area with > £4million raised (see funding section). |
| Collaborator Contribution | Infection studies |
| Impact | Che C Colpitts, Sophie Ridewood, Bethany Schneiderman, Justin Warne, Keisuke Tabata, Caitlin F Ng, Ralf Bartenschlager, David L Selwood, Greg J Towers Hepatitis C virus exploits cyclophilin A to evade PKR Elife 2020 Jun 16;9:e52237. doi: 10.7554/eLife.52237. Counteracting innate immunity is essential for successful viral replication. Host cyclophilins (Cyps) have been implicated in viral evasion of host antiviral responses, although the mechanisms are still unclear. Here, we show that hepatitis C virus (HCV) co-opts the host protein CypA to aid evasion of antiviral responses dependent on the effector protein kinase R (PKR). Pharmacological inhibition of CypA rescues PKR from antagonism by HCV NS5A, leading to activation of an interferon regulatory factor-1 (IRF1)-driven cell intrinsic antiviral program that inhibits viral replication. These findings further the understanding of the complexity of Cyp-virus interactions, provide mechanistic insight into the remarkably broad antiviral spectrum of Cyp inhibitors, and uncover novel aspects of PKR activity and regulation. Collectively, our study identifies a novel antiviral mechanism that harnesses cellular antiviral immunity to suppress viral replication. We were the first group to show that a host-directed PROTAC could have antiviral activity. |
| Start Year | 2020 |
| Description | COMPLEX: The Degradation of Complex Modern Polymeric Objects in Heritage Collections: A System Dynamics Approach (Katherine Curran) |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Dr Simoni Ros collaborates with the UCL Institute for Sustainable Heritage in a research project named as COMPLEX: The Degradation of Complex Modern Polymeric Objects in Heritage Collections: A System Dynamics Approach. This project is led by Professor Associate Dr Katherine Curran, principal investigator and responsible for acquiring the starting grant from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 716390). |
| Collaborator Contribution | From the collaboration named above, a new MSc project has been started in the UCL MSc Applied Analytical Chemistry, in which the student Luka Nunar will explore NMR spectroscopy to develop new methodologies for the quantification of plasticiser contents and the degradation extent in historic plasticised artifacts based on solution and solid-state 1H and 13C NMR techniques. The UCL 700 MHz NMR facility has also contributed to two MRes dissertation projects from the UCL Institute for Sustainable Heritage, involving the students Isabella del Gaudio (title: Study of water sorption and diffusion in cellulose acetate) and Rose King (title: Plasticiser loss from cellulose acetate), which have investigated degradation processes of cellulose acetate, involving the investigation of deacetylation and plasticiser loss. The research has evolved in PhD projects involving the same students and both projects currently benefit from their use of the UCL 700 MHz NMR facility. |
| Impact | [1] In preparation for submission in the Polymer Degradation and Stability journal: "Quantifying the degradation state of plasticised cellulose acetate-based historic artefacts by NMR spectroscopy", by Simoní Da Ros, Abil E. Aliev, Isabella del Gaudio, Rose King, Anna Pokorska, Mark Kearney, Katherine Curran. [2] Argyro Gili, Rose King, Luca Mazzei, Josep Grau-Bové, Robert Koestler, Michael Petr, Odile Madden, Simoní Da Ros, Katherine Curran. Modelling and Measuring the Diethyl Phthalate Plasticiser loss from Cellulose Acetate in different ventilation scenarios. Presented at "The Plastics Heritage Congress 2019", Lisbon, 2019. (Oral presentation) [3] Del Gaudio I, Hunter-Sellars E, Da Ros S, Parkin I, Duncan J, Moore A, Williams D, Curran K. Stability of cellulose acetate films in museum collections. Presented at "The Polymer Degradation Discussion Group Conference", Malta, 2019. (Poster presentation) [4] Argyro Gili, Rose King, Luca Mazzei, Simoní Da Ros, Josep Grau-Bové, Robert Koestler, Michael Petr, Odile Madden, Katherine Curran. A Predictive Model and Measurements for the Impact of Ventilation on Diethyl Phthalate Plasticiser Loss from Cellulose Acetate. Presented at the "Plastics and Peril Conference", Cambridge, 2020. (Poster presentation) [5] Argyro Gili, Rose King, Luca Mazzei, Simoní Da Ros, Josep Grau-Bové, Robert, Koestler, Michael Petr, Odile Madden, Katherine Curran. Decision making in conservation based on modelling and measuring diethyl phthalate plasticiser loss from cellulose acetate in varied ventilation conditions. Presented at the "Plastics and Peril Conference", Cambridge, 2020. (Oral presentation) |
| Start Year | 2019 |
| Description | Combined high resolution x-ray and DFT Bader analysis to reveal a proposed Ru-H ··· Si interaction in Cp(IPr)Ru(H)2SiH(Ph)Cl (Abil Aliev) |
| Organisation | Francis Crick Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Multinuclear 1H, 13C and 29Si NMR measurements and analysis. |
| Collaborator Contribution | DFT calculations |
| Impact | This collaboration has led to a publication, |
| Start Year | 2018 |
| Description | Drugs for treatment of neurodegenerative diseases (Paul Fish, Alz) |
| Organisation | Dementia Discovery Fund |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Compounds are sought for use as inhibitors of key targets for treatment of neurodegenerative diseases such as neurodegeneration, Alzheimer's disease and dementia. The 700MHz NMR facility is used for structural characterisation of newly synthesised compounds. |
| Collaborator Contribution | Dementia Discovery Fund is a spin out company. |
| Impact | The following publications are relevant: Beilstein J. Org. Chem. 2019, 15, 2790-2797. doi:10.3762/bjoc.15.271 Med. Chem. Commun. 2019, 10, 1361 DOI: 10.1039/c9md00096h |
| Start Year | 2019 |
| Description | EGFR-Targeted Semiconducting Polymer Nanoparticles for Photoacoustic Imaging |
| Organisation | University of Cambridge |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have prepared novel semiconducting polymer nanoparticles for photoacoustic imaging, conjugated to peptides targeted to cancer cells. As part of this, we have developed a novel NMR approach to characterise the level of bioconjugation of the targeting peptides to the nanoparticles. |
| Collaborator Contribution | Preparation of semiconducting polymer nanoparticles. |
| Impact | A manuscript is currently under preparation. |
| Start Year | 2019 |
| Description | Mechanistic study of boron-catalysed amidation reactions (Tom Sheppard) |
| Organisation | AstraZeneca |
| Department | Research and Development AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | In 2021, Prof Tom Sheppard (UCL Chemistry) and others have begun a new EPSRC-funded project on the mechanistic study of boron-catalysed amidation reactions (EP/T030488/1) in collaboration with Professor Andy Whiting (Durham University), Professor Henry Rzepa (Imperial College London), Dr Jordi Burés (University of Manchester) and scientists from GSK, AstraZeneca & Syngenta. This project will make extensive use of the 700 MHz NMR for elucidating the structures of novel catalysts and potential reaction intermediates. Previous work in this area (outlined above in (1) in Findings) also led to funding for a 3-year collaborative PDRA with AstraZeneca. The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds was undertaken by the use of 11B NMR. We have shown that greater insight into the structures present in such systems can be obtained by using DFT chemical shift calculations to support or exclude proposed reaction intermediates. |
| Collaborator Contribution | AstraZeneca has funded two 3-year PDRAs based at Macclesfield (the PDRAs are AZ employees). These are linked to the amidation (EPSRC EP/T030488/1) and the CH-Activation projects. |
| Impact | Publications: C. E. Coomber, M. J. Porter, A. E. Aliev, P. D. Smith, T. D. Sheppard, Tuning Reactivity in Pd-Catalysed C(sp3)-H Arylations via Directing Group Modifications and Solvent Selection, Advanced Synthesis & Catalysis 2020, 362, 5105. doi: 10.1002/adsc.202000726 Arkhipenko S, Sabatini MT, Batsanov AS, Karaluka V, Sheppard TD, Rzepa HS, ... Whiting A. (2018). Mechanistic insights into boron-catalysed direct amidation reactions. Chemical science, 9(4), pp. 1058-1072. Coomber CE, Laserna V, Martin LT, Smith PD, Hailes HC, Porter MJ, ... Sheppard TD. (2019). Catalytic direct amidations in tert-butyl acetate using B(OCHCF). Organic & biomolecular chemistry, 17(26), pp. 6465-6469. doi: 10.1039/C9OB01012B Rzepa HS, Arkhipenko S, Wan E, Sabatini MT, Karaluka V, Whiting A, ... Sheppard TD. (2018). An Accessible Method for DFT Calculation of B NMR Shifts of Organoboron Compounds. The Journal of organic chemistry, 83(15), pp. 8020-8025. doi: 10.1021/acs.joc.8b00859 Sabatini MT, Boulton LT, Sheppard TD. (2017). Borate esters: Simple catalysts for the sustainable synthesis of complex amides. Science advances, 3(9), pp. e1701028. doi: 10.1126/sciadv.1701028 Sabatini MT, Karaluka V, Lanigan RM, Boulton LT, Badland M, Sheppard TD. (2018). Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts. Chemistry (Weinheim an der Bergstrasse, Germany), 24(27), pp. 7033-7043. doi: 10.1002/chem.201800372 |
| Start Year | 2021 |
| Description | Mechanistic study of boron-catalysed amidation reactions (Tom Sheppard) |
| Organisation | GlaxoSmithKline (GSK) |
| Department | GlaxoSmithKline Medicines Research Centre |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | In 2021, Prof Tom Sheppard (UCL Chemistry) and others have begun a new EPSRC-funded project on the mechanistic study of boron-catalysed amidation reactions (EP/T030488/1) in collaboration with Professor Andy Whiting (Durham University), Professor Henry Rzepa (Imperial College London), Dr Jordi Burés (University of Manchester) and scientists from GSK, AstraZeneca & Syngenta. This project will make extensive use of the 700 MHz NMR for elucidating the structures of novel catalysts and potential reaction intermediates. Previous work in this area (outlined above in (1) in Findings) also led to funding for a 3-year collaborative PDRA with AstraZeneca. The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds was undertaken by the use of 11B NMR. We have shown that greater insight into the structures present in such systems can be obtained by using DFT chemical shift calculations to support or exclude proposed reaction intermediates. |
| Collaborator Contribution | AstraZeneca has funded two 3-year PDRAs based at Macclesfield (the PDRAs are AZ employees). These are linked to the amidation (EPSRC EP/T030488/1) and the CH-Activation projects. |
| Impact | Publications: C. E. Coomber, M. J. Porter, A. E. Aliev, P. D. Smith, T. D. Sheppard, Tuning Reactivity in Pd-Catalysed C(sp3)-H Arylations via Directing Group Modifications and Solvent Selection, Advanced Synthesis & Catalysis 2020, 362, 5105. doi: 10.1002/adsc.202000726 Arkhipenko S, Sabatini MT, Batsanov AS, Karaluka V, Sheppard TD, Rzepa HS, ... Whiting A. (2018). Mechanistic insights into boron-catalysed direct amidation reactions. Chemical science, 9(4), pp. 1058-1072. Coomber CE, Laserna V, Martin LT, Smith PD, Hailes HC, Porter MJ, ... Sheppard TD. (2019). Catalytic direct amidations in tert-butyl acetate using B(OCHCF). Organic & biomolecular chemistry, 17(26), pp. 6465-6469. doi: 10.1039/C9OB01012B Rzepa HS, Arkhipenko S, Wan E, Sabatini MT, Karaluka V, Whiting A, ... Sheppard TD. (2018). An Accessible Method for DFT Calculation of B NMR Shifts of Organoboron Compounds. The Journal of organic chemistry, 83(15), pp. 8020-8025. doi: 10.1021/acs.joc.8b00859 Sabatini MT, Boulton LT, Sheppard TD. (2017). Borate esters: Simple catalysts for the sustainable synthesis of complex amides. Science advances, 3(9), pp. e1701028. doi: 10.1126/sciadv.1701028 Sabatini MT, Karaluka V, Lanigan RM, Boulton LT, Badland M, Sheppard TD. (2018). Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts. Chemistry (Weinheim an der Bergstrasse, Germany), 24(27), pp. 7033-7043. doi: 10.1002/chem.201800372 |
| Start Year | 2021 |
| Description | Mechanistic study of boron-catalysed amidation reactions (Tom Sheppard) |
| Organisation | Sengenia Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | In 2021, Prof Tom Sheppard (UCL Chemistry) and others have begun a new EPSRC-funded project on the mechanistic study of boron-catalysed amidation reactions (EP/T030488/1) in collaboration with Professor Andy Whiting (Durham University), Professor Henry Rzepa (Imperial College London), Dr Jordi Burés (University of Manchester) and scientists from GSK, AstraZeneca & Syngenta. This project will make extensive use of the 700 MHz NMR for elucidating the structures of novel catalysts and potential reaction intermediates. Previous work in this area (outlined above in (1) in Findings) also led to funding for a 3-year collaborative PDRA with AstraZeneca. The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds was undertaken by the use of 11B NMR. We have shown that greater insight into the structures present in such systems can be obtained by using DFT chemical shift calculations to support or exclude proposed reaction intermediates. |
| Collaborator Contribution | AstraZeneca has funded two 3-year PDRAs based at Macclesfield (the PDRAs are AZ employees). These are linked to the amidation (EPSRC EP/T030488/1) and the CH-Activation projects. |
| Impact | Publications: C. E. Coomber, M. J. Porter, A. E. Aliev, P. D. Smith, T. D. Sheppard, Tuning Reactivity in Pd-Catalysed C(sp3)-H Arylations via Directing Group Modifications and Solvent Selection, Advanced Synthesis & Catalysis 2020, 362, 5105. doi: 10.1002/adsc.202000726 Arkhipenko S, Sabatini MT, Batsanov AS, Karaluka V, Sheppard TD, Rzepa HS, ... Whiting A. (2018). Mechanistic insights into boron-catalysed direct amidation reactions. Chemical science, 9(4), pp. 1058-1072. Coomber CE, Laserna V, Martin LT, Smith PD, Hailes HC, Porter MJ, ... Sheppard TD. (2019). Catalytic direct amidations in tert-butyl acetate using B(OCHCF). Organic & biomolecular chemistry, 17(26), pp. 6465-6469. doi: 10.1039/C9OB01012B Rzepa HS, Arkhipenko S, Wan E, Sabatini MT, Karaluka V, Whiting A, ... Sheppard TD. (2018). An Accessible Method for DFT Calculation of B NMR Shifts of Organoboron Compounds. The Journal of organic chemistry, 83(15), pp. 8020-8025. doi: 10.1021/acs.joc.8b00859 Sabatini MT, Boulton LT, Sheppard TD. (2017). Borate esters: Simple catalysts for the sustainable synthesis of complex amides. Science advances, 3(9), pp. e1701028. doi: 10.1126/sciadv.1701028 Sabatini MT, Karaluka V, Lanigan RM, Boulton LT, Badland M, Sheppard TD. (2018). Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts. Chemistry (Weinheim an der Bergstrasse, Germany), 24(27), pp. 7033-7043. doi: 10.1002/chem.201800372 |
| Start Year | 2021 |
| Description | Metagenomic ene-reductases for the bioreduction of sterically challenging enones (Helen Hailes) |
| Organisation | Almac Group |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Prof H. Hailes (Department of Chemistry, UCL), Dr J. Ward (Biochemical Engineering, UCL), Dr C. Orengo (Structural and Molecular Biology, UCL) and Dr Tom Moody (Almac) are involved in this collaboration. The 700MHz facility was essential to determine the stereochemistry of ene-reductase enzyme products. In this work, a sequence-based functional metagenomics strategy was used to identify novel ene-reductase enzymes from a drain metagenome. Several new ene-reductases were discovered and effectively applied in the stereoselective bioreduction of bicyclic Wieland-Miescher and Hajos-Parish ketones. Notably, this is the first time such bulky substrates have been successfully transformed with wild-type ene-reductases and the enzymes also showed remarkable organic solvent robustness which is ideal for industrial applications. Funding BBRSC BB/N01877X/1 & BB/L007444/1 |
| Collaborator Contribution | The enzymes prepared by Prof H. Hailes (Department of Chemistry, UCL), Dr J. Ward (Biochemical Engineering, UCL) and Dr C. Orengo (Structural and Molecular Biology, UCL) are used in the company. For detailed description, see D. Dobrijevic, L. Benhamou, A. E. Aliev, N. Dawson, D. Baud, D. Méndez Sánchez, N. Tappertzhofen, T. S. Moody, C. A. Orengo, H. C. Hailes, J. M. Ward, 'Ene-reductases from a drain metagenome for the selective bioreduction of bicyclic enones', RSC Adv., 2019, 9, 36608-36614. A new iCASE studentship was also funded starting in Sept 2020 on a new enzyme type. Another grant application has been submitted by Prof H Hailes (UCL) together with Almac. There are contracts that were signed (with Biochemical Engineering, UCL) with MTAs included and materials (enzymes) were transferred that are being used in commercial applications. Almac contributed £132k and an industrial perspective/time at attendance for meetings, etc. |
| Impact | Publication in RSC Advances in 2019: D. Dobrijevic, L. Benhamou, A. E. Aliev, N. Dawson, D. Baud, D. Méndez Sánchez, N. Tappertzhofen, T. S. Moody, C. A. Orengo, H. C. Hailes, J. M. Ward, 'Ene-reductases from a drain metagenome for the selective bioreduction of bicyclic enones', RSC Adv., 2019, 9, 36608-36614. |
| Start Year | 2017 |
| Description | Multienzyme Cascades Incorporating Methyltransferases for the Diversification of Alkaloids (Helen Hailes) |
| Organisation | University College London |
| Department | Biochemical Engineering |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Structural characterisation, chemical synthesis. |
| Collaborator Contribution | Biochemical studies. |
| Impact | Publications: DOI 10.1002/anie.202104476 The use of methyltransferases in vitro in multi-enzyme cascades, including for the generation of SAM in situ has been reported. Up to seven enzymes were used for the regioselective diversification of natural and non-natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C-1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule. The use of methyltransferases in vitro in multi-enzyme cascades, for the diversification of natural and non-natural THIQs was described. Regioselectivites of the methyltransferases were interestingly dependent on the group at C-1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule. DOI 10.1021/acs.orglett.1c02110 Chemoenzymatic cascades toward various 13-methyl-tetrahydroprotoberberbine scaffolds using a stereoselective Pictet-Spenglerase, regioselective catechol O-methyltransferases and selective chemical Pictet-Spengler reactions have been presented. All reactions could be performed sequentially, without the workup or purification of any synthetic intermediates. Moreover, the naturally occurring alkaloids have the (+)-configuration and importantly here, a strategy to the (-)-isomers was developed. A methyl group at C-8 was also introduced with some stereocontrol, influenced by the stereochemistry at C-13. Furthermore, a single step reaction was found to convert tetrahydroprotoberberine alkaloids into the analogous protoberberine scaffold, avoiding the use of harsh oxidizing conditions or a selective oxidase. This work provides facile, selective routes toward novel analogues of bioactive alkaloids. A novel cascades using norcoclaurine synthases to produce tetrahydroprotoberberine and protoberberine alkaloids were presented. DOI 10.1002/cctc.202101008 Transaminases were directly reacted with hydrazones in a novel approach to form amine products. Several substrates were investigated, including those with furan and phenyl moieties. It was determined that the amine yields increased when an additional electrophile was added to the reaction mixture, suggesting that they can sequester the hydrazine released in the reaction. Pyridoxal 5'-phosphate (PLP), a cofactor for transaminases, and polyethylene glycol (PEG)-aldehydes were both found to increase the yield of amine formed. Notably, the amination of (S)-1-amino-2-(methoxymethyl) pyrrolidine (SAMP) hydrazones gave promising results as a method to form chiral ß-substituted amines in good yield. A novel reaction using transaminases to convert hydrazones to amines was described. |
| Start Year | 2018 |
| Description | Multiple Sclerosis (David Selwood) |
| Organisation | Queen Mary University of London |
| Department | Barts and The London School of Medicine and Dentistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | David Selwood: MS is both an autoimmune and a neurodegenerative disease. Through collaboration with Profs David Baker and Gavin Giovanonni (Barts) we established the utility of sodium channel blockade for preventing neurodegeneration in MS models, identifying prototypes without CNS effects (a). More recently, we extended this work to encompass potassium channel activators (big conductance BK channel) with potential to alleviate MS related spasticity (b), and potentially provide a new way to prevent neurodegeneration in MS. Our BK channel activator VSN16R reached phase 2 clinical studies for spasticity, though it did not meet its clinical endpoints (NCT02542787). In all, through grants and fundraising for the Canbex Therapeutics spin-out we raised around £9million for the development of this drug. Follow-up work is focussed on the neuroprotective potential for this target and a new grant has been agreed with FF/NMSS. |
| Collaborator Contribution | Medical Research |
| Impact | This collaboration is multi-disciplinary. Involves organic chemistry, synthesis, structure determinations, drug discovery, pharmaceuticals. |
| Start Year | 2017 |
| Description | NPRC Natriuretic peptide C agonists for heart failure (David Selwood) |
| Organisation | Queen Mary University of London |
| Department | William Harvey Research Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | David Selwood: In collaboration with Prof Adrian Hobbs at William Harvey (Barts) We have developed three chemical series of small molecule NPRC agonists and obtained both BHF and investor funding from the UCL Apollo fund for progression towards the clinic. |
| Collaborator Contribution | Medical research, clinical trials. |
| Impact | This collaboration is multi-disciplinary, involving chemistry and drug discovery. |
| Start Year | 2020 |
| Description | Neuropilin-1 in vascular and immune biology (David Selwood). |
| Organisation | University College London |
| Department | Institute of Structural and Molecular Biology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | David Selwood: Working with Snezana Djordjevic (UCL ISMB) and Ian Zachary (UCL) and with Prof. Stella Tsirka (Stony Brook, USA) we helped to establish a role for neuropilin-1 in the immune system and in collaboration with Prof Tsirka we demonstrated the involvement of the TGFbeta pathway. We also demonstrated that blockade of neuropilin-1 could be an effective strategy against gliomas in mice. We obtained >£1m funding from biotech and developed effective small molecule inhibitors of this protein. |
| Collaborator Contribution | Research |
| Impact | Powell J, Mota F, Steadman D,.Selwood DL. Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFß) Production in Regulatory T-Cells. J Med Chem. 2018 May 10;61(9):4135-4154. The design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists have been reported. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFß production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies. We showed that NRP1 antagonists could regulate the activity of Treg cells. |
| Start Year | 2017 |
| Description | Noncovalent Interactions of p Systems with Sulfur |
| Organisation | University of Southampton |
| Department | Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The relative strength of noncovalent interactions between a thioether sulfur atom and various p systems in designed top pan molecular balances was determined by NMR spectroscopy. Compared to its oxygen counterpart, the sulfur atom displays a remarkable ability to interact with almost equal facility over the entire range of p systems studied, with the simple alkene emerging as the most powerful partner. With the exception of the O···heteroarene interaction, all noncovalent interactions of sulfur with p systems are favoured over oxygen. |
| Collaborator Contribution | Experimental structure determinations in the solid state were carried by our partners Dr. G.J.Tizzard and Prof. S. J. Coles from School of Chemistry, University of Southampton. |
| Impact | Publication at http://onlinelibrary.wiley.com/wol1/doi/10.1002/anie.201708485/abstract |
| Start Year | 2017 |
| Description | Organic and Perovskite Solar Cells (Bob Schroeder, UCL) |
| Organisation | King Abdullah University of Science and Technology (KAUST) |
| Country | Saudi Arabia |
| Sector | Academic/University |
| PI Contribution | A research collaboration, which has led to a recent publication in Chemistry of Materials, titled "A Nonionic Alcohol Soluble Polymer Cathode Interlayer Enables Efficient Organic and Perovskite Solar Cells" (DOI 10.1021/acs.chemmater.1c01430). |
| Collaborator Contribution | Preparation of samples for structural characterisation. Interlayer materials were studied for organic solar cells. |
| Impact | Publication DOI 10.1021/acs.chemmater.1c01430 |
| Start Year | 2020 |
| Description | Peptide ligation in water (Matt Powner) |
| Organisation | Simons Foundation |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | Amide bond formation is one of the most important reactions in both chemistry and biology. In 2007, the ACS Green Chemistry Institute voted 'amide formation avoiding poor atom economy reagents' as the top challenge for organic chemistry; this remains an unmet challenge. The universal genetic code establishes that the biological role of peptides predates Life's last universal common ancestor and that peptides played an essential role in the origins of life on Earth. Prof. M Powner (Chemistry, UCL) and his group have demonstrated the facile, selective and iterative coupling to a-aminonitriles in water to make peptide bonds. The unique reactivity of a-aminonitriles provides a direct link between the canonical peptide structures of biology and prebiotic synthesis. Traceless sulfide-mediated peptide ligation has been applied to the coupling reactions of all amino acid residues, with remarkably selective coupling in all cases. It was shown that the unique reactivity a-aminonitriles makes them singularly well-suited to (protecting-group-free) ligation at neutral pH. |
| Collaborator Contribution | Simons Foundation has contributed £120k towards the 700MHz NMR facility used by Prof. M Powner (Chemistry, UCL) and his group in their research. |
| Impact | Publication in Nature: Canavelli, P., Islam, S., Powner, M.W. Peptide ligation by chemoselective aminonitrile coupling in water. Nature, 571, 546-549 (2019). doi:10.1038/s41586-019-1371-4. |
| Start Year | 2017 |
| Description | Precursor design to develop new compounds for use in thin film growth (Carmalt and Parkin) |
| Organisation | Pilkington Glass |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Prof Claire Carmalt and Prof Ivan Parkin (Chemistry, UCL) are involved in investigating precursor design to develop new compounds for use in thin-film growth (Impact Acceleration Account award to UCL 2017-20, EP/R511638/1 and for grant EP/L017709) |
| Collaborator Contribution | The partners provide research placements for our students and analysis of the thin films which we deposit. They are also involved in technical meetings with us and the students and provide advice on scale up. They are currently funding 4 EngD or PhD studentships and each studentship has a confidentiality agreement |
| Impact | The UCL 700MHz NMR facility allowed for a detailed characterisation of a ZnO precursor and information of the structure of the compound formed. |
| Start Year | 2017 |
| Description | Tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass (Helen Hailes) |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | Professor Helen Hailes (Department of Chemistry, UCL), Professor Tom Sheppard (Department of Chemistry, UCL), Dr Gary Lye (Biochemical Engineering, UCL) and Dr Christopher J. Tame (GSK) are involved in this collaboration. For details, see the following publication: L. Benhamou, R. W. Foster, D. P. Ward, K. Wheelhouse, L. Sloan, C. J. Tame, D.-K. Bucar, G. J. Lye, H. C. Hailes, T. D. Sheppard, 'Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass', Green Chem., 2019, 21, 2035-2042. For this publication, the facility was invaluable in characterizing the products generated from biomass-derived starting materials. Selective dehydrations of pentose sugars were achieved under basic or acidic conditions, and the equipment allowed NMR reaction monitoring and the ability to distinguish between the isomeric products formed. Fragments for medicinal chemistry applications containing primary alcohol, ketone, carboxylic acid or amine functional groups were generated, suitable for incorporation into fragment/lead libraries. Funding EPSRC (EP/K503745/1) and building upon outputs from EP/K014897. |
| Collaborator Contribution | GSK and AstraZeneca have added the samples of the chiral fragments prepared by Professor Helen Hailes (Department of Chemistry, UCL), Professor Tom Sheppard (Department of Chemistry, UCL) and Dr Gary Lye (Biochemical Engineering, UCL) for use in their fragment libraries. For further details, see the following publication: L. Benhamou, R. W. Foster, D. P. Ward, K. Wheelhouse, L. Sloan, C. J. Tame, D.-K. Bucar, G. J. Lye, H. C. Hailes, T. D. Sheppard, 'Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass', Green Chem., 2019, 21, 2035-2042. |
| Impact | Joint publication in Green Chemistry: L. Benhamou, R. W. Foster, D. P. Ward, K. Wheelhouse, L. Sloan, C. J. Tame, D.-K. Bucar, G. J. Lye, H. C. Hailes, T. D. Sheppard, 'Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass', Green Chem., 2019, 21, 2035-2042. |
| Start Year | 2017 |
| Description | Tin chemical shift anisotropy in tin dioxide |
| Organisation | Rutherford Appleton Laboratory |
| Department | Scientific Computing Department |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Experimental NMR measurements of 119Sn and 31P NMR powder lineshapes using 300 MHz and 700 MHz NMR facilities. |
| Collaborator Contribution | Computational predictions of NMR chemical shift anisotropy |
| Impact | Publication at https://www.sciencedirect.com/science/article/pii/S0926204017301303?via%3Dihub#! |
| Start Year | 2017 |
| Description | Tin chemical shift anisotropy in tin dioxide |
| Organisation | University of Oxford |
| Department | Department of Materials |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experimental NMR measurements of 119Sn and 31P NMR powder lineshapes using 300 MHz and 700 MHz NMR facilities. |
| Collaborator Contribution | Computational predictions of NMR chemical shift anisotropy |
| Impact | Publication at https://www.sciencedirect.com/science/article/pii/S0926204017301303?via%3Dihub#! |
| Start Year | 2017 |
| Description | A visit and spectra for The King Fahad Academy Bromyard Avenue London |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A visit took place on 31 October 2017, during which the NMR equipment including the new 700 MHz NMR was demonstrated. This was followed by measurements of NMR spectra for the student projects (Extended Essay in Chemistry). |
| Year(s) Of Engagement Activity | 2017 |
| Description | NMR visits for schools |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | The new equipment was demonstrated to school pupils visiting UCL Chemistry on the Spectroscopy Day in September 2017 and in April 2018. |
| Year(s) Of Engagement Activity | 2017,2018,2019 |
| URL | https://www.ucl.ac.uk/chemistry/schools/schools-programme |
| Description | Provision of NMR service to users from Industry and Academia |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Postgraduate students |
| Results and Impact | Users from other UCL departments and other UK universities visited the facility. Spectra were recorded on the new facility for users from other universities, as well as from industrial companies. We have run NMR spectra for such companies as Abcam Plc (Cambridge), Byotrol, Darr House, Gurit, Key Organics. Researchers from Birkbeck College and Westminster University, as well as from various UCL departments, including Dementia Research Centre, Chemical Engineering, Eastman Dental Institute, Royal Free Hospital, have used the facility on the regular basis. |
| Year(s) Of Engagement Activity | 2017,2018,2019,2020,2021,2022 |