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.

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.

Publications

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Description Many research groups from UCL and other UK academic and industrial organisations have already made use of the multinuclear 700 MHz NMR facility at UCL/Chemistry. It is likely that the research carried out by these groups will lead to significant developments supported by patents. As an example, verification of the identity of compounds on the 700 MHz NMR was carried out on a confidential basis for a commercial company. This is expected to support a patent application process, provided that any of the compounds that have been analysed at UCL demonstrate a useful level of biological activity as a starting point in the herbicide/fungicide/insecticide sphere. We have also run over 560 NMR spectra for Abcam Plc (Cambridge) between November 2017 and March 2021. The 19F NMR capability of the facility was used by researchers from Key Organics, as well as from UCL School of Pharmacy. Since July 2017, the facility has been used by users from the UCL Dementia Research Centre on a regular basis, which focuses on clinical research into various forms of dementia. The instrument was also used for Covid-19 related research in 2020 by researchers from Prof G Bataglia (UCL Chemistry) and Prof D Delwood (UCL Wolfson Institute) groups.

The new facility was also used for training new users. In particular, 118 and 116 new users were trained in 2017/18 and 2018/19. Between May 2019 - February 2020, we trained 124 new users.

Covid Impact: COVID-19 has significantly reduced the laboratory output of the research groups in 2020/21 reducing the average time each researcher can access the lab and NMR instruments, by approximately 50% due to social distancing constraints in UCL laboratories and the weekly cohort system introduced in June 2020. Following the first lockdown in Mar-May 2020, a new access system to the NMR instruments, including preliminary online booking, was implemented in Jun 2020, where selected users (90 in Mar 2021) from each research group place samples in sample changers of our NMRs, including the 700MHz instrument, and their group members, including new NMR users, remotely access the spectrometer PCs to submit and queue NMR experiments. Remarkably, having remote access to the NMR instruments have resulted in a significant increase in the number of spectra run by our researchers over the recent months despite the weekly cohort system. In particular, for the period of 1 Nov 2020 - 31 Jan 2021, the number of spectra run on the 700MHz instrument increased by 32% compared to the same period a year ago.

The most significant achievement from the award is that our researchers from UCL and outside are provided with easy and immediate access to the multinuclear 700 MHz NMR facility with a broadband cryoprobe. Access to such a spectrometer with diverse capabilities facilitates and enhances the structural research by our users. Below we list some of the research subject areas and findings, which were received in response to our request to contribute to this report (last updated in March 2021):

Prof Matthew Powner (Department of Chemistry, UCL, co-applicant in the EPSRC application for the multinuclear 700 MHz NMR facility):
1. We have discovered a chemoselective peptide ligation in water (see Canavelli et al. Nature, 2019). By exploiting aminonitiriles we have discovered a highly robust mechanism to access thioacids, thioester and their facile and selective coupling to a-aminonitriles in water. Two essential features enable peptide ligation in water: the reactivity and pKaH of a-aminonitriles make them compatible with ligation at neutral pH and N-acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. The unique reactivity of a-aminonitriles provides a direct link between canonical peptide structures of biology and prebiotic synthesis. All amino acids and their derivatives were coupled in good-to-excellent yields. We observed unprecedented protecting-group-free ligation for all 20 proteinogenic side-chain residues-including His, Asp, Lys, Cys, Ser, Thr and Tyr, which are all essential to enzyme catalysis but notoriously difficult to ligate under previously reported prebiotic conditions. Interestingly, although we observed poor selectivity for a-coupling of amino acid lysine (1.2:1 a/e) and amino acid amide lysinamide (2.7:1 a/e), lysine nitrile ligated with exceptional a-selectivity (>80:1 a/e). The intermolecular coupling of aminonitriles is also observed to outcompete lysine thioacid lactamization across a broad pH range to give Ac-a-Lys-Gly-CN. The chemoselective coupling of lysine residues at both the C and N termini of peptides underscores that aminonitrile ligation is not only prebiotically plausible, but that it is also predisposed to yield a-peptides.
2. 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). Aminonitriles are generally readily produced by Strecker reactions, but the origin of cysteine-the thiol-bearing amino acid-was not understood. The aminothiol moiety of cysteine is chemically incompatible with nitriles at physiological pH, and it is widely believed that cysteine was a biological invention and a late addition to the genetic code. The importance of cysteine (and its derivatives, such as co-enzyme A) is directly at odds with the prevailing hypothesis which assumes its absence at the origin of life. Cysteine is the primary organic source of sulfide in biology. It is also an important residue within enzyme active sites, with key functions in catalysis and electron transfer, as well as being essential in iron-sulfur proteins and forming inter- and intrapeptide crosslinks. It, therefore, seems almost inconceivable that cysteinyl thiols were not present during the development of nascent biology, and yet this is not the prevailing view. We have now shown that cysteine is a product of simple prebiotic chemistry. This chemistry had remained undiscovered, because the origins of life researchers have focused on amino acid synthesis and ligation, rather than aminonitrile chemistry. Our discovery supports the hypothesis that cysteine was simply a secondary product of serine chemistry at the origins of life (as it is today in biology - as a part of 'the serine family' of amino acids).
3. 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). Thiol-catalysed peptide ligations are remarkably specific and selective to proteinogenic peptide synthesis. For example, the reaction of Ac-Gly-CN and Ac-ß-Ala-CN (1:1; 200 mM) with Gly (200 mM) and Ac-Cys-OH (30 mol%) results in exclusive a-amidonitrile coupling to furnish Ac-GlyN-Gly-OH (65%) with no detectable beta-coupling of Ac-ß-Ala-CN. We also observed only a-ligation upon challenging our catalytic ligation with N-acetylglutamine dinitrile. Finally, we only observed coupling of proteinogenic Ala in competition with a,a-disubstituted (non-proteinogenic amino acid) Aib. The observed selectivity may have been a key element in the emergence of proteinogenic a-peptides in extant biology. Thiol-catalysed coupling of a-amidonitriles with a-amino acids is highly general; all proteinogenic a-amino acids coupled with Ac-Gly-CN to give peptidyl amidines in good yields at pH 7. However, we observed that dipeptides derived from Ser, Thr and Asn underwent pronounced amidine hydrolysis (at pH 7) to the corresponding peptides. In the reactions of Ser and Thr, we observed oxazoline intermediates, suggesting that intramolecular catalysis by the amino acid side chain was responsible for rapid amidine hydrolysis. Having observed that the peptidyl amidine derived from Asn hydrolysed, we envisaged that amino amides (and therefore peptides) would behave similarly. We next demonstrated amides intramolecularly catalysed amidine hydrolysis by coupling the proteinogenic amino amides, resulting in selective dipeptide synthesis, irrespective of their side chain. Therefore, thiol-catalysis can be used to streamline (prebiotic) peptide fragment ligations, side-stepping the stoichiometric formation of thioacids and instead directly couple peptide-nitrile fragments. To test this novel catalytic-fragment ligation we coupled glycyl peptide nitriles with various peptides observed excellent yields of peptides. It is remarkable that a single amino acid residue, cysteine, provides robust catalysis for peptide ligation in water and their inherent catalytic activity makes simple cysteinyl peptides an excellent starting point from which to evolve more complex enzymes and protometabolic reactions in an abiotic environment. Our data support a scenario in which nitriles served as an early energy currency on the primordial Earth, perhaps acting as a forerunner to ATP and thioesters that drive reactions in extant biology.
4. 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.
5. 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). The generational simplicity of accessing arabino-nucleosides suggests that ANA may have played a key role in primordial nucleic acids prior to or during the emergence of RNA. We collaborated with Dimitar Sasselov (Harvard Astronomy) and Rafal Szabla (Edinburgh Chemistry) to understand the mechanism of our novel purine photo-reduction, and uncovered the chemical mechanism that favours the reduction of canonical nucleosides A and G, but the photochemical destruction of non-canonical inosine (I). Photochemical selection is observed in both ribo- and arabino-stereochemistries and provides a chemical selection for the canonical nucleosides over non-canonical inosine.
6. We have developed methods for the photochemical selection of nucleotide stereochemistry, which lead to a novel synthesis of Watson-Crick base pairing TNA nucleoside that are punitive evolutionary precursors to RNA. (See Colville and Powner under peer review 2021).
7. 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. We have now developed this work further to realise acetylation controlled nucleotide photoanomerisation.
8. We have demonstrated that N-phospho-aminonitriles can not only be highly efficiently synthesised in neutral water but the neutral phosphorostrecker reaction provides excellent selectivity for a proteinogenic amino acid over non-natural a,a-disubstituted amino nitrile (see Ashe et al in Nature - Communications Chemistry, 2019).
9. 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).
Access to UCL high-field NMR has been fundamental to all our advances.

Prof David Selwood (Wolfson Institute for Biomedical Research, UCL):
1. Cancers hide (cloak) themselves from immune system attack by several means. The new chemicals described by us block one of these cloaking mechanisms and reveal the tumour to the immune system. This establishes a new way to treat tumours. The key finding is that the immune response of regulatory T-cells can be affected by a small molecule antagonist of the neuropilin-1 protein. The discovery of this antagonist (EG01377) is described in our paper titled "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".
2. Inhibitors of lentiviral innate defence mechanisms in human stems cells were discovered. Transiently blocking these defences greatly enhances the efficiency of gene transfer into stem cells. This work will have a major impact on gene therapy for rare bloodborne diseases. The 700MHz NMR offers precise and high definition assessment of the structures of the complex natural products such as depsipeptides which are used for these new therapies.
3. PROTACs, with potential as new antiviral therapies were discovered. These molecules are organic chemistry constructs with bivalent protein binding activity allowing selective chemical knockdown of host intracellular proteins. Part of this work was published in eLife in 2020.

Dr Hien Nguyen (City University): We have developed a range of novel low cost, portable and selective fibre optic chemical sensors for the detection of drugs and heavy metals. The use of the NMR facility at UCL is essential in the organic synthesis stage where various novel fluorescent receptors have been developed and used as the sensing materials for the sensors. Two papers have been published in 2019/20, titled "Novel coumarin-based pH-sensitive fluorescent probes for the highly alkaline pH region" and "A Turn-On Fluorescence-Based Fibre Optic Sensor for the Detection of Mercury".

Dr Vijay Chudasama (Department of Chemistry, UCL): The use of the UCL 700MHz NMR facility was paramount in helping us elucidate the structure of two different tautomers of a medicinally important heterocycle - indazole. This was the key finding during the development of synthesis for both indazole tautomers through the use of a single branch point intermediate. We were able to develop the efficient formation of 1H- and 2H- indazoles from a single branch point intermediate. The UCL 700MHz NMR facility was also used to characterise the structure of all the analogues formed through this method.

Drs Hannah Woodward, Dr Ben Atkinson and David Steadman (Alzheimer's Research UK UCL Drug Discovery Institute): We regularly use the 700 MHz and other NMR instruments at UCL Chemistry to obtain high-resolution NMR spectra. This allows us to fully characterise all of the small molecules that we synthesise in our research projects, which are aimed at finding modulators of targets implicated in the progression of Alzheimer's or other neurodegenerative diseases. As an example, a new efficient chiral synthesis of enantiopure arimoclomol was reported recently. This arimoclomol has progressed to human clinical studies for evaluation as a potential treatment for SOD1 (superoxide dismutase 1 gene) positive familial amyotrophic lateral sclerosis (ALS). Off-target pharmacology was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data were generated in vivo in mouse and showed a low brain : plasma ratio. The reported pharmacology and pharmacokinetic studies will be helpful in gaining a better understanding of the pharmacokinetic-pharmacodynamic relationship of arimoclomol in disease models. Overall, our research projects are aimed at finding small molecule modulators of targets implicated in the progression of Alzheimer's or other neurodegenerative diseases. We have submitted a patent application which has compounds that were characterised on the 700 as well as a research paper which is currently under review with Med. Chem. Comm. journal of the Royal Society of Chemistry. Tool compounds for use in neurodegenerative research and compounds for use as inhibitors of key targets for the treatment of neurodegenerative diseases were discovered recently.

Dr Salvador Tomas (Department of Biological Sciences, Birkbeck College): By allowing the careful characterization of the relevant molecular tools and the analysis of self-assembly, data gathered using the UCL NMR facility has enabled us to (i) develop a mathematical model of cooperative assembly in supramolecular polymers; (ii) carry out the detailed study of chemical reactivity in lipid vesicles, and (iii) develop a mathematical model of membrane adhesion. The UCL NMR facility helped us to characterise the cooperativity in self-assembly described in our publication.

Prof Erik Arstad, Dr Thibault Gendon and Dr Michael Porter (Institute of Nuclear Medicine, UCL and Department of Chemistry, UCL): The 700 MHz NMR facility together with other NMRs at UCL Chemistry is used in our research daily as part of our research on aromatic radiofluorination. In addition to routine analysis, the NMR spectrometers were used to elucidate reaction mechanisms and predict the outcome of the radiofluorination reactions. In particular, the 700 MHz NMR was used to confirm the structure of complex molecules, which otherwise is difficult to analyse with the other instruments. We have shown that the efficiency of aromatic radiofluorination using dibenzothiophene sulfonium salts is correlated with the 19F NMR chemical shift of the non-radioactive fluorinated reference. Recently, we have reported a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [18F]fluoride to give [18F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labelling efficiency for clinically relevant Positron Emission Tomography (PET) tracers.

Dr Michael Porter (Department of Chemistry, UCL): We have developed novel organic transformation. The 700 MHz NMR has been valuable in identifying and quantifying the products from (i) a novel electrochemical trifluoromethylation and (ii) a novel oxidative cyclisation of homopropargylic sulfonamides.

Prof Claire Carmalt and Dr Caroline Knapp (Department of Chemistry, UCL): Our NMR studies, including variable-temperature measurements, have focused on gallium alkoxides (please see our recently published paper titled "Structural and Dynamic Properties of Gallium Alkoxides", DOI: 10.1021/acs.inorgchem.9b01496). These are useful as precursors to gallium oxide, which in turn is used in the formation of amorphous oxide semiconductors employed in thin-film photovoltaic devices, as well as in the development of processes towards sustainable high quality transparent conducting oxide (TCO) films and gas sensing materials. The NMR spectra of chloro gallium bis(alkoxides) were found to vary with the nature of the ligand and the temperature and allowed to establish the dynamics of the molecules studied.

Prof Helen Hailes (Department of Chemistry, UCL):
1. For the publication "Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass", the facility was invaluable in characterizing the products generated from biomass-derived starting materials. Selective dehydration of pentose sugars was 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.
2. For the publication 'A Biomimetic Phosphate Catalyzed Pictet-Spengler Reaction for the Synthesis of 1,1'-Disubstituted and Spiro-Tetrahydroisoquinoline Alkaloids', the facility was invaluable for reaction monitoring as the products are readily oxidized, hygroscopic and difficult to purify. In this work, a range of novel 1,1'-disubstituted and spiro-tetrahydroisoquinoline alkaloids were readily prepared in one-step and good yields, via this atom-efficient, sustainable synthetic route. Funding BBRSC (BB/N01877X/1).
3. For the publication 'Ene-reductases from a drain metagenome for the selective bioreduction of bicyclic enones', the 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.
4. For the publication 'Acceptance and Kinetic Resolution of Alpha-Methyl-Substituted Aldehydes by Norcoclaurine Synthases', we have reported the unusual acceptance of alpha-substituted aldehydes, by wild-type Thalictrum flavum Norcoclaurine Synthases to give tetrahydroisoquinoline products. Moreover, the kinetic resolution of several alpha-substituted aldehydes to give tetrahydroisoquinolines with two defined chiral centres in a single step with high conversions was achieved. Active site-mutants of Thalictrum flavum Norcoclaurine Synthases were then used which demonstrated the potential to enhance the stereoselectivities in the reaction and improve yields. Funding BBRSC (BB/N01877X/1).
5.For the publication 'Identification and catalytic properties of new epoxide hydrolases from the genomic data of soil bacteria', the facility was invaluable in characterizing the products generated by the epoxide hydrolases identified. New epoxide hydrolases for use in synthesis were discovered and their stereoselectivities were studied. Funding Wellcome Trust [grant number: 108877/Z/15/Z], BBSRC [grant number: BB/L007444/1]. Collaboration: J. Ward, Biochem Eng UCL.
6. For the publication 'Carprofen elicits pleiotropic mechanisms of bactericidal action with the potential to reverse antimicrobial drug resistance in tuberculosis', the facility was invaluable for product characterisation. In this work, Carprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen's anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice and this immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations. In summary. new anti-mycobacterial drugs were discovered and studied. Funding the Wellcome Trust (grant code: 108877/Z/15/Z), the BSAC (grant code: bsac-2019-0030) and PreDiCT-TB consortium (http://www.predict-tb.eu) funded by the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu; grant agreement number: 115337), resources of which were composed of financial contribution from the European Union's Seventh Framework Programme (grant code: FP7/2007-2013) and EFPIA companies' in-kind contribution. Collaboration: S. Bhakta, Birkbeck College, London.
7. For the publication 'Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases', the facility was essential for product characterisation. In this work, benzaldehydes were explored as substrates and found to be accepted by both wild-type and mutant constructs of norcoclaurine synthase (NCS). In particular, the variant M97V gave a range of (1S)-aryl-THIQs in high yields (48-99%) and e.e.s (79-95%). A co-crystallised structure of the M97V variant with an active site reaction intermediate analogue was also obtained with the ligand in a pre-cyclisation conformation, consistent with (1S)-THIQs formation. Selected THIQs were then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrated valuable biocatalytic approaches to a range of (1S)-THIQs. Funding BBRSC; BB/N01877X/1 for D.M.-S. and BB/R021643/1 and 17-ERACoBioTech for F.S. and Wellcome Trust (096626/Z/11/Z) for B.R.L. Collaboration: J. Ward in Biochem Eng UCL, Nick Keep in Birkbeck, Jenny Andexer at the University of Freiburg and Michael Richter at the Fraunhofer Institute.
8. For the publication 'Norcoclaurine Synthase Mediated Stereoselective Synthesis of 1,1'-Disubstituted, Spiro- and Bis-Tetrahydroisoquinoline Alkaloids', we discovered that wild-type NCS and selected variants can be used with aliphatic, cyclic, a-substituted cyclic, heterocyclic, and bicyclic ketones to access challenging non-natural tetrahydroisoquinoline alkaloids (THIAs). We found that fused bicyclic ketones as well as diketones could also be accepted by some of the NCS variants, and in silico modelling was used to provide insights into the rationale for this. Funding BBRSC (BB/N01877X/1) a UCL Dean's Prize and UCL-China Scholarship Council Joint Research Scholarship to J. Z., and a Birkbeck Anniversary PhD scholarship to R.R as part of the London Interdisciplinary Doctoral Program. Collaboration: Dr N. Keep Birkbeck College, J. Ward Biochem Eng, UCL.

Prof Tom Sheppard (Department of Chemistry, UCL):
1. The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds is greatly facilitated by the use of 11B NMR. However, the identification and characterization of reaction intermediates in often complex systems is far from trivial, as 11B NMR does not provide any detailed structural information. 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. We have reported a rapid and accessible approach to the calculation of 11B NMR shifts that is applicable to a wide range of organoboron compounds.
2. We have shown how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo-propargylic alcohols provides a useful route to 3-halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. A novel ring expansion of propargylic alcohols containing a cyclopropylalkyne is shown to provide access to halogenated alkenyl-cyclobutanes.
3. In 2021, we 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)) also led to funding for a 3-year collaborative PDRA with AstraZeneca
4. We have carried out a detailed study of directing group effects in Pd-catalysed C-H activation reactions of aliphatic amines in collaboration with AstraZeneca. This work made extensive use of the 700 MHz NMR for structure determination of often-complex products (publication 10.1002/adsc.202000726). This work led to further funding for a 3-year PDRA collaboration with AstraZeneca.
5. Collaboration also with Prof Matt Powner on prebiotic amidation (publication Foden CS, Islam S, Fernández-García C, Maugeri L, Sheppard TD, Powner MW. (2020). Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water. Science (New York, N.Y.), 370 (6518), pp. 865-869)

Prof Alethea Tabor (Department of Chemistry, UCL):
1. We have used the 700 MHz NMR machine to continue her studies on the folding and biological activity of the tarantula toxin ProTx-II. This is an inhibitory cystine knot (ICK) peptide that shows highly selective and potent binding to the Nav1.7 ion channel and hence is an important lead for the treatment of chronic pain. In recent work her group have developed methods for preparing analogues of ProTx-II that can be derivatised with biotin or fluorophores, or with photoactivatible groups, to probe the binding of ProTx-II to Nav1.7, and they have used 700 MHz NMR to demonstrate whether the resulting peptides are correctly folded.
2. The 700 MHz NMR machine was also used to develop new techniques to characterise the surface functionalisation of semiconducting polymer nanoparticles (SNP). These SNP are being developed as novel contrast agents for photoacoustic and near infra-red imaging of tumours, which will allow for precision image-guided surgery of cancer patients. We are pioneering the use of surface-modified SNP that have n-ethylene glycol coatings (to prolong circulation in vivo) and peptide epitopes targeted to cell surface receptors, such as EGFR, that are overexpressed on certain cancer cells. Mass spectrometry and TEM techniques cannot give accurate quantitation of whether the surface functionalisation is complete: however, using the 700 MHz NMR we have been able to follow the progress of the reactions and optimise the surface functionalisation. The results will be published soon when photoacoustic measurements and in vitro cell assays are complete.

Dr Gareth Williams and Karolina Dziemidowicz, PhD Candidate (School of Pharmacy, UCL): The 700MHz NMR facility, including its 19F NMR capability, was used in our project titled "Perfluorophenyl azide functionalisation of biodegradable polymers". This project focuses on the surface modification of electrospun polycaprolactone fibres to enable therapeutic protein delivery.

Dr Mukhlesur Rahman (School of Health, Sports and Bioscience, University of East London; Currently in Liverpool John Moores University): Have discovered terpenes with potential antibacterial activity against a series of clinical isolates of multi-drug resistant and methicillin resistant staphylococcus aureus. The structures of compounds were established using the analysis of one-dimensional and two-dimensional NMR data and mass spectra.

Prof Ipsita Roy and Dr Pooja Bassnet (Department of Life Science, University of Westminster): We have used the 700MHz NMR facility for the research project involving the production of a family of biodegradable polymers such as polyhydroxyalkanoates (PHAs). PHAs are produced by a range of bacterial species using fermentation technology. We use NMR to identify the structure of the PHAs produced. The monomeric composition of PHAs is affected by the type of carbon substrate and the media composition. PHAs are used for a range of medical applications such as medical device development (coronary artery stents, nerve conduits, wound healing patches), as tissue engineering scaffolds in Regenerative Medicine and controlled drug delivery.

Fane F. K. Mensah, PhD Candidate, and Prof Geraldine Cambridge (Division of Medicine, Centre of Rheumatology Research, UCL): CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). We have reported the results of our investigations of the relationship between CD24 expression and B cell maturation. The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was investigated using the 700MHz NMR facility at UCL Chemistry. Currently, there is a manuscript under preparation in which we describe changes in an additional 26 metabolites using the spectral data obtained on the 700MHz NMR facility at UCL Chemistry. In both studies, we used the 700 MHz NMR to study the metabolic processes that occur during B cell maturation upon in vitro stimulation by measuring the relative levels of different metabolites present in the culture medium. For the first time, we have been able to follow changes in metabolite concentrations as well as changes in B cell phenotypes throughout in vitro B cell culture. This has not been done before and the developed assay can be used to test interventions during culture to follow changes in metabolite consumption and secretion, specific for B cells.

Prof Junwang Tang and Dr Christopher Windle (Department of Chemical Engineering, UCL): We have discovered a new catalyst for the selective oxidation of methane. Two papers have been published: "Covalent grafting of molecular catalysts on C3NxHy as robust, efficient and well-defined photocatalysts for solar fuel synthesis" and "Rational Design of High-Concentration Ti3+ in Porous Carbon-Rich TiOx Nanosheets for Highly-Efficiency Photocatalytic Ammonia Synthesis".

Dr Stefan Guldin (Department of Chemical Engineering, UCL): For the publication "Fractionation of block copolymers for pore size control and reduced dispersity in mesoporous inorganic thin films", our findings are relevant to mesoporous inorganic thin films, which are promising materials for a variety of applications, including sensing, catalysis, protective coatings, energy generation and storage. In many cases, precise control over a bicontinuous porous network on the 10 nm length scale is crucial for their operation. A particularly promising route for structure formation utilizes block copolymer (BCP) micelles in solution. We have shown how chromatographic fractionation of BCPs provides a powerful method to control the pore size and dispersity of the resulting mesoporous thin films. The 700 MHz NMR facility at UCL Chemistry was used for structural studies in this work.

Prof Ivan Parkin and Cláudio Lourenco, PhD Candidate (Department of Chemistry, UCL): The aim of our project is to investigate active components of peroxide- and ROS-based antimicrobial systems which promote cleaning and antimicrobial effects (ROS = Reactive Oxygen Species). NMR studies are crucial for the determination of the stoichiometry of chemical reactions under different atmospheric conditions and concentrations. We also aim at developing new analytical methods for investigating how different reactant chemicals interact with components of biofilms and biofouling. Improved, novel chemistries would have a widespread application in a range of disinfectant applications. On a different project, we have already used the 700MHz facility to determine the authenticity of different glue samples.

Prof Ivan Parkin and Georgia Fleet, PhD Candidate (Department of Chemistry, UCL): A new method is being developed for analysing biofilm residues in collaboration with the Eastman dental hospital and GSK that uses the 700MHz NMR instrument.

Prof Chris Blackman (Department of Chemistry, UCL): A novel nickel dialkylaminoalkoxide precursor has been developed for chemical vapour deposition (CVD) of nickel oxide. A manuscript based on this work was recently submitted to Physica Status Solidi A.

Prof Gopinathan Sankar and Junwen Gu, PhD Candidate (Department of Chemistry, UCL): We investigate the mesoporous structure formation from commercial zeolite while maintaining the microporous character within the same crystal. Here the effect of pH (between 9 and 11) induced by the use of mild organic ammonium hydroxides and cetyltrimethylammonium bromide (CTAB) on the formation of mesostructures is of particular interest. The investigation also involves the determination of the effect of the Si/Al ratio of the starting zeolite Y on the mesostructure formation within the same pH range. The work also will investigate the creation of macroporous silicalite material resulting in macropores within silicalite crystals.

Dr Gemma Louise-Davis (Department of Chemistry, UCL). The 700 MHz NMR has been used in the following projects:
1. Preparation of metallasilsesquioxanes as novel precursors for MRI contrast agents. This project involves the development of new precursors in the development of high signal contrast agents for MRI. Utilising traditional inorganic synthetic chemistry techniques, complexes composed of Gd-chelates can be prepared as used in the development of nanostructured contrast agents with significantly higher signal than traditional molecular agents, whilst reducing the risk of metal leakage and dangers associated with this.
2. Development of hybrid organic-inorganic composites for diagnostic MRI contrast agents. Medical imaging agents capable of changing their signal profile in situ in the body could be exploited for non-invasive disease diagnostics, of value to clinical medicine. In this project, thermoresponsive polymer species are being developed which can respond to specific environmental markers. In combination with well-established high signal nanocomposite MRI contrast agents, these can hence provide a new route to contrast agents whose signal can be turned 'on' or 'off' in the presence of disease.
3. Targeted imaging agents using glycan chemistry. Bowel cancer is a highly prevalent disease that is often diagnosed at late stages due to lack of symptoms in the earlier, more treatable stages. As such, a route to early diagnosis of this disease is key to increasing survival rates. Current screening through colonoscopies uses diagnostic technician skills to observe and identify cancerous polyps, which are often difficult to distinguish from healthy polyps present in the bowel. This project aims to use sugar chemistry to develop a tool to assist with colonoscopic evaluations of polyps. Targeting of sugars released by cancerous polyps will be exploited to 'tag' these polyps with a high signal imaging agent which will aid easy diagnosis during colonoscopic examinations.

Dr Simoni Da Ros and Dr Katherine Curran (Bartlett School Env, Energy & Resources, Faculty of the Built Environment, UCL): In the project dealing with historic plastics of cultural heritage significance, it has been discovered that hydrolysis plays an important role in the degradation of cellulose acetate and cellulose nitrate materials, as observed by the reduction in the degree of substitution of reference materials which have been aged thermally. It has also been verified that plasticiser loss and cellulose acetate deacetylation are not independent processes and may impact each other. Such discoveries were only feasible due to the high sensitivity of the 700MHz instrument, which allowed to develop accurate methods for the determination of plasticiser content and degree of substitution. In summary, the analysis involving the UCL 700MHz NMR facility has supported the hypothesis that deacetylation plays an important role in the degradation processes of cellulose acetate historic plastics. Experiments have been carried out to determine the relationship between environmental variables such as storage temperature and relative humidity and the rate of deacetylation. Experiments have also been conducted to study the kinetics of plasticiser loss in different environments and data acquired using the NMR facility have supported the hypothesis that the loss of diethyl phthalate from cellulose acetate may be diffusion controlled. Within the Institute of Sustainable Heritage, the 700MHz instrument has supported two MRes, three 3 PhD and the ERC Starting Grant Complex projects, involving Isabella del Gaudio, Rose King, Mark Kearney, Simoni Da Ros and Argyro Gili. These projects involve collaborations with external UCL partners, such as Tate, Arkema, Getty Conservation Institute, Dow Chemicals Ltd, Museum of London and Lacerta Technology. Further details on the ERC Starting Grant COMPLEX project can be found here: https://www.ucl.ac.uk/bartlett/heritage/research/projects/current-projects/complex.

Dr Bob Schroeder and Lewis Cowen, PhD Candidate (Department of Chemistry, UCL):
1. Mechanism of Fluoride Doping of BDOPV Organic Semiconductor. Polymeric and molecular semiconductors based on benzodifurandione-based oligo(p-phenylene vinylene (BDOPV) have been shown to have high electron mobilities. Fluoride anions can be used as n-dopants, i.e. a means of introducing negative charge carriers on to BDOPV molecular semiconductors. The mechanisms by which these charges are introduced and the structure of the doped semiconductor are poorly understood. We use NMR experiments in conjunction with other spectroscopic techniques to probe the structural changes in BDOPV organic semiconductors induced by the introduction of n-doping fluoride anions. Both 1H and 19F NMR titrations of a fluoride anion source with organic semiconductor have given insight into the mechanism of doping in two different solvents. It was discovered that fluoride anions act as a base to deprotonate water in non-protic solvents and the resultant hydroxyl anions form a complex with the semiconductor. 700 MHz NMR was used to identify strongly hydrogen bonding phenol type protons in the 1H NMR. When carried out in the protic solvent chloroform, fluoride anions deprotonate the solvent and doping is quenched.
2. Quaternary Ammonium Moieties as n-Dopants for Organic Semiconductors. The 700 MHz NMR was used as part of a full spectroscopic characterisation of self-doping organic semiconductors. A combination of 1H, 13C and 2D NMR studies has allowed us to begin a structural characterisation of the doped species which has never been attempted before. We have now developed an understanding of what intramolecular reactions may be taking place. The structural data from the 700 MHz NMR combined with device performance data is helping us understand the optimum conditions for and the activation energy of doping.

Dr Jon Wilden (Department of Chemistry, UCL): The work in the Wilden group is focused on two main themes (i) new radical methodology including development and mechanistic aspects of transition metal-free reactions, and (ii) the development of novel peptidomimetics and biologically active molecules. The 700 MHz NMR was used for structure determinations and characterisations in the following research projects: 1) Kate Peck: Enamine Sulfonamide-Alkyne Cycloaddition Reactions; 2) Mark Radigois: Fundamental Studies on Electron Transfer Reactions (EPSRC PDRA EP/M02220X/1); 3) Theodore Hayes: A Novel Enediyne Synthesis from Alkynyl Sulfonamides via Non- Classical Carbenoids; 4) Yi Luo: Towards Understanding the Synthesis and Reactivity of Alkynyl Sulfonamides; 5) Ana-Miruna Androniciu: Synthesis of alpha-aminosulfonamide peptidomimetics. Recently, the 700MHz NMR was also used in the project titled "Electrochemical Reduction of Aerial O2 for Clean, Green, Allylic and Propargylic C-H Activation Reactions".

Prof Jim Anderson (Department of Chemistry, UCL):
1. For the publication "Investigation of the [1,5]-hydride shift as a route to nitro-Mannich cyclisations", more general conditions were found for the [1,5]-hydride shift nitro-Mannich reaction. Lewis acid Gd(OTf)3 catalysed conditions were shown to be more general and the reaction was found to be very sensitive to the stability of the intermediate iminium ion. The 700MHz NMR was used for the structural characterisation of reaction products.

2. For the publication "A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-14,15-Dehydrostrempeliopine", total synthesis of some complex natural products has been developed. The 700MHz NMR facility was instrumental in deciphering complex stereochemistry in small quantities of advanced intermediates when we were working out our synthetic route.

3. For the publication "Asymmetric synthesis of piperidines using the nitro-Mannich reaction", a diastereoselective nitro-Mannich reaction was employed to control the stereochemistry of functionalized piperidines containing 3 contiguous stereocentres in the 2-,3- and 4- positions. The high-resolution provided by the 700MHz NMR allowed full characterisation of various piperidines.

Dr Jamie Baker (Department of Chemistry, UCL): Albumin-drug conjugates and cysteine-to-lysine transfer antibody fragments were studied. Amongst other things, we have used the 700MHz NMR facility to probe the rates associated with new bioconjugation reactions. We have used these findings to develop reagents for the construction of next-generation protein conjugates, which allow the selective delivery of drugs (or detectable moieties for diagnostics) to target cells. The 700 MHz NMR was also used in one-pot thiol-amine bioconjugation to maleimides: simultaneous stabilisation and dual functionalisation. In the relevant publication (A. Wall, A. G. Wills, N. Forte, C. Bahou, L. Bonin, K. Nicholls, M. T. Ma, V. Chudasama*, J. R. Baker*, Chem. Sci., 2020, 11, 11455-11460), we have presented the first example of an alternative approach to maleimide-conjugate stabilisation, which also infers dual functionalisation in a one-pot fashion. We have applied this conjugation strategy to peptides and proteins to generate stabilised trifunctional conjugates.

Dr Cally Haynes (Department of Chemistry, UCL): The Haynes group has been using the 700MHz machine to acquire characterising data for challenging samples of molecules designed to exhibit switchable or controllable solubility. These samples included organic and metal-organic amphiphilic molecules with a tendency to undergo further self-assembly/ aggregation in solution. It was also used to obtain a full spectral characterisation of newly synthesised metal-organic amphiphiles. The title of the relevant project is 'Anion controlled assembly of metal-organic amphiphiles'. The expected long-term findings of this project will be of interest to diverse chemical research fields including supramolecular chemistry, inorganic materials, soft materials, drug delivery and catalysis.

Dr Stefan Howorka (Department of Chemistry, UCL): Insight into the structure and function of photosensitive chemical probes has been achieved via collaborations within UCL Chemistry (Tracey Clarke, Jon Wilden, Guiseppe Battaglia), within UCL (Stephan Beck, UCL Cancer), Cambridge (Hugo Bronstein, Shankar Balasubramanian). We have uncovered the relationship between BODIPY structure and spectroscopic properties to design fluorophores for bioimaging. We have also gained insight into the solvent-dependent photophysics of a red-shifted, biocompatible coumarin photocage. In addition, we have developed a photo-responsive small-molecule approach for the opto-epigenetic modulation of DNA methylation.

Dr Alistair Miller (Darr House): The analysis carried out on the 700MHz NMR allowed to develop collaboration with University of Exeter, leading to a PhD project titled "Authentication of compounds for screening for insecticidal activity."

Dr Will Travis (Gurit UK Ltd, Newport): The NMR spectra recorded on the 700MHz instrument helped develop materials for the composites industry with application in predominately wind turbine and marine industries. The work is still under development and is likely to reach the market later next year. The work has not resulted in academic publications and while patents are under draft they will not include the NMR data.

Dr Abil Aliev (Department of Chemistry, UCL, principal investigator in the EPSRC application for the multinuclear 700 MHz NMR facility):
1. The structure of a new compound, Cp(IPr)Ru(H)2SiH(Ph)Cl (IPr = 1,3-bis(2,6-diisopropylphenyl)-imidazole-2-ylidene) has been established using 1H, 13C and 29Si NMR chemical shifts and J couplings, as well as the X-ray structural analysis and DFT calculations. (in collaboration with Dr J. Saßmannshausen, The Francis Crick Institute).
2. We have used 300 MHz and 700 MHz NMR instruments to measure 119Sn chemical shift anisotropy (CSA) and have shown that a static powder pattern must be analysed in order to improve the accuracy of the CSA asymmetry measurements. (in collaboration with Dr A. Bartok, Rutherford Appleton Laboratory, and Prof J Yates, Department of Materials, University of Oxford).
3. Through detailed NMR measurements and their analysis, we have compared noncovalent interaction of sulfur and oxygen. It was found that compared to oxygen, the sulfur atom can interact with the almost equal facility over the entire range of pi systems studied. The results are important for understanding noncovalent interactions present in proteins (in collaboration with Prof Motherwell, Department of Chemistry, UCL, and Prof Coles. School of Chemistry, University of Southampton). An invited review was also published in 2019 in Chemistry - A European Journal of Chemistry.

In addition to those listed above, the 700 MHz NMR instrument has been used by:
Prof Andrea Sella (Department of Chemistry, UCL, in collaboration with researchers from Department of Physics, UCL)
Prof Charles Marson (Department of Chemistry, UCL)
Prof Giuseppe Battaglia (Department of Chemistry, UCL)
Dr Hugo Bronstein (Department of Chemistry, UCL)
Dr Kreso Bucar (Department of Chemistry, UCL)
Prof Xiao Guo (Department of Chemistry, UCL)
Dr Derek MacMillan (Department of Chemistry, UCL)
Dr Robert Palgrave (Department of Chemistry, UCL)
Prof William Motherwell (Department of Chemistry, UCL)
Dr Tung Chun Lee (Institute for Materials Discovery, UCL)
Prof Jonathan Knowles (Eastman Dental Institute, UCL)
Prof Kishor Gulabivala (Eastman Dental Institute, UCL)
Dr Elaine Allan (Eastman Dental Institute, UCL)
Dr Justin Warne (Division of Infection & Immunity, UCL)
Dr Kerstin Sander (Centre for Radiopharmaceutical Chemistry, UCL)
Dr Rose King (Institute of Sustainable Heritage, UCL)
Dr Stephen Hilton (School of Pharmacy, UCL)
Dr Matthew Todd (School of Pharmacy, UCL)
Dr Philip Lowden (Birkbeck College)
PDRA Dr Islam Saidul (Department of Chemistry, UCL)
PDRA Dr Daniel Whitaker (Department of Chemistry, UCL)
PDRA Dr Christian Fernández-García (Department of Chemistry, UCL)
PDRA Dr Laure Benhamou (Department of Chemistry, UCL)
PDRA Dr Thibault Gendron (Department of Chemistry, UCL)
PDRA Dr Dana Chan (Department of Chemistry, UCL)
PDRA Dr Fabien Thoreau (Department of Chemistry, UCL)
PDRA Dr Fatih Sirindil (Department of Chemistry, UCL)
PDRA Dr Yangwei Deng (Department of Chemistry, UCL)
PDRA Dr Robert James Smith (Wolfson Institute, UCL)
PDRA Dr Ben Graham (Wolfson Institute, UCL)
PDRA Dr Suresh Moorthy (Institute for Materials Discovery, UCL)
PDRA Dr Fahima Idiris (School of Pharmacy, UCL)
PDRA Dr Ben Woods (Birkbeck College)
PhD Candidate Cristina Perez Rivero (University of Westminster)
PhD Candidate Yakub Naheem (Royal Free Hospital, UCL)
PhD Candidates Ankan Biswas and Sara Malferrari (Royal Free Hospital, UCL)
PhD Candidate Zalike Keskin Erdogan (Eastman Dental Institute, UCL)
PhD Candidate Mohammad Aljaber (Eastman Dental Institute, UCL)
PhD Candidate Benjamin Bowles (School of Pharmacy, UCL)
Dr Rachel Platel (Lancaster University)
Dr Andrew Atkinson (Kings College)
Prof Eduardo Humeres (Federal University of Santa Catarina, Brazil)
Dr. Fabiola Sciscione (Royal Free Hospital, UCL)
Prof Craig Butts and PhD Candidate Catherine McIntyre (Bristol University)
PhD Candidate Nazanin Owji (Eastman Dental Institute, UCL)
PhD Candidate Sarene Saw (Eastman Dental Institute, UCL)
Drs Louise-Anne Pilcher and John Wong (Abcam)
Dr Will Travis (Gurit UK)
Drs Daniel Dumas and Mrs Lorna Bankole (Key Organics Ltd)
PhD Candidate Prachi Dubey (University of Westminster)
PhD Candidate Lorena Lizarraga (University of Westminster)
PhD Candidate Chivu Alexandru (Royal Free Hospital, UCL)
PhD Candidate Huang He (Chemical Engineering, UCL)
PhD Candidate Holly Siddique (School of Health, Sports and Bioscience, University of East London)
Dr Obeng Melody (Royal Free Hospital, UCL)
Dr James Sipthorp (Alzheimer's Research UK UCL Drug Discovery Institute)
Dr Elliott Bayle (Alzheimer's Research UK UCL Drug Discovery Institute)

and many others.
Exploitation Route Prof Matthew Powner (Department of Chemistry, UCL, co-applicant in the EPSRC application for the multinuclear 700 MHz NMR facility): Elucidating the chemical origins of life. Investigating the origins of Life on other planets (including Mars and current NASA missions of sample return), exploration of exoplanet atmosphere and astrochemistry, developing green chemical strategies to synthesis and catalysis in water. Overall, our findings are of interest to those involved in researching chemical origins of life, as well as pharmaceuticals and fine chemicals. Selective peptide ligations can be used more generally and more specifically for developing a model for the origins of life on Earth and the context of prebiotic chemistry on exo-planets.
Prof David Selwood (Wolfson Institute for Biomedical Research, UCL): Our findings described above could be developed into a new modality of anti-tumour treatment. The gene therapy enhancers could be licenced and used by pharma companies worldwide. Our new PROTAC discoveries could be developed as new antiviral therapies by industry.
Dr Hien Nguyen (City University): Through publications and commercialisation.
Dr Vijay Chudasama (Department of Chemistry, UCL): Our work has the potential to be used by medical groups who wish to synthesise analogues of heterocyclic-based bioactive compounds for testing. As the two tautomers are observed to have differing bioactive effects, the synthesis, therefore, gives easy access to a much larger range of potentially useful indazole analogues. We have developed several methodologies 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.
Drs Hannah Woodward, Dr Ben Atkinson and David Steadman (Alzheimer's Research UK UCL Drug Discovery Institute): The reported studies described above will contribute towards a better understanding of pharmacokinetic and pharmacodynamic properties of an experimental drug. Tool compounds discovered could be used for further study and research to understand neurodegenerative diseases and disorders.
Dr Salvador Tomas (Department of Biological Sciences, Birkbeck College): The use of the mathematical tools developed to build up smart lipid vesicles with a range of applications. Our research results can be used by those involved in the development of responsive nanomaterials and nanoreactors for sensing and drug delivery.
Prof Erik Arstad, Dr Thibault Gendon and Dr Michael Porter (Institute of Nuclear Medicine, UCL and Department of Chemistry, UCL): The radiochemistry we developed is likely to have a significant impact on radiopharmaceutical research and lead to the development of the next generation diagnostic tracers. We are already planning for translation of one such tracer for first in human studies. The method we published allows radiochemists to acquire the 19F NMR spectrum of the molecule they wish to radiolabel and quickly determine whether our new radiolabelling methodology is suitable for their target or not. 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 diagnostic positron emission tomography (PET) tracers.
Dr Michael Porter (Department of Chemistry, UCL): The reactions we have developed may have more widespread use for the synthesis of biologically active compounds in the pharmaceutical and agrochemical sectors. Our research is relevant to the developments of pharmaceuticals and agrochemicals.
Prof Claire Carmalt and Dr Caroline Knapp (Department of Chemistry, UCL): Understanding the dynamics of gallium alkoxide precursors will be useful to others involved in the development of new oxide semiconductors, transparent conducting oxide (TCOs) films and gas sensing materials.
Prof Helen Hailes (Department of Chemistry, UCL):
1. Both AstraZeneca and GSK have samples of the fragments prepared for use in fragment libraries and will provide feedback on an annual basis.
2. We have 2 collaborators, one academic group and a company who are screening the products.
3. The grant is co-funded by ALMAC group and the company have the enzymes for industrial applications.
4 & 5. New enzyme applications.
6. New anti-TB drug hits.
7 & 8. New tetrahydroisoquinoline synthesis of drug like molecules.

Prof Tom Sheppard (Department of Chemistry, UCL): The findings described above could be used by others for 11B NMR characterisations of reaction intermediates and products. The methodology developed by us can be employed for the preparation of various classes of organic compounds, including those which are of interest to the pharmaceutical industry.
Prof Alethea Tabor (Department of Chemistry, UCL): The methods developed for the studies of folding and aggregation of peptide toxins and peptide surfactants can be employed by other researchers working in the area of biomedicine and peptide chemistry.
Dr Mukhlesur Rahman (School of Health, Sports and Bioscience, University of East London; Currently in Liverpool John Moores University): Bioassay-guided phytochemical investigation on members of the Zingiberacae family can be further explored for the identification of lead anti-Staphylococcal compounds.
Prof Ipsita Roy and Dr Pooja Bassnet (Department of Life Science, University of Westminster): We use NMR to identify the structure of biodegradable polymers, which are useful for a range of medical applications such as medical device development (coronary artery stents, nerve conduits, wound healing patches), as tissue engineering scaffolds in Regenerative Medicine and controlled drug delivery.
Fane F. K. Mensah, PhD Candidate, and Prof Geraldine Cambridge (Division of Medicine, Centre of Rheumatology Research, UCL): Experiments reported by us have not been done before. The developed assay can be used to test interventions during the cell culturing in order to follow changes in metabolite consumption and secretion specific for B cells.
Prof Junwang Tang and Dr Christopher Windle (Department of Chemical Engineering, UCL): Our findings provide significant information for the development of new more efficient methane oxidation catalysts.
Dr Stefan Guldin (Department of Chemical Engineering, UCL): We study material formation on the nanoscale by molecular self-assembly and build functional nano-architectures for a variety of fields ranging from chemical sensing and biomedical diagnostics to photovoltaics and optical coatings. For the publication "Fractionation of block copolymers for pore size control and reduced dispersity in mesoporous inorganic thin films", our findings offer a route to obtain a library of monodisperse block copolymers from a polydisperse feedstock and provide important insights on the direct relationship between macromolecular characteristics and the resulting structure-directed mesopores, in particular related to dispersity.
Prof Ivan Parkin and Cláudio Lourenco, PhD Candidate (Department of Chemistry, UCL): The work carried out in collaboration with industrial partners is relevant for disinfectant applications.
Dr Simoni Da Ros and Dr Katherine Curran (Bartlett School Env, Energy & Resources, Faculty of the Built Environment, UCL): The 700MHz NMR instrument has been highly valuable for achieving several key findings, as explored in the 2021 publication by Da Ros et al. Main key discoveries relate to the determination of kinetic mechanisms involved in plasticiser loss and deacetylation in cellulose acetate historical artefacts. These have in turn been translated to key findings in conservation strategies involving the management of environmental storage conditions. The instrument was key for the development of methods that allowed for quantifying plasticiser loss and average degree of substitution in the above-mentioned artefacts. The NMR spectroscopy is significantly underused in heritage sciences. Our work is helping to raise awareness of its potential in a new field of NMR applications. The findings are expected to impact the conservation strategies in museums and archives or other organisations involved in the preservation of historic plastics. Moreover, by understanding the mechanism of degradation and its main causes, the research may contribute to the development of recycling technologies, which is very important for the management of global solid plastic waste.
Dr Bob Schroeder and Lewis Cowen, PhD Candidate (Department of Chemistry, UCL): Our research is of interest to those involved in the design and synthesis of functional materials for organic electronic applications. An insight into the relatively unknown mechanisms of n-type doping in organic semiconductors allows others to achieve efficient doping in new materials. The development of stable self-doping organic semiconductors will make device processing using doped materials much easier. Lightweight processable energy harvesting materials specifically in organic thermoelectrics and organic photovoltaics.
Prof Jim Anderson (Department of Chemistry, UCL): The divergent synthetic route developed by us will be used for the synthesis of similar alkaloid targets for the investigation of their biological activity.
Dr Jamie Baker (Department of Chemistry, UCL): Reagents and methods for the construction of protein conjugates, such as the ones we have developed, are widely sought. For example, antibody-drug conjugates represent a rapidly class of targeted therapeutics, with 3 approved in the last year. However the reactions to attach the drugs to antibodies are known to be suboptimal - we anticipate our reactions could have a major contribution to the next generation of such conjugates. The stabilisation-dual modification strategy developed by us is likely to have widespread utility in the bioconjugates field, and also in surrounding areas where maleimide chemistry is also widely used e.g. polymer chemistry, nanoparticles, materials etc. The 700 MHz NMR was crucial to this study, as it was employed in characterisation for the key reagents and in establishing the rates of the newly discovered reactions.
Dr Cally Haynes (Department of Chemistry, UCL): The expected long-term findings of the project using the 700MHz facility will be of interest to diverse chemical research fields including supramolecular chemistry, inorganic materials, soft materials and catalysis. The novel molecules under investigation could be of interest in drug delivery and discovery, since we aim to apply these structures to control the pharmacokinetic and pharmacodynamic properties of therapeutic and diagnostic cargoes.
Dr Stefan Howorka (Department of Chemistry, UCL): Develop new photosensitive chemical tools to advance chemical biology, molecular biology, and biomedicine.
Dr Abil Aliev (Department of Chemistry, UCL, principal investigator in the EPSRC application for the multinuclear 700 MHz NMR facility): 1. The work on Ru-H ··· Si interaction will be of interest to those working in the area of organometallic chemistry, as well as in studies of a noncovalent interaction in general; 2. Others working in the area of solid-state NMR spectroscopy, as well as structural characterisations of solid materials, will benefit from the results published by us using tin NMR; 3. The interest in noncovalent interactions has been grown fast over the last two decades and our publication titled "Noncovalent Interactions of pi Systems with Sulfur - The Atomic Chameleon of Molecular Recognition" will benefit those interested in noncovalent interactions of sulfur and oxygen atoms. Dr Abil Aliev was invited to write a review article following this publication (DOI doi.org/10.1002/chem.201900854).
Sectors Aerospace, Defence and Marine,Agriculture, Food and Drink,Chemicals,Education,Electronics,Energy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology

URL https://www.simonsfoundation.org/life-sciences/origins-of-life/simons-collaboration-on-the-origins-of-life/
 
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 synthesis of new tetrahydroisoquinolines. Eight 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. 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 and David Steadman (Alzheimer's Research UK UCL Drug Discovery Institute): Tool compounds discovered could be used for further study and research to understand neurodegenerative diseases and disorders. 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 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. 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. 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 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