This research proposal has its origin in the special properties of the selectively fluorinated molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane, which we prepared and reported in 2015. This is cyclohexane ring system which emerges as the most polar aliphatic compound recorded and it has interesting properties such as the ability to associate with both cations and anions. The cyclohexane ring is highly unusual in that it has polarised faces. The fluorine face is negatively polarised and the hydrogen face is positively polarised. In 2015 this ring system was challenging to make, and particularly to make derivatives, however in 2017 a direct hydrogenation method was developed by Glorius's lab in Munster, which allows access to derivatived forms of the ring system directly from aromatic precursors. Relevant to this proposal will be the synthesis of a series of substituted pentafluorocyclohexanes, where all substituents are on the same side of the cyclohexane ring. With this development, this research programme aims to explore applications of these pentafluorocyclohexane ring systems, exploring properties relevant to medicinal and biological chemistry (interactions with amino acids and proteins) as well as in organic materials and we have selected a particular focus in the areas of liquid crystals. In the context of medicinal and biological chmeistry we want to explore how these ring systems will be expected to interact and bind with proteins. The negatively and positively polarised faces have the potential to make interactions with amino acid side chains with a complementary electrostatic profile. This will be explored by tagged 'pull-down' assays and proteins of high affinity will be identified by proteomics techniques. Candidate proteins will be progressed to co-crytsalisation structural (X-ray) studies for close structural analysis. In a complementary approach we will prepare tripeptides, from amino acid combinations that are known to be predisposed towards crystallinity. We will prepare a range of these with an amino acid with an all cis-2,3,4,5,6-pentafluorocyclohexyl side chain to explore how it interacts with other amino acid side chains. This study will extend to exploring the binding of this ring system to viral proteases, by making appropriate changes to drug molecules by replacing cyclohexyl or fluoroaromatic rings with the all cis-2,3,4,5,6-pentafluorocyclohexyl side chain. Structural biology(X-ray) analysis will allow us to determine how these ring systems interact with the protein, and this will inform medicinal chemists as to the potential of this motif. The programme will extend to CF3 containing cyclohexanes, but particulary rings with more than one CF3 and with a defined stereochemistry. We have recently demonstrated that cyclohexanes with multiple CF3 groups attached to the aliphatic ring can also be accessed efficiently by the direct hydrogenation of arylCF3 precursors. The programme will extend to exploring the preparation, properties and chemistry of cyclohexanes with two and three CF3 groups with defined stereochemistries. These are also highly polarised aliphatics and these novel motifs will be introduced into liquid crystal architectures to exemplify properties and potential. The liquid crystal aspect is supported by Merck Liquid Crystal Division in Darmstadt who will carry out detailed analysis of prpared materials. In overview the programme will explore an exciting class of organic chemistry motif which have potential to contribute new properties in a range of discovery chemistry arenas.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

This project aims to develop two recent discoveries from the St Andrews laboratory. Project 1: The first project develops from a recent syntheses of 1,2,3,4- and 1,2,4,5-tetrafluorocyclohexanes. Importantly the stereochemistry of the molecules has all of the fluorines on the same face of the cyclohexanes. We find that this makes these cyclohexanes very polar. TWhen cyclohexane adopts a chair conformation, then there are always two diaxial C-F bonds. This polarity renders these compounds crystalline solids, and NMR experiments reveal that the two faces are highly polarised. So the project aims now to incorporate this motif into more meaningful structures. We think that the all-syn tetrafluorocyclohexane motif can have wide ranging roles in developing performance molecules for pharmaceuticals and agrochemicals research. However in this project we will use liquid crystals as a background to explore their properties. Many liquid crystalline molecules that are used in modern displays for personal computers, smart phones and iPads etc contain fluorine atoms. This is because the C-F bond is polar, but it has low viscosity, and thus it can orientate and cycle very rapidly in changing electric fields. The all-syn tetraflurocyclohexane motifs appear to have exactly the correct caharacteristics for a particular class of LC's known as -ve dieletric anisotropic LC's. These are molecules where the dipole is orientated perpendicular to the molecular axis. The project requires that we develop chemistry around a phenyl derivative of the 1,2,4,5-tetrafluorocyclohexane. We plan to carry out a diversity of chemistry on this motif, and also to improve synthetic protocols. We want also to explore synthesis routes to other derivatives of the tetrafluorocyclohexane ring system eg. carboxylic acid and amine motifs we feel will be extremely attractive for medicinal chemistry research. One of the leading research companies and global suppliers of perfomance LC's, Merck in Darmstadt, Germany, have agreed to support the project by evaluating candidate compounds as LC's and they will assist in providing facilities to scale up the synthesis of these motifs. This aspect of the project will be successful if we can demonstrate a practical application of the all-syn tetrafluorocyclohexane and illustrate to the wider community its potential in the development of performance organic molecules. Project 2. The second project was stimulated by a new reaction carried out in the laboratory, which recognised that if an acetylenethioether is treated with an HF source, it generates a fluoroviny thioether (RS(F)=CH2). More significantly we find that the fluorovinyl thioether is a relatively stable entity. There is hardly any literature on this motif and in this research we want to explore its potential in the early stage design of enzyme inhibitors (fragment approach). We have recognised that the motif approximates the steric and electronic profile of an enol of a thioester. Thioester enols/ates are important intermediates in enzymology, eg. enzymes that process acetyl-CoA such citrate and malate synthase, acetyl-CoA carboxylase, and enoyl reductases of fatty acid biosynthesis are attractive. Therefore we want to assess if the fluorovinyl thioether moiety will be recognised and bind to these enzyme active sites by co-crystallisation X-ray studies. This requires that we synthesise appropriate motifs that represent truncated pantetheinyl moieties carrying the RS(F)=CH2 motif. These compounds will be co-crystallised with enzymes over-expressed in E. coli. In discussions with Syngenta they have suggested we explore such ligands for enoyl reductase, a target relevant to the agrochemical sector. A successful outcome will show that this motif binds to these enzyme active sites (by X-ray crystallography), and provides a starting poing for fragment based inhibitor development. The programme will introduce this motif to the wider research community.

Gestational diabetes (too much sugar in the blood in pregnancy) and pregnancy hypertensive disorders (high blood pressure that occurs in pregnancy, and which can lead to fits in the mother and death in the baby) cause significant maternal and neonatal mortality and morbidity in low and middle income countries and there is no systematic approach to prevention. The estimated global prevalence of gestational diabetes is 16%, with higher rates in in South Asia and Africa [1]. Gestational diabetes increases the incidence of the adverse outcomes of caesarean section, pregnancy induced hypertensive disease, excessive birthweight, birth injury, future obesity and future diabetes: untreated, it contributes to a cycle which promotes obesity and diabetes in future generations[2]. Pregnancy hypertensive disorders account for 17.3% of maternal deaths in low socio-economic countries, and are the second commonest cause of maternal death after haemorrhage[3]. In resource rich countries, testing for gestational diabetes is undertaken in women at high risk, together with treatment of those affected and regular self-monitoring of blood sugar levels. Such an approach is inappropriate in resource poor settings due to the high cost of testing and blood sugar monitoring, and the lack of availability of blood sugar monitoring kits. However, measurement of maternal body mass index (weight and height) cheaply and effectively identifies a high-risk group for both gestational diabetes and pregnancy hypertensive disorders. Additionally, one of the treatments (metformin) for gestational diabetes is relatively cheap, widely available, and safe, regardless of blood sugar levels [4-6]. Recent in vitro and clinical data suggest that metformin might reduce the incidence and severity of pregnancy hypertensive disorders [6-8]. We propose that metformin could be a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings. This is a feasibility study of a clinical trial to determine whether metformin is effective in preventing gestational diabetes and pregnancy hypertensive disorders in women at high risk of both conditions. In this feasibility study, we will find out if it is possible for us to do a full trial, how big such a trial would be, and how expensive it would be. We will ask obese pregnant women in participating sites in Malawi and Zambia to take either metformin or matching placebo tablets. We will see how many women wish to participate, how many take the treatment, and what effect the treatment has. We will also be able to see how common gestational diabetes and pregnancy hypertensive disorders are in this population. Although this feasibility study is too small to answer the question "Is routine administration of metformin a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings" it will facilitate a larger (and likely more expensive study) to be able to do so. Our group of clinicians, researchers and policy makers in Malawi, Zambia and the UK has the necessary expertise to carry out both the feasibility study and a further substantive study, and we are well placed to be able to translate the results of the research into clinical practice. References 1. International Diabetes Federation (IDF) IDF Diabetes Atlas, 7th Edition, 2015. 2. NICE, Diabetes in pregnancy. NICE guideline 2015. 3. Global Burden of Disease Maternal Mortality and Morbidity Collaborators, Lancet, 2016. 388: p. 1775-1812. 4. Balsells, M., et al., BMJ, 2015. 350: p. h102. 5. Chiswick, C., et al., Lancet Diabetes Endocrinol, 2015. 3: p. 778-86. 6. Syngelaki, A., et al., N Engl J Med, 2016. 374: p. 434-43. 7. Brownfoot, F.C., et al., Am J Obstet Gynecol, 2016. 214: p. 356 e1-356 e15. 8. Romero, R., et al., Am J Obstet Gynecol, 2017. 217: p. 282-302

The interface between a liquid, such as water, and air is called a free surface, and its shape is determined by a balance between the surface tension of the interface (which acts rather like the tension in the skin of a child's balloon) and how the molecules of the water interact with those of the solid container (called the "wettability"). Everyday phenomena arising from the interplay between these effects are the characteristic curved meniscus which forms as the free surface meets the surface of a partly-filled glass, and the ability of a water strider insect to sit on the surface of a pond or river. At small (millimetre) scales, both effects are important, and so understanding the subtle interplay between surface tension and wettability effects is key to understanding and controlling the flow of liquids at these scales. An important phenomenon for many practical and industrial settings, ranging from rain on a window or windscreen to industrial coating processes, is how and when a thin layer of fluid breaks up into small rivulets, or a larger rivulet breaks up into smaller rivulets. This seemingly everyday problem exhibits fascinating and complex behaviour which depends in a complicated manner on an array of parameters, including the fluid volume, the slope of the substrate and the wettability, as well as the inherent properties of the liquid (such as density and viscosity). Our over-arching research ambition in this proposal is to explore, understand, and hence actively manipulate, the free surface shapes that can be adopted by a flowing liquid, in the size range from tens of microns (1/100th of a millimetre) to millimetre scales. While effects at this length-scale may not be present in standard liquids, we will use nematic liquid crystals, which are complex liquids with viscosities dependent on the speed and direction of the flow compared to the orientation of the elongated molecules that make up this type of liquid. Exerting control of the orientation of the molecules will itself have a profound influence on the manner of flow. However, this proposal goes significantly further than this, aiming to generate new approaches to free surface shape manipulation via the selection of the relative strengths of internal, surface and externally imposed forces. Creating this ability to control the relative stabilities of shape and flow morphologies provides a novel route between a variety of topologically distinct free surface flow regimes. Although fascinating from a fundamental scientific point of view, this work will also have considerable impact in a number of application areas. Indeed, liquid crystals are ubiquitous - from the Liquid Crystal Display (LCD) in your TV and mobile phone to the microscopic layer of molecules that make up the wall of every cell in your body, these materials are hugely important. Over the last 50 years, liquid crystal research and display device development has been driven by a need to understand and exploit interactions between elasticity, applied electric fields, and solid boundaries. Understanding and controlling these competing interactions has spawned an LCD industry worth around $95 billion. However, progress beyond the current technology that would enable innovation in flow-enhancement and microfluidic applications requires an improved fundamental scientific understanding of the dynamic interactions between all of the above effects as well as the effects of flow-induced alignment, defect textures, and free surfaces in flowing nematic liquid crystals. Elucidating these interactions are the focus of this proposal and it is hoped that our work can then lead to insight and developments in new areas such as: defect-mediated 3D photonic devices for all optical storage and soft computing; microfluidic applications such as reconfigurable micro-cargo transport; and advances in large-scale manufacturing and small-scale advanced device development where device filling processes must be reliable.