Portrait of Dr Jennifer Hiscock

Dr Jennifer Hiscock

Lecturer in Chemistry

About

Dr Jennifer Hiscock is currently a Lecturer in Chemistry within the School of Physical Sciences. She has authored 40 scientific publications, which have been cited over 1,650 times to date (December 2018). 

Jennifer graduated from the University of Exeter in 2007 with a first in Biomedicinal Chemistry (BSc Hons) and was awarded a PhD from the University of Southampton in 2010, studying selective anion co-ordination using neutral hydrogen bond donating receptors under the supervision of Professor Philip Gale (now University of Sydney) and Professor Michael Hursthouse. She went on to conduct postdoctoral research with Professor Philip Gale, alongside Dr M. Sambrook (Dstl (UK)) until 2015, gaining expertise in novel organocatalyst design, vesicle preparation, anion transport and supramolecular material design. During this period she also obtained her PRINCE2 project management qualifications.

In 2015 Jennifer began her independent career at the University of Kent when she was awarded the three-year Caldin Research Fellowship within the School of Physical Sciences. This was followed by a permanent lectureship position in 2016 and accompanied by the University of Kent Faculty of Sciences Prize for Starting Research in 2017. She currently manages the NMR facilities, in addition to other equipment held within the materials and molecular characterisation facilities in the School of Physical Sciences. 

She is a member of the Royal Society of Chemistry Macrocyclic and Supramolecular Chemistry Group and sits on the editorial boards for both Supramolecular Chemistry and Frontiers Chemistry (supramolecular section).

Research interests

The interests of the Hiscock research group centre around developing the application of supramolecular chemistry to the modern-day world. At present this research is focused in three interdisciplinary areas, using the expertise of students with cell biology, chemistry, forensic science, forensic chemistry and biochemistry backgrounds. These students all work together, exchanging knowledge and skill sets in a cohesive and enabling environment.

Details of research interest areas are as follows.

The synthesis, characterisation and prediction of those properties associated with supramolecular self-associating amphiphiles (SSAs)

Molecules that have an uneven number of hydrogen bond donating and accepting groups within the same chemical structure are ‘frustrated’ in nature. This is because not all those binding modes can be fulfilled simultaneously. If these molecular structures also contain both hydrophobic and hydrophilic groups, then, as well as being ‘frustrated’ in nature, these molecules will also exhibit amphiphilic physicochemical properties. The group has synthesised over 70 members from this class of compound, gaining an understanding as to how those molecular self-association properties effect those amphiphilic physicochemical properties and any resultant nanostructure formation in multiple phases.

The development of novel antimicrobials and antibiotic adjuvant delivery vehicles

By the year 2050 it is predicted that antimicrobial resistant bacteria will have decreased global GDP by £66.7 trillion and cause more global annual deaths than cancer. Therefore, the development of novel antimicrobials/antibiotics or antibiotic adjuvants is of the upmost importance. A number of those SSAs synthesised to date have been shown to exhibit antimicrobial and/or antibiotic adjuvant properties against both Gram positive (eg MRSA) and Gram negative (eg E. coli) bacteria. The group is now developing ever more effective antimicrobials and/or antibiotic adjuvants and deriving any associated modes of action.

The use of low molecular weight hydrogen bond donating receptors to identify small molecule simulants for toxic compounds to aid the development of decontamination and remediation technologies

There are many toxic compounds that are released accidentally or purposely into our environment every day. These classes of toxic compounds include (but are not limited to) pesticides, fertilisers and industrial waste. There is an ongoing global need to decontaminate and remediate the effects of these compounds when released into the environment; however, when developing these technologies the target chemicals may be far too toxic to handle within an everyday laboratory. In these instances, the toxic compounds need to be substituted with an appropriate simulant that allows novel decontamination or remediation technologies to be developed safely.       

Publications

Article

  • Tyuleva, S., Allen, N., White, L., Pepes, A., Shepherd, H., Saines, P., Ellaby, R., Mulvihill, D. and Hiscock, J. (2018). A Symbiotic Supramolecular Approach to the Design of Novel Amphiphiles with Antibacterial Properties Against MSRA. Chemical Communications [Online] 55. Available at: http://dx.doi.org/10.1039/C8CC08485H.
    Herein, we identify Supramolecular Self-associating Amphiphiles (SSAs) as a novel class of antibacterials with activity towards Methicillin-resistant Staphylococcus aureus. Structure-activity relationships have been identified in the solid, solution and gas phases. Finally, we show that when supplied in combination, SSAs exhibit increased antibacterial efficacy against these clinically relevant microbes.
  • White, L., Tyuleva, S., Wilson, B., Shepherd, H., Ng, K., Holder, S., Clark, E. and Hiscock, J. (2018). Towards the prediction of global solution state properties for hydrogen bonded, self-associating amphiphiles. Chemistry - A European Journal [Online] 24:7761-7773. Available at: https://doi.org/10.1002/chem.201801280.
    Through this extensive structure-property study we show that critical micelle concentration correlates with self-associative hydrogen bond complex formation constant, when combined with outputs from low level, widely accessible, computational models. Herein, we bring together a series of 39 structurally related molecules obtained through stepwise variation of a hydrogen bond donor-acceptor amphiphilic salt. The self-associative and corresponding global properties for this family of compounds have been studied in the gas, solid and solution states. Within the solution state we have shown the type of self-associated structure present to be solvent dependent. In DMSO, this class of compound show a preference for hydrogen bonded dimer formation, however moving into aqueous solutions the same compounds are found to form larger self-associated aggregates. This observation has allowed us the unique opportunity to investigate and begin to predict selfassociation events at both the molecular and extended aggregate level.
  • Gumbs, T., White, L., Wells, N., Shepherd, H. and Hiscock, J. (2018). ’Frustrated’ hydrogen bonded self-associated systems as templates towards DNA incorporated nanostructure formation. Supramolecular Chemistry [Online] 30:42-51. Available at: http://dx.doi.org/10.1080/10610278.2017.1351613.
    Herein, we present the synthesis of a thymine nucleobase appended ‘frustrated’ monomer, which exhibits self-association in DMSO solutions through the formation of hydrogen bonds. This self-association process has been explored in both competitive DMSO solutions and the solid state, using a combination of NMR and single crystal X-ray diffraction techniques. The self-associative equilibria within the solution state are balanced in such a way that the hydrogen bond donating (HBD) and accepting (HBA) thymine residue present within the monomeric structure is free to coordinate further guest species such as the complimentary DNA base adenine. The adenine simulants, 2-aminopyridine and 2,6-diaminopyridine have been used to explore the potential of these self-associated structures towards the coordination of complimentary DNA base pairs.
  • White, L., Wells, N., Blackholly, L., Shepherd, H., Wilson, B., Bustone, G., Runacres, T. and Hiscock, J. (2017). Towards quantifying the role of hydrogen bonding within amphiphile self-association and resultant aggregate formation. Chemical Science [Online] 8:7620-7630. Available at: https://dx.doi.org/10.1039/C7SC03888G.
    Herein, we present a series of five tetrabutylammonium (TBA) sulfonate–urea amphiphilic salts. In solution these amphiphilic salts have been shown to form a variety of self-associated species. The proportion and type of which are both solvent and concentration dependent. In DMSO-d6 a variety of NMR experiments provide evidence towards the formation of mainly dimeric over larger aggregate species. Increasing the percentage of water was shown to increase the concentration of the larger aggregates over dimers in solution. A correlation was established between critical micelle concentration (CMC) values obtained in a 1?:?19 EtOH?:?H2O mixture, dimeric self-association constants obtained in a DMSO-d6 – 0.5% H2O and the results of simple semi-empirical PM6 computational modelling methods. This approach begins to quantify the role of hydrogen bonding in amphiphile self-association and the effects it imparts on surfactant properties. This consequently provides preliminary evidence that these properties maybe predicted by simple low level computational modelling techniques.
  • Hiscock, J., Bustone, G. and Clark, E. (2017). Decontamination and Remediation of the Sulfur Mustard Simulant CEES with “Off-the-Shelf” Reagents in Solution and Gel States: A Proof-of-Concept Study. ChemistryOpen [Online] 6:497-500. Available at: https://doi.org/10.1002/open.201700063.
    The decontamination and remediation of sulfur mustard chemical warfare agents remains an ongoing challenge. Herein, we report the use of “off-the-shelf” metal salts alongside commercially available peroxides to catalyze the degradation of the simulant 2-chloroethyl ethyl sulfide (CEES) in solution and encapsulated within a supramolecular gel.
  • Busschaert, N., Park, S., Baek, K., Choi, Y., Park, J., Howe, E., Hiscock, J., Karagiannidis, L., Marques, I., Félix, V., Namkung, W., Sessler, J., Gale, P. and Shin, I. (2017). A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations. Nature Chemistry [Online] 9:667-675. Available at: http://dx.doi.org/10.1038/nchem.2706.
    Perturbations in cellular chloride concentrations can affect cellular pH, autophagy and lead to the onset of apoptosis. With this in mind synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in the lysosomal pH which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.
  • Hiscock, J., Wells, N., Ede, J., Gale, P. and Sambrook, M. (2016). Biasing hydrogen bond donating host systems towards chemical warfare agent recognition. Organic and Biomolecular Chemistry [Online] 14:9560-9567. Available at: http://doi.org/10.1039/c6ob01210h.
    A series of neutral ditopic and negatively charged, monotopic host molecules have been evaluated for their ability to bind chloride and dihydrogen phosphate anions, and neutral organophosphorus species dimethyl methylphosphonate (DMMP), pinacolyl methylphosphonate (PMP) and the chemical warfare agent (CWA) pinacolyl methylphosphonofluoridate (GD, soman) in organic solvent via hydrogen bonding. Urea, thiourea and boronic acid groups are shown to bind anions and neutral guests through the formation of hydrogen bonds, with the urea and thiourea groups typically exhibiting higher affinity interactions. The introduction of a negative charge on the host structure is shown to decrease anion affinity, whilst still allowing for high stability host-GD complex formation. Importantly, the affinity of the host for the neutral CWA GD is greater than for anionic guests, thus demonstrating the potential for selectivity reversal based on charge repulsion.
  • Hiscock, J., Shepherd, H. and Blackholly, L. (2016). ‘Frustrated’ hydrogen bond mediated amphiphile self-assembly – a solid state study. CrystEngComm [Online] 18:7021-7028. Available at: http://dx.doi.org/10.1039/C6CE01493C.
    Herein, we present the synthesis of ten structurally related ‘frustrated’ amphiphiles, from which were obtained eleven single crystal X-ray structures, allowing observation of the hydrogen bonding modes present in the solid state. We previously reported the synthesis of a novel amphiphilic salt which contains both hydrogen bond donating (HBD) and hydrogen bond accepting (HBA) functionalities. This amphiphilic salt was shown to self-associate in the solution state, aided by the formation of hydrogen bonds. The exact nature of the hydrogen bonding modes involved in this self-association process remains unclear due to the combination of HBD and HBA groups present in the amphiphile structure. This results in a ‘frustrated’ system with access to a variety of possible hydrogen bonding modes.
  • Blackholly, L., Shepherd, H. and Hiscock, J. (2016). ’Frustrated’ hydrogen bond mediated amphiphile self-assembly - a solid state study. CrystEngComm [Online] 18:7021-7028. Available at: http://dx.doi.org/10.1039/C6CE01493C.
    Herein, we present the synthesis of ten structurally related ‘frustrated’ amphiphiles, from which were obtained eleven single crystal X-ray structures, allowing observation of the hydrogen bonding modes present in the solid state. We previously reported the synthesis of a novel amphiphilic salt which contains both hydrogen bond donating (HBD) and hydrogen bond accepting (HBA) functionalities. This amphiphilic salt was shown to self-associate in the solution state, aided by the formation of hydrogen bonds. The exact nature of the hydrogen bonding modes involved in this self-association process remains unclear due to the combination of HBD and HBA groups present in the amphiphile structure. This results in a ‘frustrated’ system with access to a variety of possible hydrogen bonding modes.
  • Hiscock, J., Bustone, G., Wilson, B., Belsey, K. and Blackholly, L. (2016). In situ modification of nanostructure configuration through the manipulation of hydrogen bonded amphiphile self-association. Soft Matter [Online] 2016:4221-4228. Available at: http://dx.doi.org/10.1039/c6sm00529b.
    Herein, we report the synthesis of a novel amphiphilic salt containing a number of hydrogen bond donating (HBD) and accepting (HBA) functionalities. This amphiphile has been shown to self-associate via hydrogen bond formation in a DMSO solution, confirmed through a combination of NMR, UV-Vis and dynamic light scattering and supported by X-ray diffraction studies. The combination of different HBD and HBA functionalities within the amphiphile structure gives rise to a variety of competitive, self-associative hydrogen bonding modes that result in the formation of ‘frustrated’ hydrogen bonded nanostructures. These nanostructures can be altered through the addition of competitive HBD arrays and/or HBA anionic guests. The addition of these competitive species modifies the type of self-associative hydrogen bonding modes present between the amphiphilic molecules, triggering the in situ formation of novel hydrogen bonded nanostructures.
  • Hiscock, J., Sambrook, M., Wells, N. and Gale, P. (2015). Detection and remediation of organophosphorus compounds by oximate containing organogels. Chemical Science [Online] 6:5680-5684. Available at: http://dx.doi.org/10.1039/C5SC01864A.
    A series of supramolecular diamide organogels containing a reactive compound for the remediation of organophosphorus (OP) species, in particular OP chemical warfare agents (CWAs), has been prepared in DMSO. The organogels have been found to absorb, encapsulate and decontaminate various OP CWA simulants in situ. At high simulant concentrations the gels also undergo a gel–sol transition releasing high local concentrations of remediation agent.
  • Kadam, S., Martin, K., Haav, K., Toom, L., Mayeux, C., Pung, A., Gale, P., Hiscock, J., Brooks, S., Kirby, I. and Leito, I. (2015). Towards the Discrimination of Carboxylates by Hydrogen-Bond Donor Anion Receptors. Chemistry - A European Journal [Online] 21:5145-5160. Available at: https://doi.org/10.1002/chem.201405858.
    The binding constants (log?Kass) of small synthetic receptor molecules based on indolocarbazole, carbazole, indole, urea and some others, as well as their combinations were measured for small carboxylate anions of different basicity, hydrophilicity and steric demands, that is, trimethylacetate, acetate, benzoate and lactate, in 0.5?% H2O/[D6]DMSO by using the relative NMR?based measurement method. As a result, four separate binding affinity scales (ladders) including thirty?eight receptors were obtained with the scales anchored to indolocarbazole. The results indicate that the binding strength is largely, but not fully, determined by the strength of the primary hydrogen?bonding interaction. The latter in turn is largely determined by the basicity of the anion. The higher is the basicity of the anion the stronger in general is the binding, leading to the approximate order of increasing binding strength, lactate<benzoate<acetate?trimethylacetate, which holds with all investigated receptors. Nevertheless, there are a number of occasions when the binding order changes with changing of the carboxylate anion, sometimes quite substantially. Principal component analysis (PCA) reveals that this is primarily connected to preferential binding of trimethylacetate, supposedly caused by an additional hydrophobic/solvophobic interaction. These findings enable making better predictions, which receptor framework or cavity is best suited for carboxylate anions in receptor design.
  • Piana, F., Facciotti, M., Pileio, G., Hiscock, J., Van Rossom, W., Brown, R. and Gale, P. (2015). Organophosphorus chemical warfare agent simulant DMMP promotes structural reinforcement of urea-based chiral supramolecular gels. RSC Advances [Online] 5:12287-12292. Available at: http://doi.org/10.1039/c4ra15241g.
    Six urea-based supramolecular gels have been obtained in situ by mixing either (R)-(?)-1-(1-naphthyl)ethyl isocyanate or (±)-1-(1-naphthyl)ethyl isocyanate with various amines. This allowed a comparative study on the effects of chirality on the response of the molecular gels to the presence of the neutral organophosphate guest dimethyl methylphosphonate (DMMP). The inversion test results show that the absence of enantiomeric purity causes marked instability of the gel network in the presence of the guest. DSC and rheology measurements reveal the promotion of a structural reinforcement of the gels when 0.01 mL of DMMP interacts with the enantiomerically pure systems. This effect was investigated by means of electrostatic potential surface calculations and 31P–{1H} NMR spectroscopy.
  • Hiscock, J., Sambrook, M., Ede, J., Wells, N. and Gale, P. (2015). Disruption of a binary organogel by the chemical warfare agent soman (GD) and common organophosphorus simulants. Journal of Materials Chemistry A [Online] 3:1230-1234. Available at: http://dx.doi.org/10.1039/C4TA04834B.
    The chemical warfare agent (CWA) soman (GD) acts as a molecular stimulus for the disruption of an anthracene-based binary organogel prepared in cyclohexane. The CWA simulants dimethyl methylphosphonate (DMMP) and diethyl chlorophosphate (DCP) were also found to disrupt the binary organogel through changes in solvent polarity and reactions with the gelator.
  • Hiscock, J., Kirby, I., Herniman, J., Langley, G., Clark, A. and Gale, P. (2014). Supramolecular gels for the remediation of reactive organophosphorus compounds. RSC Advances [Online] 4:45517-45521. Available at: http://dx.doi.org/10.1039/C4RA07712A.
    Pyridine-based gels formed with a cyclohexyl diamide gelator have been shown to undergo a gel–sol transition upon addition of the organophosphorus (OP) chemical warfare agent (CWA) simulant diethyl chlorophosphate (DCP). This is due to a reaction between the gelator and DCP resulting in the disruption of the intermolecular hydrogen bonded gelator matrix and therefore the loss of gel stability. This selective phase change reliant on the presence of a reactive OP species provides a novel remediation and sensory method for this class of toxic compound.
  • Hiscock, J., Sambrook, M., Cranwell, P., Watts, P., Vincent, J., Xuereb, D., Wells, N., Raja, R. and Gale, P. (2014). Tripodal molecules for the promotion of phosphoester hydrolysis. Chemical Communications [Online] 50:6217-6220. Available at: http://dx.doi.org/10.1039/C4CC00333K.
    A series of low molecular weight tripodal amide/histidine-containing compounds (1–2) have been synthesised and shown to increase the rate of bis-(p-nitrophenyl) phosphate (BNPP) and soman (GD) breakdown in buffered aqueous solution.
  • Hiscock, J., Piana, F., Sambrook, M., Wells, N., Clark, A., Vincent, J., Busschaert, N., Brown, R. and Gale, P. (2013). Detection of nerve agent via perturbation of supramolecular gel formation. Chemical Communications [Online] 49:9119-9121. Available at: http://dx.doi.org/10.1039/C3CC44841J.
    The formation of tren-based tris-urea supramolecular gels in organic solvents is perturbed by the presence of the nerve agent soman providing a new method of sensing the presence of organophosphorus warfare agents.
  • Haav, K., Kadam, S., Toom, L., Gale, P., Busschaert, N., Wenzel, M., Hiscock, J., Kirby, I., Haljasorg, T. and Leito, I. (2013). Accurate Method To Quantify Binding in Supramolecular Chemistry. Journal of Organic Chemistry [Online] 78:7796-7808. Available at: http://dx.doi.org/10.1021/jo400626p.
    An approach for accurate and comparable measurement of host–guest binding affinities is introduced whereby differences in binding strength (?logKass values) are measured between two host molecules toward a particular guest under identical solvent conditions. Measuring differences instead of absolute values enables obtaining highly accurate results, because many of the uncertainty sources (the solvation/association state of the guest in solution, deviations in solvent composition, etc.) cancel out. As a proof of concept, this method was applied to the measurement of the binding strength of 28 synthetic anion receptors toward acetate in acetonitrile containing 0.5% water. The receptors included differently substituted indolocarbazoles, ureas, thioureas, and some others. Possible deprotonation of more acidic receptors of each compound class by acetate was checked by measuring their acidities (?pKa values) relative to acetic acid in the same solvent. A self-consistent (consistency standard deviation 0.04 log units) binding affinity scale ranging for around 2.7 log units was constructed from the results. Absolute logKass values were found by anchoring the scale to the absolute logKass values of two receptor molecules, determined independently by direct measurements. This new approach is expected to find use in accurate quantification of a wide range of binding processes relevant to supramolecular chemistry.
  • Karagiannidis, L., Hiscock, J. and Gale, P. (2013). The influence of stereochemistry on anion binding and transport. Supramolecular Chemistry [Online] 25:626-630. Available at: https://doi.org/10.1080/10610278.2013.806809.
    Bis(thio)urea receptors (1–4) based on 1,2-bisaminocyclohexane are shown to function as transmembrane anion antiporters. The results show that cis-receptors have a greater propensity for anion transport than analogous trans-receptors. Stability constants using 1H NMR techniques highlight the significance of stereoisomerism on anion binding in solution, as cis-receptors bind anions more strongly than trans-receptors.
  • Basschaert, N., Bradberry, S., Wenzel, M., Haynes, C., Hiscock, J., Kirby, I., Karagiannidis, L., Moore, S., Wells, N., Herniman, J., Langley, G., Horton, P., Light, M., Marques, I., Costa, P., Felix, V., Frey, J. and Gale, P. (2013). Towards predictable transmembrane transport: QSAR analysis of anion binding and transport. Chemical Science [Online] 4:3036-3045. Available at: http://dx.doi.org/10.1039/C3SC51023A.
    The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure–activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.
  • Cranwell, P., Hiscock, J., Haynes, C., Light, M., Wells, N. and Gale, P. (2013). Anion recognition and transport properties of sulfamide-, phosphoric triamide- and thiophosphoric triamide-based receptors. Chemical Communications [Online] 49:874-876. Available at: http://dx.doi.org/10.1039/C2CC38198B.
    Studies of sulfamide, phosphoric triamide and thiophosphoric triamide-based organocatalysts show that the phosphorus containing systems are effective new hydrogen bonding motifs for the recognition and transport of anions.
  • Barba-Bon, A., Costero, A., Parra, M., Gil, S., Martinez-Manez, R., Sancenon, F., Gale, P. and Hiscock, J. (2013). Neutral 1,3-Diindolylureas for Nerve Agent Remediation. Chemistry - A European Journal [Online] 19:1586-1590. Available at: https://doi.org/10.1002/chem.201202028.
    Efficient neutralization of nerve?agent simulants by 1,3?diindolylureas in a neutral medium was investigated (see scheme; DCP=diethylchlorophosphate, DCNP=diethylcyanophosphonate). The rate of hydrolysis of the simulants was found to increase by as much as 45?% in the presence of these compounds. A mechanism based on the simulant complexation was established.
  • Haynes, C., Berry, S., Garric, J., Herniman, J., Hiscock, J., Kirby, I., Light, M., Perkes, G. and Gale, P. (2013). Small neutral molecular carriers for selective carboxylate transport. Chemical Communications [Online] 49:246-248. Available at: http://dx.doi.org/10.1039/C2CC37468D.
    A series of neutral thiourea receptors were found to mediate the antiport of chloride with a range of biologically relevant carboxylate anions across phospholipid bilayers. Simple structural modification of the carriers resulted in a change in the lactate/pyruvate transport selectivity.
  • Hiscock, J., Gale, P., Lalaoui, N., Light, M. and Wells, N. (2012). Benzimidazole-based anion receptors exhibiting selectivity for lactate over pyruvate. Organic & Biomolecular Chemistry [Online] 10:7780-7788. Available at: http://dx.doi.org/10.1039/C2OB26299A.
    The influence of anions on tautomerism in benzimidazole containing anion receptors has been studied via a variety of techniques in both solution and the solid state. The results show that hydrogen bonding interactions between the receptors and guests have a significant effect of the nature of the tautomer present. The compounds show a preference for complexation of lactate over pyruvate.
  • Sambrook, M., Hiscock, J., Cook, A., Green, A., Holden, I., Vincent, J. and Gale, P. (2012). Hydrogen bond-mediated recognition of the chemical warfare agent soman (GD). Chemical Communications [Online] 48:5606-5607. Available at: http://dx.doi.org/10.1039/C2CC31096A.
    NMR titration studies in acetonitrile-d3/DMSO-d6 mixtures demonstrate that diindolylurea-based receptors can form complexes with the organophosphorus nerve agent soman in organic solution.
  • Hiscock, J., Gale, P. and Haynes, M. (2012). Tris-(2-aminoethyl)amine-based tripodal trisindolylureas: new receptors for sulphate. Supramolecular Chemistry [Online] 24:355-360. Available at: https://doi.org/10.1080/10610278.2012.671486.
    A series of tren-based amide or urea linked tris-indole anion receptors have been synthesised and their anion complexation properties studied in DMSO-d6/water mixtures.
  • Haynes, C., Moore, S., Hiscock, J., Marques, I., Costa, P., Felix, V. and Gale, P. (2012). Tunable transmembrane chloride transport by bis-indolylureas. Chemical Science [Online] 3:1436-1444. Available at: http://dx.doi.org/10.1039/C2SC20041D.
    A series of bis-indolylureas have been found to mediate chloride transport across vesicle bilayers. The anion transport activity of these receptors may be readily modulated by small structural changes to the receptor scaffold as shown by the combination of experimental chloride efflux studies and molecular dynamics simulations in water and POPC bilayers.
  • Gale, P., Hiscock, J., Lalaoui, N., Light, M., Wells, N. and Wenzel, M. (2012). Benzimidazole-based anion receptors: tautomeric switching and selectivity. Organic & Biomolecular Chemistry [Online] 10:5909-5915. Available at: http://dx.doi.org/10.1039/C1OB06800H.
    Tautomeric switching is observed in a series of benzimidazole-based anion receptors upon addition of basic anions. An N-methylbenzimidazole based receptor selectively interacts with dihydrogen phosphate over a variety of other putative anionic guests via a combination of donated and accepted hydrogen bonds.
  • Wenzel, M., Hiscock, J. and Gale, P. (2012). Anion receptor chemistry: highlights from 2010. Chemical Society Reviews [Online] 41:480-520. Available at: http://dx.doi.org/10.1039/C1CS15257B.
    This critical review covers advances in anion complexation in the year 2010. The review covers both organic and inorganic systems and also highlights the applications to which anion receptors can be applied such as sensing, anion transport, control of molecular motion and gelation.
  • Markuc, D., Hiscock, J., Light, M., Gale, P. and Plavec, J. (2011). NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas. Beilstein Journal of Organic Chemistry [Online] 7:1205-1214. Available at: http://dx.doi.org/10.3762/bjoc.7.140.
    The conformational properties of 1,3-diindolylureas and thioureas were studied by a combination of heteronuclear NMR spectroscopy and quantum mechanics calculations. NOE experiments showed that the anti–anti conformer along the C7–N7? bonds was predominant in DMSO-d6 solution in the absence of anions. Anion-induced changes in the 1H and 15N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong deshielding of ureido protons and moderate deshielding of indole NH was observed upon the addition of acetate, benzoate, bicarbonate and dihydrogen phosphate, which indicated that the predominant hydrogen bond interactions occurred at the urea donor groups. Binding of oxo-anions caused conformational changes along the C7–N7? bonds and the syn–syn conformer was preferred for anion–receptor complexes. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations.
  • Chapman, R., Hiscock, J., Gale, P. and Bryce, D. (2011). A solid-state 35/37Cl NMR study of a chloride ion receptor and a GIPAW-DFT study of chlorine NMR interaction tensors in organic hydrochlorides. Canadian Journal of Chemistry [Online] 89:822-834. Available at: https://doi.org/10.1139/v10-177.
    The results of a 35/37Cl solid-state nuclear magnetic resonance (SSNMR) study of the 1-butyl-3-methylimidazolium chloride complex of meso-octamethylcalix[4]pyrrole (1) are reported. Line shapes obtained from magic-angle-spinning and stationary powder samples collected at 9.4 and 21.1 T are analyzed to provide the 35/37Cl quadrupolar tensor and chemical shift (CS) tensor and their relative orientation. The relatively high symmetry of the chloride ion coordination environment is manifested in the small value of the quadrupole coupling constant, CQ(35Cl) = 1.0 MHz. The isotropic chemical shift of 120 ppm (with respect to NaCl(s)) is at the upper edge of the typical range seen for organic hydrochlorides. Consideration of chemical shift anisotropy (span, ? = 50 ppm) and non-coincidence of the quadrupolar and CS tensors were essential to properly simulate the experimental spectra. The utility of gauge-including projector-augmented wave density functional theory (GIPAW-DFT) calculations of chlorine quadrupolar and CS tensors in organic chlorides was explored by validation against available benchmark experimental data for solid amino acid hydrochlorides. The calculations are shown to systematically overestimate the value of the 35Cl quadrupole coupling constant. Additional calculations on various hydrated and solvated models of 1 are consistent with a structure in which solvent and water of hydration are absent.
  • Gale, P., Hiscock, J., Jie, C., Hursthouse, M. and Light, M. (2010). Acyclic indole and carbazole-based sulfate receptors. Chemical Science [Online] 7:215-220. Available at: http://dx.doi.org/10.1039/C0SC00202J.
    The anion complexation properties of a series of acyclic receptors consisting of diindolylurea groups appended with amide, amidoindole or amidocarbazole groups have been studied. The receptors selectively bind and encapsulate sulfate via either six or eight hydrogen bonds. Receptors containing eight hydrogen bond donors perturb the pKa of bound dihydrogen phosphate and bicarbonate to the extent that they are deprotonated by free anion in solution.
  • Gale, P., Hiscock, J., Moore, S., Caltagirone, C., Hursthouse, M. and Light, M. (2010). Anion-Anion Proton Transfer in Hydrogen Bonded Complexes. Chemistry - an Asian Journal [Online] 5:555-561. Available at: https://doi.org/10.1002/asia.200900230.
    Complexation of dihydrogen phosphate by an anion receptor containing six hydrogen bond donor groups has been shown to reduce the pKa of the bound anionic species to such an extent that addition of further aliquots of dihydrogen phosphate result in deprotonation of the bound species with the resultant formation of a monohydrogen phosphate receptor complex. X?ray crystallographic studies confirm monohydrogen phosphate complex formation in the solid state. In this way, this study explains the formation of complexes with unusual stoichiometries when investigating the binding of dihydrogenphosphate anion to hydrogen?bonding receptors.
  • Edwards, P., Hiscock, J., Gale, P. and Light, M. (2010). Carbamate complexation by urea-based receptors: studies in solution and the solid state. Organic & Biomolecular Chemistry [Online] 8:100-106. Available at: http://dx.doi.org/10.1039/B917140A.
    The interactions of a series of urea based neutral hydrogen bond donor anion receptors have been investigated with i) alkylcarbamate anions formed by the reaction of carbon dioxide with primary aliphatic amines and ii) the zwitterionic species formed by the reaction of carbon dioxide with 1,4,5,6-tetrahydropyrimidine. Significant downfield chemical shift changes were observed for the urea NH protons in many cases, consistent with host?:?anion hydrogen bonding interactions, and thus stabilisation of the carbon dioxide bound species. In the case of the alkylammonium-alkylcarbamate salts, this represents successful competition with electrostatic interactions between the alkylcarbamate and alkylammonium components of the salt. A synchrotron structure of a ternary complex formed by an amide appended diindolylurea, the ammonium carbamate salt formed by 1,3-diaminopropane and CO2 and 18-crown-6, was elucidated and shows the carbamate group bound by six hydrogen bonds (accepting five and donating one) to the functionalised diindolylurea.
  • Hiscock, J., Gale, P., Caltagirone, C., Hursthouse, M. and Light, M. (2010). Fluorescent carbazolylurea- and carbazolylthiourea-based anion receptors and sensors. Supramolecular Chemistry [Online] 22:647-652. Available at: https://doi.org/10.1080/10610271003637087.
    A series of carbazolylurea- and carbazolylthiourea-based receptors have been synthesised and their anion complexation and fluorescence properties were studied. The urea compounds show selectivity for oxo-anion complexation over chloride and the fluorescence of compound 1 is selectively quenched by benzoate anions in DMSO/0.5% water. However, the thiourea compounds show reduced anion affinities compared to the urea analogues.
  • Edwards, P., Hiscock, J. and Gale, P. (2009). Stabilisation of alkylcarbamate anions using neutral hydrogen bond donors. Tetrahedron Letters [Online] 50:4922-4924. Available at: https://doi.org/10.1016/j.tetlet.2009.06.058.
    The interactions of a series of urea-based anion receptors and alkylcarbamate species formed by the reaction of carbon dioxide with primary amines have been investigated by 1H NMR. Significant downfield shifts in the NH proton signals of the receptors in the presence of the alkylcarbamates were observed, consistent with classical host:anion hydrogen-bonding. This observation demonstrates that neutral hydrogen bond donor receptors can compete with ammonium cations to bind carbamates in DMSO-d6 solution.
  • Fisher, M., Gale, P., Hiscock, J., Hursthouse, M., Light, M., Schmidtchen, F. and Tong, C. (2009). 1,2,3-Triazole-strapped calix[4]pyrrole: a new membrane transporter for chloride. Chemical Communications [Online] 2009:3017-3019. Available at: http://dx.doi.org/10.1039/B904089G.
    A new triazole-strapped calix[4]pyrrole synthesised via ‘click’ chemistry shows high affinity for chloride and lipid bilayer chloride transport properties.
  • Hiscock, J., Caltagirone, C., Light, M., Hursthouse, M. and Gale, P. (2009). Fluorescent carbazolylurea anion receptors. Organic & Biomolecular Chemistry [Online] 2009:1781-1783. Available at: http://dx.doi.org/10.1039/B900178F.
    A series of fluorescent carbazolylurea base anion receptors have been synthesised that show a high affinity for oxo-anions (particularly bicarbonate and acetate). The fluorescence of dicarbazolylurea (1) is quenched upon addition of benzoate anions in DMSO–0.5% water.
  • Caltagirone, C., Gale, P., Hiscock, J., Hursthouse, M., Light, M., Gale, P. and Tizzard, G. (2009). 2-Amidoindole-based anion receptors. Supramolecular Chemistry [Online] 21:125-130. Available at: https://doi.org/10.1080/10610270802348243.
    Four receptors containing either 2-amidoindole or 7-nitro-2-amidoindole groups have been synthesised and shown to complex oxoanions in DMSO-d 6/0.5% water solution. X-ray crystal structure elucidation reveals that receptor 1 complexes dihydrogen phosphate ion pairs in the solid state, which are part of a continuous chain. While this receptor binds dihydrogen phosphate in a 1:1 stoichiometry in solution, compound 4, which contains 7-nitroindole groups, does form 1:2 receptor:dihydrogen phosphate complexes in DMSO-d 6/0.5% water.
  • Caltagirone, C., Hiscock, J., Hursthouse, M., Light, M. and Gale, P. (2008). 1,3-Diindolylureas and 1,3-Diindolythioureas: Anion Complexation studies in Solution and the Solid State. Chemistry - A European Journal [Online] 14:10236-20243. Available at: https://doi.org/10.1002/chem.200801639.
    1,3?Diindolylureas and thioureas have been synthesised and their anion complexation properties in solution studied. Whilst diindolylthioureas showed only moderate affinities and selectivities, diindolylureas show remarkably high affinity for dihydrogen phosphate in solution for an acyclic, neutral receptor in water/[D6]DMSO mixtures. These easy?to?make compounds adopt relatively planar conformations in the solid?state and are able to donate four hydrogen bonds and yet not fill the coordination sphere of carbonate or phosphate, allowing two or three receptors to bind to each anion in the solid?state.
  • Caltagirone, C., Gale, P., Hiscock, J., Brooks, S., Hursthouse, M. and Light, M. (2008). 1,3-Diindolylureas: high affinity dihydrogen phosphate receptors. Chemical Communications [Online] 2008:3007-3009. Available at: http://dx.doi.org/10.1039/B806238B.
    Neutral 1,3-di(1H-indol-7-yl)ureas are selective dihydrogen phosphate receptors in polar solvent mixtures (DMSO-d6–25% water).

Thesis

  • White, L. (2018). Symbiotic Supramolecular Chemistry - The Development of Smart Soaps.
    Supramolecular chemistry is continually being explored, applied and expanded in many countries all over
    the world. The complexity of this area of science means that it is continually researched.
    This study has demonstrated the importance of the self-assembly between surfactants structures
    and supramolecular aggregation. Within this thesis the design, synthesis, characterization and binding
    properties of five amphiphilic molecules are discussed. These molecules were investigated in the gaseous
    phase, solid and solution states by a variety of complementary analytical techniques with the results
    demonstrating that the anionic monomers have a propensity to self-associate into a variety of aggregated
    species.
    A selection of 1H and DOSY NMR experiments were conducted in DMSO-d6, providing evidence
    that these molecules tend to form dimeric rather than larger aggregated species. The presence of
    hydrogen bonding was further confirmed by 1H NMR self-association studies, showing a down field
    change in chemical shift due to both the urea NH. The data when fitted to dimerization/Equal K (EK)
    binding model showed that the dimerization constant increases in line with the increase of aromatic
    substituents. By direct observation it was established that the sulfonate-anion molecules self-associated
    through intermolecular hydrogen bonds to form aggregated species of either irregular or spherical shape
    in solution. The size and type of these species was both concentration, and solute dependent. CMC values
    and dimerization constants correlated well with the computationally derived Emax and Emin values, giving
    preliminary evidence that self-association properties may be predicted by low level computational
    modelling methods. This innovative, cohesive branch of supramolecular chemistry will revolutionise the
    study and scope of non-covalent interactions beyond the molecule.
  • Wilson, B. (2017). Assay Development and Efficacy Testing of Novel and Established Antimicrobials.
    Over the past 25 years, new antimicrobial discovery has ground to a halt, this combined
    with a rise in antimicrobial resistance in pathogenic bacteria, is causing the number of
    effective treatments available to humankind decrease.
    For my thesis, I explored the testing methods for screening antimicrobial compounds and
    found them to be inefficient. One of the limiting factors for the discovery of new antimicrobial
    compounds are the efficacy testing assays and high-throughput screening methods used
    by researchers. These methods mainly measure the ability of a compound to diffuse
    through or across a medium, be it agar, filter papers or testing strips.
    Within this thesis I developed new testing assays for a family of novel antimicrobials, as
    their efficacy wasn't measurable by the standard procedures. I also measured the MIC50
    and MIC100 values of all the compounds in the group. They had measurable antimicrobial
    effect against Gram-Positive bacteria - comparable with established compounds like
    Vancomycin, and measurable interaction with Gram-Negative bacteria, coating the cells
    and inhibiting growth.
    I then further explored the coating interaction, adding the compounds to bacteria, but also
    adding solutions of established antimicrobials, I found that the compound boosted the
    efficacy of the established compounds and was also able to overcome resistance
    mechanisms developed by the bacteria.
    Finally, I developed a modular, 3D printed robot to standardise and increase the accuracy
    of the new testing methods.
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