ANSTO :: Browsing by Author "Krause-Heuer, AM"

Browsing by Author "Krause-Heuer, AM"

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Advancements in the provision of deuterated lipids for neutron applications from the National Deuteration Facility
(Australian Institute of Nuclear Science and Engineering (AINSE), 2020-11-11) Yepuri, NR; Moir, M; Krause-Heuer, AM; Klenner, MA; Darwish, TA
Molecular deuteration significantly increases the options for structure-function investigations using neutron scattering and diffraction techniques. Chemical deuteration activities, where catalysed 1H/2H exchange is followed by custom chemical synthesis, have led to diverse neutron scattering and reflectometry studies previously hampered by the lack of appropriate scattering contrast in multi-component samples. Deuteration of phospholipids is a common practice to elucidate membrane structure, dynamics and function, by providing selective visualisation in neutron scattering. Although analogous deuterium? (2H) and hydrogen? containing (1H) molecules have similar physicochemical properties, these isotopes of hydrogen result in vastly different for neutron scattering signals. Over the past few years the National Deuteration Facility (ANSTO) has increased its synthetic capability to produce complex deuterated molecules including lipids and phospholipids. Such synthetically challenging molecules are perdeuterated phytantriol1, tail deuterated POPC, and perdeuterated POPC.2 Phytantriol is an interfacially-active lipid that is chemically robust, non-digestible and forms particles with internal bicontinuous cubic phase structures (cubosomes) when dispersed with non-ionic surfactants at physiological temperatures. The tail-deuterated POPC, perdeuterated POPC and tail-deuterated GMO isotopologues would also provide suitable contrast for many neutron experiments and so these have been also our synthetic targets. Recently neutron reflection was employed to investigate the impact of phospholipid saturation (POPC-d64) and presence of cholesterol in cell model membranes on LDL and HDL lipid exchange and removal processes.3 Neutron reflection data that distinguish the effect of phospholipid acyl chain saturation and the presence of cholesterol on the ability of lipoproteins to exchange lipids to/from model membrane will be presented.
ANSTO’s National Deuteration Facility: recent advancements and an overview on molecular deuteration capabilities for neutron applications
(Australian Institute of Nuclear Science and Engineering (AINSE), 2020-11-11) Wilde, KL; Cagnes, MP; Duff, AP; Klenner, MA; Krause-Heuer, AM; Moir, M; Rekas, A; Russell, RA; Yepuri, NR; Darwish, TA
The National Deuteration Facility (NDF) at the Australian Nuclear Science and Technology Organisation (ANSTO) provides deuteration through both biological and chemical techniques for a diversity of molecules and applications and is the only facility of its type in the Southern Hemisphere with the specialised expertise and infrastructure for both biological and chemical molecular deuteration. Molecular deuteration of organic compounds and biomolecules significantly increases the options in complex structure function investigations using neutron scattering and reflectometry, nuclear magnetic resonance (NMR), mass spectrometry (MS) and other techniques. Deuteration (substitution of the naturally occurring hydrogen stable isotope deuterium (2H or D) for 1H (or H)) can provide contrast and improved resolution to assist investigations into the relationship between molecular structure and function of molecules of both biological and synthetic origin. By developing a suite of capabilities in both in vivo deuteration of biomolecules and chemical deuteration of small organic molecules, the NDF provides access to a broad range of deuterated molecules for research and industry. Variably deuterated proteins can be produced via recombinant expression in Escherichia coli and other microbial systems utilised to produce deuterated cellulose and cholesterol. By tailoring deuteration approaches with the ongoing development of chemical deuteration protocols for a broader range of molecular classes than available commercially, the NDF has increased the range of systems that can be investigated using deuterated molecules. Lipids, phospholipids (including head or tail or head/tail deuterated mono-unsaturated lipids such as POPC and DOPC), heterocyclics, aromatics, surfactants, ionic liquids, saturated and unsaturated fatty acids, sugars and match-out detergents have been deuterated. Common neutron applications include partially deuterated proteins for SANS experiments investigating multiprotein systems, neutron crystallography of perdeuterated proteins, neutron reflectometry of lipid bilayers systems and SANS using saturated lipid vesicles, or detergents amongst others. An overview and update on the NDF will be provided which will include details on the NDF User Program (e.g. information on the available modes of access), recent advancements in custom deuterated molecules available and brief highlights of deuterated molecule utilisation for neutron experiments at ANSTO’s Australian Centre for Neutron Scattering (ACNS). © 2020 The Authors.
Behaviour of single transmembrane peptides during in meso crystallization from the contrast-matched lipidic cubic phase of monoolein
(Australian Institute of Nuclear Science and Engineering (AINSE), 2018-11-19) van't Hag, L; de Campo, L; Tran, N; Sokolova, AV; Trenker, R; Call, M; Garvey, CJ; Leung., A; Darwish, TA; Krause-Heuer, AM; Knott, RB; Meikle, T; Gras, S; Drummond, CJ; Mezzenga, R; Conn, C
In meso membrane protein crystallization within a lipidic mesophase has revolutionized the structural biology of integral membrane proteins (IMPs). High-resolution structures of these proteins are crucial to understanding fundamental cellular processes at a molecular level, and can lead to new and improved treatments for a wide range of diseases via rational drug design. However, overall success rates of the promising in meso crystallization technique remain low because of a fundamental lack of understanding about factors that promote crystal growth. In particular, to date, two decades from invention of the method, the protein-eye-view of the in meso crystallization mechanism had not been solved. We have investigated this for the first time using small-angle neutron scattering (SANS). Contrast-matching between the scattering of the lipid membrane formed by MO and the aqueous solution was used to isolate and track the scattering of single-transmembrane peptides during the growth of protein crystals in meso. No peptide enrichment was observed at the flat points of the diamond cubic QIID phase of MO in contrast to suggestions in several modeling studies. During in meso crystallization of the DAP12 peptide a decrease in form factor and a transient fluid lamellar Lα phase could be observed providing direct evidence for the proposed crystallization mechanism. Synthesis of fully deuterated MO was required for this purpose and scattering of this new material in various solvents and under a range of conditions will be described, specifically regarding the effect of the relative scattering length densities (SLD) of the headgroup, acyl chain and solvent, which can advance the use of neutron scattering with other self-assembly materials. © The Authors.
Biodegradability of sol-gel silica microparticles for drug delivery
(Springer, 2009-01) Finnie, KS; Waller, DJ; Perret, FL; Krause-Heuer, AM; Lin, HQ; Hanna, JV; Barbé, CJ
The biodegradability of porous sol–gel silica microparticles in physiological buffers has been investigated using a USP4 flow-through dissolution tester. In the open configuration, which most closely models in-vivo conditions, the particles dissolved rapidly at pH 7.4, with a rate dependent on the surface area and media flow rate. In the closed configuration, the fastest dissolving 4 mg silica sample was almost completely dissolved in 100 mL of buffer after 36 h. The initial dissolution rates appeared relatively linear but dropped off as dissolved SiO2 concentrations approached 20–25 ppm. Addition of serum proteins acted to slow dissolution by 20–30%, suggesting a slower degradation in vivo. Silica microparticles administered for controlled release drug delivery would therefore be expected to be eliminated relatively rapidly from the body, depending on the sample size and local fluid flow conditions. © 2009, Springer. The original publication is available at www.springerlink.com
Chemical disorder in a frustrated J1/J2 quantum spin chain material
(Australian Institute of Physics, 2018-01-30) Rule, KC; Mole, RA; Zanardo, J; Krause-Heuer, AM; Darwish, TA; Lerch, MLF
Recently a new one-dimensional (1D) quantum spin chain system has been synthesised: catena-dichloro(2-Cl-3Mpy)copper(II), [where 2-Cl-3Mpy=2-chloro-3-methylpyridine]. We shall refer to this compound as cd-Cu. Preliminary calculations and bulk magnetic property measurements indicate that this system does not undergo magnetic ordering down to 1.8K and is a prime candidate for investigating frustration in a J1/J2 system (where the nearest neighbour interactions, J1, are ferromagnetic and the next nearest neighbour interactions, J2, are antiferromagnetic) [1]. Calculations predicted 3 possible magnetic interaction strengths for J1 below 6meV depending on the orientation of the ligand [2]. For one of the predicted J1values, the existence of a quantum critical point is implied. A deuterated sample of cd-Cu was produced at the National Deuteration Facility and the excitations measured using the PELICAN TOF spectrometer. Scattering was weak from this sample, but indicated the most likely scenario involves an average of the 3 possible magnetic excitations in this material, rather than the random array of exchange interactions as predicted by Herringer et al., [2]. This may indicate the possibility of tuning the chemical structure to favour a system which may exhibit a quantum critical point.
Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter
(Elsevier B. V., 2019-01) Fraser-Spears, R; Krause-Heuer, AM; Basiouny, M; Mayer, FP; Manishimwe, M; Wyatt, NA; Dobrowolski, JC; Roberts, MP; Greguric, ID; Kumar, N; Koek, W; Sitte, HH; Callaghan, PD; Fraser, BH; Daws, LC
Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders. © 2021 Elsevier B.V.
Crystal growth and characterisation of a new J1-J2 spin-chain material
(Australian Institute of Nuclear Science and Engineering, 2016-11-29) Zanardo, J; Rule, KC; Krause-Heuer, AM; Mole, RA; Lerch, MLF
Recently a new one-dimensional (1D) quantum spin chain system has been synthesised: catena-dichloro(2-Cl-3Mpy)copper(II), [where 2-Cl-3Mpy=2-chloro-3-methylpyridine] [1]. Preliminary calculations and bulk magnetic property measurements indicate that this system does not undergo magnetic ordering down to 1.8K and is a prime candidate for investigating frustration in a J1/J2 system (where the next nearest neighbour interactions, J2, are antiferromagnetic and the nearest neighbour interactions, J1, are ferromagnetic) [2]. Calculations predict 3 possible magnetic excitations below 6meV which may reveal the nature of the random static structural disorder predicted in this material. One method for directly observing the magnetic excitations is neutron scattering and measurements have been performed on the neutron Time of Flight spectrometer PELICAN at ANSTO [3]. To a first approximation, linear spin-wave theory has been used to model the expected neutron excitations for this J2/J1 system using the Matlab package SpinW. The results of this project may provide valuable insight into the nature of magnetic frustration in materials. To optimise the observed magnetic signal via the reduction of incoherent neutron scattering, this compound was deuterated at the National Deuteration Facility at ANSTO. In this presentation we will outline our deuterated growth procedure as well as the characterisation methods performed to understand the material further. This work forms the Honours thesis project of Jack Zanardo from University of Wollongong.
Deuterated phospholipids to study the structure, function and dynamics of membrane proteins using neutron scattering
(Australian Nuclear Science and Technology Organisation, 2021-11-26) Yepuri, NR; Moir, M; Krause-Heuer, AM; Darwish, TA
Contrast matching and contrast variation in neutron scattering provide unparalleled power for understanding the structure, function, and dynamics of a selected component in a multicomponent system. A sophisticated contrast study often requires the availability of deuterated molecules in which deuterium atoms are introduced in a predictable and controlled fashion to replace protons. This can be achieved by direct deuteration of precursors followed by custom chemical synthesis, for which expertise and capabilities have been developed at facility (NDF), ANSTO. It this paper we will discuss recent high impact research output using deuterated phospholipids produced by NDF/ANSTO. We will describe the synthesis and applications of selectively or perdeuterated unsaturated phospholipids to contrast match out the whole lipid bilayer or nano disks within a multicomponent system. Further, we also describe their role in investigations related to membrane lipoproteins (ApoE) exchange in relation to lipid unsaturation,[1] effect of membrane composition,[2] and conformational analysis Mg+2 channel by neutron scattering techniques.[2, 3]
Deuteration for biological SANS: case studies, success and challenges in chemistry and biology
(Elsevier, 2022-11) Duff, AP; Cagnes, MP; Darwish, TA; Krause-Heuer, AM; Moir, M; Recsei, C; Rekas, A; Russell, RA; Wilde, KL; Yepuri, NR
Small angle neutron scattering is a powerful complementary technique in structural biology. It generally requires, or benefits from, deuteration to achieve its unique potentials. Molecular deuteration has become a mature expertise, with deuteration facilities located worldwide to support access to the technique for a wide breadth of structural biology and life sciences. The sorts of problems well answered by small angle scattering and deuteration involve large (> 10 Å) scale flexible movements, and this approach is best used where high-resolution methods (crystallography, NMR, cryo-EM) leave questions unanswered. This chapter introduces deuteration, reviewing biological deuteration of proteins, lipids and sterols, and then steps through the ever-expanding range of deuterated molecules being produced by chemical synthesis and enabling sophisticated experiments using physiologically relevant lipids. Case studies of recent successful use of deuteration may provide illustrative examples for strategies for future experiments. We discuss issues of nomenclature for synthesised molecules of novel labeling and make recommendations for their naming. We reflect on our experiences, with cost associated with achieving an arbitrary deuteration level, and on the benefits of experimental co-design by user scientist, deuteration scientist, and neutron scattering scientist working together. Although methods for biological and chemical deuteration are published in the public domain, we recommend that the best method to deuterate is to engage with a deuteration facility. © 2022 Elsevier
Development of novel ligands for emerging radiometal isotopes
(John Wiley & Sons, Inc., 2013-04-11) Ashford, ME; Burgess, L; Cheah, WC; Krause-Heuer, AM; Fraser, BH; Greguric, ID; Lengkeek, NA
Background: The use of radiometals (non-Tc, non-Re) in targeted diagnosis and radiotherapy of different disease states has increased significantly over the last 15 years. ANSTO LifeSciences radiometals program seeks to provide a suite of radiometal tools for use in PET imaging and therapeutic modalities to improve upon the existing technologies which are currently dominated by 99mTc. This will enable researchers and clinicians to study and diagnose diseases with a greater efficacy and efficiency. Method: Many of the ligands currently available for radiometals have numerous drawbacks , including unfavourable in vivo properties such as thermodynamic and kinetic stability and poor lipophilicity. We are developing new ligand systems to have improved radiometal specificity while including design flexibility allowing us to manipulate properties such as biodistribution patterns, excretion rates, pharmacokinetics, thermodynamics and in vivo stability. The synthesis should be straightforward and cost effective and have the potential for bioconjugation in the initial design. Complexation studies are performed in vitro to assess the ligands suitability. Results: We are developing ligand systems for 68Ga, 89Zr, 64Cu, 90Y and 177Lu. We have prepared a novel analogue of the ubiquitous ligand NOTA (Figure 1, b); our system replaces the biologically labile carboxylic acid with a corresponding, biologically inert isotere, a tetrazole. This manipulation should provide additional stability and increased complex lipophilicity. Our studies have shown that a tetrazole analogue of NOTA (Figure 1, b) forms stable cold-metal complexes with potential PET metals of interest such as Ga3+. Conclusion: ANSTO LifeSciences provides a complete synthetic ligand and metal complex program, complementing its broader Radiometals Program. The aim of which is to provide an array of clinically relevant ligands that can be used in multiple applications for specific metal radiopharmaceuticals for improved patient outcomes. © 2013 John Wiley & Sons
Differential activity of decynium-22 analogs: novel targets for probing low-affinity/high-capacity biogenic amine transporters
(Federation of American Societies for Experimental Biology (FASEB), 2015-04-01) Fraser, R; Owens, A; Wyatt, NA; Krause-Heuer, AM; Greguric, ID; Callaghan, PD; Fraser, BH; Daws, LC
We study neurotransmitter clearance by low-affinity, high-capacity uptake-2 transporters. This family includes plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1-3). We have shown uptake-2 transporters limit the effectiveness of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine. Discerning the transporter type(s) involved is restricted by the lack of highly selective ligands. This project examines the pharmacological characteristics of novel uptake-2 compounds. Activity of ANSTO analogs, structurally based on the non-selective inhibitor decynium 22 (D22), was tested in human OCT3-HEK cells. Ligand competitions of [3H]MPP+ uptake were measured in whole, attached cells. Compared to D22, dose-responses of ANSTO compounds shifted 1- or 2 log-rightward, indicating reduced potency to inhibit OCT3 mediated [3H]MPP+ uptake. ANSTO analogs displayed similar potencies to corticosterone and may have higher selectivity at alternate uptake 2 subtypes. © 2015 Federation of American Societies for Experimental Biology (FASEB)
Elucidation of the electronic structure in lanthanoid-radical systems by inelastic neutron scattering
(Australian Nuclear Science and Technology Organisation, 2021-11-24) Dunstan, MA; Calvello, S; Soncini, A; Krause-Heuer, AM; Mole, RA; Boskovic, C
Single-molecule magnets (SMMs) are metal organic compounds which exhibit magnetic hysteresis and slow magnetic relaxation at low temperature. They have potential applications in high density data storage, quantum computing, and molecular spintronics. Coordination complexes of the trivalent lanthanoid (Ln(III)) ions are the current best performing SMMs, with examples showing hysteresis above liquid nitrogen temperature.[1] The magnetic properties of Ln(III) ions stems from the crystal field (CF) splitting of the ground Russel-Saunders state. These CF states give rise to the energy barrier to reversal of magnetisation, and can be tuned by modification of the ligand environment around the Ln(III) centre. Slow magnetic relaxation in Ln-SMMs can also be modulated by the introduction of magnetic exchange coupling with another magnetic moment, such as that of an organic radical ligand.[2] Quantifying the magnitude of magnetic exchange coupling in many Ln(III) systems is, however, difficult using conventional magnetometric techniques, due to the often large spin-orbit coupling. Inelastic neutron scattering (INS) is an ideal spectroscopic tool to measure both CF splitting and magnetic exchange coupling in Ln(III) systems.[3] We have used INS measurements to elucidate the magnetic exchange coupling and CF splitting in Ln(III)-semiquinonate complexes. Using this information we have rationalised the magnetic properties of these compounds, with the hope that a better understanding of the magnetic exchange in these systems can be used to design SMMs with improved performance. © 2021 The Authors
Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22
(Elsevier B. V., 2017-09-08) Krause-Heuer, AM; Fraser-Spears, R; Dobrowolski, JC; Ashford, ME; Wyatt, NA; Roberts, MP; Gould, GG; Cheah, WC; Ng, CKL; Bhadbhade, MM; Zhang, B; Greguric, ID; Wheate, NJ; Kumar, N; Koek, W; Callaghan, PD; Daws, LC; Fraser, BH
Antidepressant-like activity Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1–7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1–7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. © 2017 Elsevier B.V.
A fluorine-18 radiolabeling method enabled by rhenium(I) complexation circumvents the requirement of anhydrous conditions
(John Wiley & Sons, Inc, 2017-03-22) Klenner, MA; Pascali, G; Zhang, B; Sia, TR; Spare, LK; Krause-Heuer, AM; Aldrich-Wright, JR; Greguric, ID; Guastella, AJ; Massi, M; Fraser, BH
Azeotropic distillation is typically required to achieve fluorine-18 radiolabeling during the production of positron emission tomography (PET) imaging agents. However, this time-consuming process also limits fluorine-18 incorporation, due to radioactive decay of the isotope and its adsorption to the drying vessel. In addressing these limitations, the fluorine-18 radiolabeling of one model rhenium(I) complex is reported here, which is significantly improved under conditions that do not require azeotropic drying. This work could open a route towards the investigation of a simplified metal-mediated late-stage radiofluorination method, which would expand upon the accessibility of new PET and PET-optical probes. © 2017 John Wiley & Sons, Inc
In vivo evaluation of radiofluorinated caspase-3/7 inhibitors as radiotracers for apoptosis imaging and comparison with [18F]ML-10 in a stroke model in the rat
(Springer Nature, 2016-02-01) Médoc, M; Dhilly, M; Matesic, L; Toutain, J; Krause-Heuer, AM; Delamare, J; Fraser, BH; Touzani, O; Barré, L; Greguric, ID; Sobrio, F
The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis © 2016 Springer Nature
Inelastic neutron scattering of lanthanoid-radical molecular nanomagnets
(Australian Institute of Nuclear Science and Engineering (AINSE), 2020-11-11) Dunstan, MA; Calvello, S; Krause-Heuer, AM; Soncini, A; Mole, RA; Boskovic, C
SSingle-molecule magnets (SMMs) are materials which exhibit slow relaxation of magnetization and quantum tunneling of molecular origin. These properties make them promising for future applications in high-density data storage, as qubits in quantum computing, and in molecular spintronics.[1] The best performing SMMs are complexes of the late trivalent lanthanoid (Ln(III)) ions. The energy barrier to reversal of magnetization here stems from the crystal field (CF) splitting of the spin-orbit coupled ground state with total angular momentum J. The identity and geometry of the coordinated ligands determines the relative order, energy and composition of these CF states, such that appropriate choice of ligands can tune the CF splitting and therefore the SMM behaviour. Incorporation of organic radicals can be used to improve SMM behaviour, by shifting quantum tunneling of the magnetisation, a through-barrier relaxation pathway, from zero field.[2] The nature of magnetic exchange coupling between a Ln(III) ion and another paramagnetic moiety is, however, hard to determine, and often cannot be determined directly due to the large spin-orbit coupling inherent in many Ln compounds. Inelastic neutron scattering is a powerful experimental technique for directly measuring the CF splitting and exchange coupling in Ln(III) compounds.[3] Our group has been studying a family of compounds with formula [Ln(dbsq)Tp2], Tp– = tris(pyrazolyl)borate, dbsq– = 3,5-di-tert-butyl-semiquinonate, which show exchange coupling between the Ln(III) ion and the dbsq organic radical.[4] We have studied the INS spectra the Ln = Tb, Ho, Er, and Yb analogues on the cold neutron time-of-flight spectrometer PELICAN, as well as their magnetic properties. We observe temperature dependent CF transitions, which are compared to the energy level splitting obtained from electronic structure calculations, as well as exchange transitions in two analogues, which give us both the magnitude of and spatial information about the exchange coupling in this family of compounds.
Ionophoric properties of a tetra-tetrazole functionalised calix[4]arene
(Taylor and Francis Group, 2015-10-23) D'Alessio, D; Skelton, BW; Lengkeek, NA; Fraser, BH; Krause-Heuer, AM; Muzzioli, S; Stagni, S; Massi, M; Ogden, MI
The synthesis and characterisation of p-t-butylcalix[4]arene functionalised at the lower rim with four tetrazole moieties is reported. The macrocycle is found to be a poorer ionophore for lanthanoid cations than the bis-tetrazole–substituted analogue. Solution-phase photophysical studies strongly suggested that the cations interacted only weakly with the calixarene ligand. A mixed sodium/triethylammonium salt of the calixarene ligand was crystallised in the presence of lanthanoid cations and structurally characterised. Strong intramolecular interactions are hypothesised to be the cause of the observed behaviour. © 2015 Taylor & Francis
Lanthanoid complexation by a tris-tetrazole-functionalised calix[4]arene
(John Wiley & Sons, Inc, 2016-12-19) D'Alessio, D; Skelton, BW; Sobolev, AN; Krause-Heuer, AM; Fraser, BH; Massi, M; Ogden, MI
The synthesis and characterization of 5,11,17,23-tetra-tert-butyl-25-hydroxy-26,27,28-tris(tetrazol-5-ylmethoxy)calix[4]arene is reported. Purification of the macrocycle required the use of preparative HPLC techniques. The macrocycle was found to be a poorer ligand for complexation of lanthanoid cations than the bis(tetrazole) analogue, but somewhat more effective than the tetrakis(tetrazole)-substituted derivative. Two metal complexes of the tris(tetrazole)–calixarene were structurally characterised. A polymeric sodium salt of the tris(tetrazole)–calixarene was isolated from a solution containing yttrium and a sodium acetate buffer. A praseodymium complex was isolated in the presence of an ammonium acetate buffer, where the calixarene acts as a unidentate ligand, bound to the metal atom through one tetrazole N-atom. Increasing the amount of buffer resulted in the crystallisation of a metal-free ammonium salt of the calixarene. © 2016 John Wiley & Sons, Inc.
Mild conditions for deuteration of primary and secondary arylamines for the synthesis of deuterated optoelectronic organic molecules
(Multidisciplinary Digital Publishing Institute, 2014-11-13) Krause-Heuer, AM; Yepuri, NR; Darwish, TA; Holden, PJ
Deuterated arylamines demonstrate great potential for use in optoelectronic devices, but their widespread utility requires a method for large-scale synthesis. The incorporation of these deuterated materials into optoelectronic devices also provides the opportunity for studies of the functioning device using neutron reflectometry based on the difference in the scattering length density between protonated and deuterated compounds. Here we report mild deuteration conditions utilising standard laboratory glassware for the deuteration of: diphenylamine, N-phenylnaphthylamine, N-phenyl-o-phenylenediamine and 1-naphthylamine (via H/D exchange in D2O at 80 °C, catalysed by Pt/C and Pd/C). These conditions were not successful in the deuteration of triphenylamine or N,N-dimethylaniline, suggesting that these mild conditions are not suitable for the deuteration of tertiary arylamines, but are likely to be applicable for the deuteration of other primary and secondary arylamines. The deuterated arylamines can then be used for synthesis of larger organic molecules or polymers with optoelectronic applications. © 2014, Creative Commons.
A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis
(Royal Society of Chemistry, 2012-11-12) Krause-Heuer, AM; Howell, NR; Matesic, L; Dhand, G; Young, EL; Burgess, L; Jiang, CD; Lengkeek, NA; Fookes, CJR; Pham, TQ; Sobrio, F; Greguric, ID; Fraser, BH
Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy. © 2013 Royal Society of Chemistry

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