RECENT PUBLICATIONS

Mr Michael Moir and Prof Michael Kassiou et al

Professor Michael Kassiou

Prof Michael Kassiou

Posted 21 February 2017
Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA
Journal of Psychopharmacology, Online, 1-13, 2017.

Abstract:
ynthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with delta9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 x 1 mg/kg and 6 x 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.


Dr Prarthana Devi and A/Prof Peter Rutledge*

Associate Professor Peter Rutledge

A/Prof Peter Rutledge

Posted 21 February 2017
Cyclobutanone analogues of beta-lactam antibiotics: beta-lactamase inhibitors with untapped potential?
ChemBioChem, 18 (4), 338-351, 2017.

Abstract:
β-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H α to a ketone. Cyclobutanone analogues of various β-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the β-lactamase enzymes that impart resistance to β-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of β-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of β-lactamase; other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.


Dr Paula Kayser, Prof Brendan Kennedy* and Mr Ben Ranjbar

Professor Brendan Kennedy

Prof Brendan Kennedy

Posted 21 February 2017
Spin-orbit coupling controlled ground state in the Ir(V) perovskites A2ScIrO6 (A = Ba or Sr)
Inorganic Chemistry, 56 (4), 2204-2209, 2017.

Abstract:
The structural and magnetic properties of the two Ir(V) perovskites Ba2ScIrO6 and Sr2ScIrO6 were established. The structures were refined using a combined neutron and synchrotron data set. At room temperature the former has a cubic structure in space group Fm3̅m with a = 8.1450(3) Å, and the latter is monoclinic in P21/n with a = 5.6606(3) Å, b = 5.6366(3) Å, c = 7.9720(4) Å, and β = 89.977(5)°. Magnetization measurements show both oxides have magnetic moments close to zero as a consequence of strong spin-orbit coupling that results in a Jeff approximately 0 ground state. The distortion of the IrO6 octahedra in Sr2ScIrO6 is insufficient to generate crystal field splitting strong enough to quench the spin-orbit coupling.


Ms Saffron Bryant and Prof Greg Warr* et al

Professor Greg Warr

Prof Greg Warr

Posted 21 February 2017
Effect of protic ionic liquid nanostructure on phospholipid vesicle formation
Soft Matter, 13 (7), 1364-1370, 2017.

Abstract:
The formation of bilayer-based lyotropic liquid crystals and vesicle dispersions by phospholipids in a range of protic ionic liquids has been investigated by polarizing optical microscopy using isothermal penetration scans, differential scanning calorimetry, and small angle X-ray and neutron scattering. The stability and structure of both lamellar phases and vesicle dispersions is found to depend primarily on the underlying amphiphilic nanostructure of the ionic liquid itself. This finding has significant implications for the use of ionic liquids in soft and biological materials and for biopreservation, and demonstrates how vesicle structure and properties can be controlled through selection of cation and anion. For a given ionic liquid, systematic trends in bilayer thickness, chain-melting temperature and enthalpy increase with phospholipid acyl chain length, paralleling behaviour in aqueous systems.


Mr Ian Douglass, Ms Helen Mayger, Dr Toby Hudson and Prof Peter Harrowell*

Professor Peter Harrowell

Prof Peter Harrowell

Posted 21 February 2017
The stabilization of tubular crystals in mixtures of spherical particles
Soft Matter, 13 (7), 1344-1351, 2017.

Abstract:
Novel crystal structures in binary atomic mixtures arise when the attractive well is wide enough to allow double occupancy by small particles. The resulting crystals consist of ordered packings of self assembled linear structures comprised of a cylindrical tube of large particles enclosing a close packed core of small particles that corresponds to a stacking of overlapping icosahedra. We show that the stability of these structures depends on two essential features of the spherically symmetric pairwise interactions: (i) a radius ratio between 0.414 and 0.588, and (ii) a width w of the attractive well in the interaction between unlike particles that satisfies w > σSS where σSS is the diameter of the small particle.


Professor Greg Warr et al

Professor Greg Warr

Prof Greg Warr

Posted 21 February 2017
Mixing cations with different alkyl chain lengths markedly depresses the melting point in deep eutectic solvents formed from alkylammonium bromide salts and urea
Chemical Communications, 53 (15), 2375-2377, 2017.

Abstract:
The melting point of a deep eutectic solvent formed from a ternary mixture of ethylammonium bromide (EABr), butylammonium bromide (BABr) and urea is 10 °C, which is almost 40 °C lower than the melting points of binary DESs formed from either EABr:urea or BABr:urea mixtures. This reveals a new route to prepare room temperature DESs via mixing different cations.


A/Prof Deanna D'Alessandro and Mr Pavel Usov et al

Associate Professor Deanna D

A/Prof Deanna D'Alessandro

Posted 21 February 2017
Structural and optical investigations of charge transfer complexes involving the radical anions of TCNQ and F4TCNQ
CrystEngComm, 18 (46), 8906-8914, 2016.

Abstract:
The structures and optical band gaps of twelve radical anionic 7,7,8,8-tetracyanoquinodimethane (TCNQ) and 7,7,8,8-tetracyano-2,3,4,5-tetrafluoroquinodimethane (F4TCNQ) based charge-transfer complexes are reported. The compounds described have been categorised into three general types based upon solid-state arrangements of the donor and acceptor molecules. Crystallographic, EPR and IR spectroscopic investigations indicated that both TCNQ and F4TCNQ in each of the compounds described exist in the radical monoanion form. Visible-NIR absorption measurements indicate optical band gaps in the range of 0.79 to 1.08 eV. Whilst the packing arrangements in CT complexes are known to affect the band gap, in the cases considered here no clear relationship between the packing arrangement and the optical band gap is apparent. The results suggest that in the absence of mixed valency the packing arrangement does not impact significantly upon the magnitude of the optical band gap.


Mr Marlowe Graham, Dr Robert Baker and A/Prof Chris McErlean*

Associate Professor Chris McErlean

A/Prof Chris McErlean

Posted 14 February 2017
Cationic polyene cyclization for taiwaniaquinoid construction
European Journal of Organic Chemistry, 2017 (4), 908-913, 2017.

Abstract:
An acid-catalyzed polyene cyclization has been used to rapidly generate the 6/5/6-fused ring system of the taiwaniaquinoid natural products. The cis-fused diastereomer was formed selectively, which enabled a step-efficient synthesis of (±)-5-epi-taiwaniaquinone G.


Dr Bun Chan, Dr Katie Cergol, Prof Richard Payne, E/Prof Leo Radom, Prof Tim Schmidt* et al

Professor Tim Schmidt

Prof Tim Schmidt

Posted 14 February 2017
Hydorgen-adduction to open-shell graphene fragments: spectroscopy, thermochemistry and astrochemistry
Chemical Science, 8 (2), 1186-1194, 2017.

Abstract:
We apply a combination of state-of-the-art experimental and quantum-chemical methods to elucidate the electronic and chemical energetics of hydrogen adduction to a model open-shell graphene fragment. The lowest-energy adduct, 1H-phenalene, is determined to have a bond dissociation energy of 258.1 kJ mol-1, while other isomers exhibit reduced or in some cases negative bond dissociation energies, the metastable species being bound by the emergence of a conical intersection along the high-symmetry dissociation coordinate. The gas-phase excitation spectrum of 1H-phenalene and its radical cation are recorded using laser spectroscopy coupled to mass-spectrometry. Several electronically excited states of both species are observed, allowing the determination of the excited-state bond dissociation energy. The ionization energy of 1H-phenalene is determined to be 7.449(17) eV, consistent with high-level W1X-2 calculations.


Professor Greg Warr et al

Professor Greg Warr

Prof Greg Warr

Posted 14 February 2017
Effect of cation alkyl chain length on surface forces and physical properties in deep eutectic solvents
Journal of Colloid and Interface Science, 494, 373-379, 2017.

Abstract:
Deep eutectic solvents (DESs) have been prepared from mixtures of alkyl ammonium bromide salts (ethylammonium bromide, propylammonium bromide and butylammonium bromide) and glycerol at a 1: 2 M ratio. These DESs reveal the effect of cation alkyl chain length on interfacial structure at mica (a model anionic) surface. As the cation chain length is increased it becomes more amphiphilic and solvophobic, leading to stronger association of alkyl chains, as revealed by atomic force microscope force curve measurements. The effect of increasing cation alkyl chain length on phase transition and thermal decomposition temperatures, density, refractive index, viscosity, ionic and thermal conductivity and air liquid surface tension are also probed. Combined, these studies reveal the length of the cation alkyl chain weakly affects composition dependent properties (e.g. density, refractive index, thermal conduction, etc.) but has a stronger effect where intermolecular (ionic) forces play a role, such as on viscosity, and on surface tension and interfacial structure. To the authors knowledge, this is the first report of amphiphilic nanostructure in DESs and the first systematic study of the effect of cation alkyl chain length on physical properties.


Dr Alvaro Garcia and A/Prof Ron Clarke* et al

Associate Professor Ron Clarke

A/Prof Ron Clarke

Posted 14 February 2017
The voltage-sensitive dye RH421 detects a Na+,K+-ATPase conformational change at the membrane surface
Biochimica et Biophysica Acta, 1859 (5), 813-823, 2017.

Abstract:
RH421 is a voltage-sensitive fluorescent styrylpyridinium dye which has often been used to probe the kinetics of Na+,K+-ATPase partial reactions. The origin of the dye's response has up to now been unclear. Here we show that RH421 responds to phosphorylation of the Na+,K+-ATPase by inorganic phosphate with a fluorescence increase. Analysis of the kinetics of the fluorescence response indicates that the probe is not detecting phosphorylation itself but rather a shift in the protein's E1/E2 conformational equilibrium induced by preferential phosphate binding to and phosphorylation of enzyme in the E2 conformation. Molecular dynamics simulations of crystal structures in lipid bilayers indicate some change in the protein's hydrophobic thickness during the E1-E2 transition, which may influence the dye response. However, the transition is known to involve significant rearrangement of the protein's highly charged lysine-rich cytoplasmic N-terminal sequence. Using poly-l-lysine as a model of the N-terminus, we show that an analogous response of RH421 to the E1 –> E2P conformational change is produced by poly-l-lysine binding to the surface of the Na+,K+-ATPase-containing membrane fragments. Thus, it seems that the prime origin of the RH421 fluorescence response is a change in the interaction of the protein's N-terminus with the surrounding membrane. Quantum mechanical calculations of the dye's visible absorption spectrum give further support to this conclusion. The results obtained indicate that membrane binding and release of the N-terminus of the Na+,K+-ATPase α-subunit are intimately involved in the protein's catalytic cycle and could represent an effective site of regulation.


Mr Theophile Pelras, Dr Hien Duong, Dr Byung Kim, A/Prof Brian Hawkett and Dr Markus Muellner

Dr Markus Muellner

Dr Markus Muellner

Posted 14 February 2017
A 'grafting from' approach to polymer nanorods for pH-triggered intracellular drug delivery
Polymer, 112, 244-251, 2017.

Abstract:
We report the use of the ‘grafting from’ approach to produce inherently rod-shaped polymer nanoparticles with triggered drug release. Cylindrical polymer brushes (CPBs) can be directly used to yield functional polymer nanorods for pH-sensitive drug release of doxorubicin (DOX). Water-soluble CPBs have been produced via a straightforward one-step grafting of vinyl benzaldehyde (VBA) and poly(ethylene glycol) methyl ether methacrylate (PEGMA) comonomers, in which the VBA distributed throughout the CPBs provides a cost-effective and simple functionality for the subsequent conjugation of DOX using imine chemistry. Atomic force microscopy (AFM) underlined the rod-like conformation of the CPBs prior and after drug conjugation. Fluorescence spectroscopy studies revealed faster drug release in acidic environments (pH 5.0) compared to physiological pH conditions (pH 7.4). Fluorescence lifetime imaging microscopy (FLIM) and in vitro cell studies further highlighted the intracellular DOX release from the CPB drug carriers within MCF-7 breast cancer cells.


Michael Murphy, Katrina Zenere, Florence Ragon, Peter Southon, Cameron Kepert and Suzanne Neville

Professor Cameron Kepert

Prof Cameron Kepert

Posted 7 February 2017
Guest programmable multistep spin crossover in a porous 2-D Hofmann-type material
JACS, 139 (3), 1330-1335, 2017.

Abstract:
The spin crossover (SCO) phenomenon defines an elegant class of switchable materials that can show cooperative transitions when long-range elastic interactions are present. Such materials can show multistepped transitions, targeted both fundamentally and for expanded data storage applications, when antagonistic interactions (i.e., competing ferro- and antiferro-elastic interactions) drive concerted lattice distortions. To this end, a new SCO framework scaffold, [FeII(bztrz)2(PdII(CN)4)]·n(guest) (bztrz = (E)-1-phenyl-N-(1,2,4-triazol-4-yl)methanimine, 1·n(guest)), has been prepared that supports a variety of antagonistic solid state interactions alongside a distinct dual guest pore system. In this 2-D Hofmann-type material we find that inbuilt competition between ferro- and antiferro-elastic interactions provides a SCO behavior that is intrinsically frustrated. This frustration is harnessed by guest exchange to yield a very broad array of spin transition characters in the one framework lattice (one- (1·(H2O,EtOH)), two- (1·3H2O) and three-stepped (1·-2H2O) transitions and SCO-deactivation (1)). This variety of behaviors illustrates that the degree of elastic frustration can be manipulated by molecular guests, which suggests that the structural features that contribute to multistep switching may be more subtle than previously anticipated.


Ms Minh Lam, Dr Paul FitzGerald and Prof Greg Warr*

Professor Greg Warr

Prof Greg Warr

Posted 7 February 2017
Hydrophobic monomer type and hydrophilic monomer ionization modulate the lyotropic phase stability of diblock co-oligomer amphiphiles
Langmuir, 33 (4), 1013-1022, 2017.

Abstract:
The phase behavior and self-assembly structures of a series of amphiphilic diblock co-oligomers comprising an ionizable hydrophilic block (5 to 10 units of acrylic acid) and a hydrophobic block (5 to 20 units of n-butyl acrylate, t-butyl acrylate, or ethyl acrylate), synthesized by RAFT polymerization, have been examined by polarizing optical microscopy and small-angle X-ray scattering (SAXS). Self-assembled structure and lyotropic phase stability in these systems is highly responsive to the degree of ionization of the acrylic acid hydrophilic block (i.e., pH), concentration, and nature of the hydrophobic block. Increasing headgroup ionization switched the amphiphiles from behaving like soluble to insoluble surfactants. Liquid isotropic (micellar), hexagonal, lamellar, and discrete cubic phases were found under different solution conditions. The surfactant packing parameter was adapted to understand the self-assembly structures in these diblock co-oligomers. The hydrophobic chain structure and length were shown to strongly affect the relative stabilities of these phases, allowing the self-assembled structure to be varied at will.


Professor Thomas Maschmeyer et al

Professor Thomas Maschmeyer

Prof Thomas Maschmeyer

Posted 7 February 2017
Multiphase hydrodechlorination of polychlorinated aromatics - Towards scale-up
Chemosphere, 173, 535-541, 2017.

Abstract:
We describe a chemical technology for the reductive catalytic multiphase hydrodechlorination (HDC) of chlorinated aromatics to greatly reduce their toxicity and aid the disposal of such species. The system requires no solvent and the catalyst displays a high recycling efficiency. In the present case, 1,3-dichlorobenzene (1,3-DCB) was used as a model compound, and was quantitatively hydrodechlorinated to benzene with hydrogen, in a tri-phasic liquid system consisting of the chlorinated aromatic itself as the top organic phase, an aqueous sodium hydroxide bottom phase (that neutralises acids formed), and an Aliquat(Registered)336 (A336) intermediate phase containing a Pd/C catalyst.

Once the reaction was complete the top phase (now just benzene) and the bottom phase (now principally aqueous NaCl) were removed and the remaining catalytic A336/(Pd/C) phase recycled.

This model study was conducted on a multi-gram scale with a view of demonstrating its applicability to the detoxification of PCBs. Comparison of the Mass Intensity (MI) and turnover frequency (TOF) of our model reaction with three examples of published procedures for the HDC of DCB, indicated that the MI for our system (MI = 6.33) was lower by an order of magnitude or more than that of the others (MI = 27.9, 64.6, 96016), and that TOFs were comparable.

A preliminary cost analysis indicates approximately 2000 euro/tonne to treat tonne-scale amounts of chlorinated aromatics, making the system in principle useful for industrial implementation.


Dr TH Nguyen Pham, Mr Byung Kim, A/Prof Brian Hawkett* and Dr Binh TT Pham et al

Associate Professor Brian Hawkett

A/Prof Brian Hawkett

Posted 7 February 2017
Tunable and noncytotoxic PET/SPECT-MRI multimodality imaging probes using colloidally stable ligand-free superparamagnetic iron oxide nanoparticles
International Journal of Nanomedicine, 12, 899-909, 2017.

Abstract:
Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. 57Co2+ ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive 67Ga3+ and Cu2+-labeled SPIONs were also produced successfully using the optimized conditions from the 57Co2+-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe.


Professor Phil Gale* et al

Professor Phil Gale

Prof Philip Gale

Posted 1 February 2017
A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations
Nature Chemistry, (Advance Online), 2017.

Abstract:
Perturbations in cellular chloride concentrations can affect cellular pH and 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 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.


Professor Phil Gale* et al

Professor Phil Gale

Prof Phil Gale

Posted 1 February 2017
Transmembrane fluoride transport: Direct measurement and selectivity studies
Journal of the American Chemical Society, 138 (50), 16515-16522, 2017.

Abstract:
Fluoride has been overlooked as a target in the development of synthetic anion transporters despite natural fluoride transport channels being recently discovered. In this paper we report the direct measurement of fluoride transport across lipid bilayers facilitated by a series of strapped calix[4]pyrroles and show that these compounds facilitate transport via an electrogenic mechanism (determined using valinomycin and monensin coupled transport assays and an additional osmotic response assay). An HPTS transport assay was used to quantify this electrogenic process and assess the interference of naturally occurring fatty acids with the transport process and Cl– over H+/OH– transport selectivity.


Professor Phil Gale* et al

Professor Phil Gale

Prof Phil Gale

Posted 1 February 2017
Small-molecule uncoupling protein mimics: Synthetic anion receptors as fatty acid-activated proton transporters
Journal of the American Chemical Society, 138 (50), 16508-16514, 2017.

Abstract:
Uncoupling proteins (UCPs) regulate energy expenditure in living cells by inducing proton leakage across the mitochondrial inner membrane, thereby uncoupling adenosine diphosphate phosphorylation from nutrient oxidation. The proton transport activity of UCP1 and UCP2 requires activation by fatty acids. We report here the first examples of synthetic neutral anion receptors performing this biologically important fatty acid-activated function in phospholipid bilayers. We have shown that a tripodal thiourea possesses poor H+/OH– transport activity without fatty acids, but in the presence of long-chain fatty acids is “switched on” as a proton transporter with an activity close to that of a commonly used protonophore. The fatty acid-enhanced proton transport was also observed for other hydrogen and halogen bond-based synthetic anion transporters. We propose that these compounds induce proton permeability by catalyzing transbilayer movement (“flip-flop”) of anionic forms of fatty acids, so allowing the fatty acids to complete a proton transport cycle. Several lines of evidence have been provided to support such a fatty acid cycling mechanism. Our findings open up new applications of anion receptor chemistry and provide important clues for understanding biological activities of synthetic anion transporters and potentially the uncoupling mechanism of naturally occurring membrane proteins.


Dr Alexander Stoye and Prof Richard Payne* et al

Professor Richard Payne

Prof Richard Payne

Posted 1 February 2017
Synthesis of norfijimycin A with activity against Mycobacterium tuberculosis
Australian Journal of Chemistry, 70 (2), 229-232, 2017.

Abstract:
The total synthesis of norfijimycin A, a simplified analogue of the marine natural product fijimycin A, is described. Fijimycin A is a cyclic depsipeptide that has been shown to possess activity against methicillin-resistant Staphylococcus aureus. The natural product contains a rare N,beta-dimethyl leucine unit with unknown stereochemistry at the beta-carbon. To evaluate the importance of the beta-methyl group for antimicrobial activity, we introduced N-methyl leucine into the natural product scaffold. The resulting norfijimycin A was shown to possess significant activity against Mycobacterium tuberculosis, the etiological agent of tuberculosis.


Dr Xuejian Liu, Dr Robert Elmes and Prof Kate Jolliffe*

Professor Kate Jolliffe

Prof Kate Jolliffe

Posted 1 February 2017
Synthesis of side-chain modified peptides using iterative solid phase "click" methodology
Australian Journal of Chemistry, 70 (2), 201-207, 2017.

Abstract:
A series of side-chain modified peptides have been prepared via an iterative sequence of peptide couplings and azide–alkyne cycloadditions (‘click’ reactions) using Fmoc-solid phase peptide synthesis. This efficient modular synthetic route allows the systematic and sequential incorporation of a variety of side-chain modifications onto short peptides. The versatility of this approach was demonstrated by the synthesis of a series of short peptides with appended anion recognition motifs and fluorescent indicators.


Ms Renee Sokias, Dr Tristan Reekie and Prof Michael Kassiou* et al

Professor Michael Kassiou

Prof Michael Kassiou

Posted 1 February 2017
Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination
Medicinal Chemical Communications, 8 (1), 202-210, 2017.

Abstract:
The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel N-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5–6-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.


Mr Patrick O'Toole* and Dr Toby Hudson et al

Posted 1 February 2017
Phase diagram of heteronuclear Janus dumbbells
Soft Matter, 13 (4), 803-813, 2017.

Abstract:
Using aggregation-volume-bias Monte Carlo simulations along with successive umbrella sampling and histogram re-weighting, we study the phase diagram of a system of dumbbells formed by two touching spheres having variable sizes, as well as different interaction properties. The first sphere (h) interacts with all other spheres belonging to different dumbbells with a hard-sphere potential. The second sphere (s) interacts via a square-well interaction with other s spheres belonging to different dumbbells and with a hard-sphere potential with all remaining h spheres. We focus on the region where the s sphere is larger than the h sphere, as measured by a parameter 1 (is less than or equal to) alpha (is less than or equal to) 2 controlling the relative size of the two spheres. As alpha –> 2 a simple fluid of square-well spheres is recovered, whereas alpha –> 1 corresponds to the Janus dumbbell limit, where the h and s spheres have equal sizes. Many phase diagrams falling into three classes are observed, depending on the value of alpha. The 1.8 (is less than or equal to) alpha (is less than or equal to) 2 is dominated by a gas-liquid phase separation very similar to that of a pure square-well fluid with varied critical temperature and density. When 1.3 (is less than or equal to) alpha (is less than or equal to) 1.8 we find a progressive destabilization of the gas-liquid phase diagram by the onset of self-assembled structures, that eventually lead to a metastability of the gas–liquid transition below alpha = 1.2.


Mr Joseph Wong, A/Prof Mat Todd and A/Prof Peter Rutledge*

Associate Professor Peter Rutledge

A/Prof Peter Rutledge

Posted 1 February 2017
Recent advances in macrocyclic fluorescent probes for ion sensing
Molecules, 22 (2), 1-28, 2017.

Abstract:
Small-molecule fluorescent probes play a myriad of important roles in chemical sensing. Many such systems incorporating a receptor component designed to recognise and bind a specific analyte, and a reporter or transducer component which signals the binding event with a change in fluorescence output have been developed. Fluorescent probes use a variety of mechanisms to transmit the binding event to the reporter unit, including photoinduced electron transfer (PET), charge transfer (CT), Förster resonance energy transfer (FRET), excimer formation, and aggregation induced emission (AIE) or aggregation caused quenching (ACQ). These systems respond to a wide array of potential analytes including protons, metal cations, anions, carbohydrates, and other biomolecules. This review surveys important new fluorescence-based probes for these and other analytes that have been reported over the past five years, focusing on the most widely exploited macrocyclic recognition components, those based on cyclam, calixarenes, cyclodextrins and crown ethers; other macrocyclic and non-macrocyclic receptors are also discussed.


Dr Alvaro Garcia and A/Prof Ron Clarke* et al

Associate Professor Ron Clarke

A/Prof Ron Clarke

Posted 1 February 2017
Electrostatic stabilization plays a central role in autoinhibitory regulation of the Na+,K+ - ATPase
Biophysical Journal, 112 (2), 288-299, 2017.

Abstract:
The Na+,K+-ATPase is present in the plasma membrane of all animal cells. It plays a crucial role in maintaining the Na+ and K+ electrochemical potential gradients across the membrane, which are essential in numerous physiological processes, e.g., nerve, muscle, and kidney function. Its cellular activity must, therefore, be under tight metabolic control. Consideration of eosin fluorescence and stopped-flow kinetic data indicates that the enzyme’s E2 conformation is stabilized by electrostatic interactions, most likely between the N-terminus of the protein’s catalytic α-subunit and the adjacent membrane. The electrostatic interactions can be screened by increasing ionic strength, leading to a more evenly balanced equilibrium between the E1 and E2 conformations. This represents an ideal situation for effective regulation of the Na+,K+-ATPase’s enzymatic activity, because protein modifications, which perturb this equilibrium in either direction, can then easily lead to activation or inhibition. The effect of ionic strength on the E1:E2 distribution and the enzyme’s kinetics can be mathematically described by the Gouy-Chapman theory of the electrical double layer. Weakening of the electrostatic interactions and a shift toward E1 causes a significant increase in the rate of phosphorylation of the enzyme by ATP. Electrostatic stabilization of the Na+,K+-ATPase’s E2 conformation, thus, could play an important role in regulating the enzyme’s physiological catalytic turnover.