RECENT PUBLICATIONS

Dr Markus Muellner et al

Dr Markus Muellner

Dr Markus Muellner

Posted 21 March 2017
Modulated fragmentation of proapoptotic peptide nanoparticles regulates cytotoxicity
JACS, 139 (11), 4009-4018, 2017.

Abstract:
Peptides perform a diverse range of physiologically important functions. The formulation of nanoparticles directly from functional peptides would therefore offer a versatile and robust platform to produce highly functional therapeutics. Herein, we engineered proapoptotic peptide nanoparticles from mitochondria-disrupting KLAK peptides using a template-assisted approach. The nanoparticles were designed to disassemble into free native peptides via the traceless cleavage of disulfide-based cross-linkers. Furthermore, the cytotoxicity of the nanoparticles was tuned by controlling the kinetics of disulfide bond cleavage, and the rate of regeneration of the native peptide from the precursor species. In addition, a small molecule drug (i.e., doxorubicin hydrochloride) was loaded into the nanoparticles to confer synergistic cytotoxic activity, further highlighting the potential application of KLAK particles in therapeutic delivery.


Mr Arnold Barkhordarian and Professor Cameron Kepert*

Professor Cameron Kepert

Prof Cameron Kepert

Posted 21 March 2017
Two new porous UiO-66-type zirconium frameworks; open aromatic N-donor sites and their post-synthetic methylation and metallation
Journal of Materials Chemistry A, 5 (11), 5612-5618, 2017.

Abstract:
Two new, isostructural UiO-66-type metal–organic frameworks (MOFs), Zr-PyDC (Zr6O4(OH)5(pyridine-2,5-dicarboxylate)4(formate)3(H2O)34) and Zr-PzDC (Zr6O4(OH)4.75(pyrazine-2,5-dicarboxylate)4.5(formate)2.25(H2O)33) have been synthesised via an unusual high acidity route. Despite the chelating capability of the ligands, which incorporate pyridine and pyrazine N-functionalities, these robust MOFs are linked exclusively through carboxylate donors to leave free Lewis base donor sites. Both MOFs show increased heats of adsorption and higher loadings of CO2 and H2 than UiO-66. High-conversion post-synthetic modification of Zr-PyDC and Zr-PzDC yielded charged, N-methylated frameworks with enhanced gas adsorption capacities. Further, the metal binding properties of Zr-PyDC have been probed by post-synthetic metallation with CuII.


Matthew Lui, Lisa Cattelan, Lisa Player, Tony Masters and Thomas Maschmeyer* et al

Professor Thomas Maschmeyer

Prof Thomas Maschmeyer

Posted 21 March 2017
Extractive denitrogenation of fuel oils with ionic liquids: A systematic study
Energy & Fuels, 31 (3), 2183-2189, 2017.

Abstract:
Ionic liquids (ILs) have been suggested as useful extractants of aromatic nitrogen-containing compounds (N compounds) from fuel oils. In this systematic study, ILs based on common cations and anions are employed as extractants of the archetypical N compounds pyridine and indole from a model oil consisting of decane and toluene. The performance of these ILs as extractants of N compounds is compared and rationalized. It is demonstrated that the cation and anion sizes (offering more surface area for extractants to interact) are the major factors determining the effectiveness of N compound extraction, although hydrogen bond donor/acceptor abilities of ILs can also play a role in the removal of these N compounds. In this study, some ILs are found to dissolve a considerable amount of oil contents. This undesired property can be controlled by the size of IL ions.


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

Professor Brendan Kennedy

Prof Brendan Kennedy

Posted 17 March 2017
The impact of chemical doping on the magnetic state of the Sr2YRu06 double perovskite
Journal of Solid State Chemistry, 249, 154-159, 2017.

Abstract:
The impact of chemical doping of the type Sr2-xAxYRuO6 (A=Ca, Ba) on the low temperature magnetic properties of Sr2YRuO6, probed using variable temperature magnetic susceptibility, neutron diffraction and heat capacity measurements, are described. Specific-heat measurements of un-doped Sr2YRuO6 reveal two features at -26 and -30 K. Neutron scattering measurements at these temperatures are consistent with a change from a 2D ordered state to the 3D type 1 AFM state. Magnetic and structural studies of a number of doped oxides are described that highlight the unique low temperature behavior of Sr2YRuO6 and demonstrate that doping destabilizes the intermediate 2D ordered state.


Emeritus Professor Len Lindoy et al

Emeritus Professor Len Lindoy

E/Prof Len Lindoy

Posted 17 March 2017
Synthesis and characterisation of two Cu(I) metalloligands based on tetradentate tripodal ligands
Polyhedron, 125, 44-49, 2017.

Abstract:
Two new tetradentate tripodal ligands (L1 and L2) have been synthesized via Schiff base condensation of tris(2-aminoethyl)amine (tren) with 4-(4-pyridinyl)benzaldehyde or 4-(3-pyridinyl)benzaldehyde in ethanol. Four Cu(I) complexes [CuL1]PF6, [CuL1]I, [CuL2]PF6 and [CuL2]I (1-4) have been prepared and characterised by NMR, HR-MS, SEM-EDS, FT-IR, Raman and UV-Vis measurements. X-ray structures for 1 and 4 are presented. In both structures, the four-coordinate copper(I) centres are bound within the cavity defined by the tren backbone. In such Cu(I) complexes, steric considerations dictate that the three uncoordinated pyridine nitrogen donors will have their coordination vectors oriented in a mutually divergent manner suitable for coordination to three different metal centres and thus are preorganized to act as new tripodal metalloligands.


Mr James O'Brien-Brown, Dr Tristan Reekie, Dr Paolo Schiavini, Dr Shane Wilkinson and Prof Michael Kassiou* et al

Professor Michael Kassiou

Prof Michael Kassiou

Posted 17 March 2017
Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists
European Journal of Medicinal Chemistry, 130, 433-439, 2017.

Abstract:
Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists.


Emeritus Professor Len Lindoy et al

Emeritus Professor Len Lindoy

E/Prof Len Lindoy

Posted 17 March 2017
Modulation of redox potentials utilizing the flexible coordination sphere of a penta-coordinate complex in the solid state
Dalton Transactions, 46 (11), 3749-3754, 2017.

Abstract:
Slight changes in the coordination structure of the manganese(V)-nitrido anionic complex, [MnV(N)(CN)4]2-, induced by using a "lipid package" approach markedly made an impact on the corresponding redox potentials. The single crystals of four lipid assemblies, [dabco-(CH2)n-1-CH3]2[Mn(N)(CN)4(H2O)]·xH2O (n = 15, 16, 17 and 18; dabco = 1,4-diazabicyclo[2,2,2]octane), were synthesized and solid-state cyclic voltammetric studies demonstrated that the [MnV(N)(CN)4]2- anions with smaller "cross" NC-Mn-CN bond angles exhibit higher redox potentials. The observed trend reflects the energy change associated with the structural transformation from [MnV(N)(CN)4]2- to [MnVI(N)(CN)4]2- and is supported by the results of DFT calculations. The NC-Mn-CN bond angles in the flexible [Mn(N)(CN)4]2- structure exhibit excellent correlation with the redox potentials of the complexes in the solid state.


Professor Richard Payne et al

Professor Richard Payne

Prof Richard Payne

Posted 17 March 2017
New tuberculosis drug leads from naturally occurring compounds
International Journal of Infectious Diseases, 56, 212-220, 2017.

Abstract:
Tuberculosis (TB) continues to be a significant cause of mortality and morbidity worldwide. An estimated 2 billion individuals are infected with Mycobacterium tuberculosis and annually there are approximately 10 million new cases of clinical TB and 1.5 million deaths. Currently available drugs and vaccines have had no significant impact on TB control. In addition, the emergence of drug resistant TB is considered a public health crisis, with some strains now resistant to all available drugs. Unfortunately, the growing burden of antibiotic resistance is coupled with decreased effort in the development of new antibiotics. Natural sources are attractive starting points in the search for anti-tubercular drugs because they are extremely rich in chemical diversity and have privileged antimicrobial activity. This review will discuss recent advances in the development of TB drug leads from natural products, with a particular focus on anti-mycobacterial compounds in late-stage preclinical and clinical development.


Professor Maxim Avdeev et al

Professor Maxim Avdeev

Prof Maxim Avdeev

Posted 17 March 2017
Magnetic properties of CeMn(2-x)Co(x)Ge(4)O(12) (0 is less than or equal to x is less than or equal to 2) as a function of temperature and magnetic field
Inorganic Chemistry, 56 (5), 2750-2762, 2017.

Abstract:
Polycrystalline samples, prepared by a solid-state route, of compositions in the solid solution CeMn2-xCoxGe4O12 (x = 0.0, 0.5, 1.0, 1.5, and 2.0) were characterized by X-ray diffraction, neutron diffraction, and magnetometry. They adopt space group P4/nbm with a approximate equal 9.78 and c approximate equal 4.85 A(^o) and become anti-ferromagnetic (x = 0.0, 1.5, 2.0) or weakly ferromagnetic (x = 0.5, 1.0) at 4.2 is less than or equal to T is less than or equal to 7.6 K. The ordered moments lie along [001] when x = 0.0 and in the (001) plane otherwise. The unit cell doubles along [001] when x = 1.5 and 2.0 order anti-ferromagnetically, but the doubling is lost when a first-order metamagnetic transition to weak ferromagnetism occurs on the application of a 10 kOe magnetic field. The ordered moments at 1.6 K for x = 0.0 and 2.0 are 4.61(2) and 2.58(2) μB, respectively; the corresponding effective moments in the paramagnetic phase are 5.91 and 5.36 μB.


Dr Qingqing Zhou, Dr Tristan Reekie and Prof Michael Kassiou* et al

Professor Michael Kassiou

Prof Michael Kassiou

Posted 17 March 2017
Structural optimization and pharmacological evaluation of inhibitors targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and CDC-like kinases (CLK) in glioblastoma
Journal of Medicinal Chemistry, 60 (5), 2052-2070, 2017.

Abstract:
The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 is less than or equal to 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A’s thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.


Mr Siyao Wang, Mr Leo Corcilius and Prof Richard Payne* et al

Professor Richard Payne

Prof Richard Payne

Posted 10 March 2017
Synthesis of rhamnosylated arginine glycopeptides and determination of the glycosidic linkage in bacterial elongation factor P
Chemical Science, 8 (3), 2296-2302, 2017.

Abstract:
A new class of N-linked protein glycosylation – arginine rhamnosylation – has recently been discovered as a critical modification for the function of bacterial elongation factor P (EF-P). Herein, we describe the synthesis of suitably protected α- and β-rhamnosylated arginine amino acid “cassettes” that can be directly installed into rhamnosylated peptides. Preparation of a proteolytic fragment of Pseudomonas aeruginosa EF-P bearing both α- and β-rhamnosylated arginine enabled the unequivocal determination of the native glycosidic linkage to be α through 2D NMR and nano-UHPLC-tandem mass spectrometry studies.


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

Associate Professor Mat Todd

A/Prof Mat Todd

Posted 10 March 2017
Selective displacement of a scorpionand triazole ligand from metallocyclam complexes visualised with NMR spectroscopy
European Journal of Inorganic Chemistry, 2017 (7), 1075-1086, 2017.

Abstract:
Target-activated metal complexes (TAMCs) - complexes that remain benign until reaching a specific biomolecular target, binding to which then effects structural change that turns on cytotoxicity or other activity - hold considerable allure. The successful development of TAMCs requires analytical methods that allow clear and unequivocal visualisation of changes in the coordination geometry of these systems in solution. Towards this goal, we report an NMR-based method to monitor coordination/de-coordination of a pendant triazole ligand to/from metallocyclam complexes of zinc(II) and mercury(II). This scorpionand ligand can be displaced from the metal, which remains bound to the macrocyclic ligand, using an appropriate competing ligand: chloride for the mercury(II) complexes, piperidine or citrate for zinc(II). Triazole displacement may be visualised by monitoring the 1H NMR resonance of the single triazole C-H proton environment. Using 2H NMR spectroscopy with a specifically deuterated complex enables the same change to be monitored in a noisy 1H landscape, as would be encountered at a protein binding site or other biological context. MALDI-TOF mass spectrometry experiments provide confirmation that the changes observed by NMR spectroscopy are due to changes in triazole coordination, rather than the stripping of the metal ion from the complex.


Professor Michael Kassiou* et al

Professor Michael Kassiou

Prof Michael Kassiou

Posted 10 March 2017
Kinase targets in CNS drug discovery
Future Medicinal Chemistry, 9 (3), 303-314, 2017.

Abstract:
Originally thought to be nondruggable, kinases represent attractive drug targets for pharmaceutical companies and academia. To date, there are over 40 kinase inhibitors approved by the US FDA, with 32 of these being small molecules, in addition to the three mammalian target of rapamycin inhibitor macrolides (sirolimus, temsirolimus and everolimus). Despite the rapid development of kinase inhibitors for cancer, presently none of these agents are approved for CNS indications. This mini perspective highlights selected kinase targets for CNS disorders, of which brain-permeable small-molecule inhibitors are reported, with demonstrated preclinical proof-of-concept efficacy. This is followed by a brief discussion on the key challenges of blood–brain barrier penetration and selectivity profiles in developing kinase inhibitors for CNS disorders.


Dr Elizabeth Carter et al

Dr Elizabeth Carter

Dr Liz Carter

Posted 10 March 2017
Effects of storage conditions on the stability of spray dried, inhalable bacteriophage powders
International Journal of Pharmaceutics, 521 (1-2), 141-149, 2017.

Abstract:
This study aimed to develop inhalable powders containing phages active against antibiotic-resistant Pseudomonas aeruginosa for pulmonary delivery. A Pseudomonas phage, PEV2, was spray dried into powder matrices comprising of trehalose (0-80%), mannitol (0-80%) and l-leucine (20%). The resulting powders were stored at various relative humidity (RH) conditions (0, 22 and 60% RH) at 4 °C. The phage stability and in vitro aerosol performance of the phage powders were examined at the time of production and after 1, 3 and 12 months storage. After spray drying, a total of 1.3 log titer reduction in phage was observed in the formulations containing 40%, 60% and 80% trehalose, whereas 2.4 and 5.1 log reductions were noted in the formulations containing 20% and no trehalose, respectively. No further reduction in titer occurred for powders stored at 0 and 22% RH even after 12 months, except the formulation containing no trehalose. The 60% RH storage condition had a destructive effect such that no viable phages were detected after 3 and 12 months. When aerosolised, the total lung doses for formulations containing 40%, 60% and 80% trehalose were similar (in the order of 105 pfu). The results demonstrated that spray drying is a suitable method to produce stable phage powders for pulmonary delivery. A powder matrix containing greater than or equal to 40% trehalose provided good phage preservation and aerosol performances after storage at 0 and 22% RH at 4 °C for 12 months.


Dr Paula Kayser-Gonzalez, Mr Sean Injac, Prof Brendan Kennedy* and Mr Andre Menezes de Oliveira et al

Professor Brendan Kennedy

Prof Brendan Kennedy

Posted 10 March 2017
Thermal expansion in BaRuO3 perovskites - an unusual case of bond strengthening at high temperatures
Dalton Transactions, 46 (9), 2974-2980, 2017.

Abstract:
The temperature dependences of the structures of three polytypes of BaRuO3 have been investigated between room temperature and 1000 °C using high resolution synchrotron X-ray diffraction. The structural studies reveal a systematic decrease of the Ru-Ru distance as the pressure required to prepare the polytype increases. The O-O distance across the shared face increases as the Ru-Ru separation decreases. The 9R and 4H polytypes undergo unexceptional changes with increasing temperature. In 6H-BaRuO3 there is an apparent increase in the Ru-Ru interaction at around 650 °C and a concurrent reduction in the O-O distance, indicating an anomalous strengthening of the Ru-Ru interactions upon heating.


Dr Carol Hua and A/Prof Deanna D'Alessandro* et al

Associate Professor Deanna D

A/Prof Deanna D'Alessandro

Posted 10 March 2017
Redox state manipulation of a tris(p-tetrazolylphenyl)amine ligand and its Mn2+ coordination frameworks
Dalton Transactions, 46 (9), 2998-3007, 2017.

Abstract:
In situ spectroelectrochemical experiments coupled with UV/Vis/NIR, EPR, magnetism and fluorescence techniques have enabled insights into the electronic properties of the tris(p-tetrazolylphenyl)amine (H3TTPA) ligand and the new Mn2+ frameworks [Mn3(TTPA)2(MeOH)6]n (1) and [Mn3(TTPA)2(DMF)6]n (2). Oxidation of H3TTPA generated the triarylamine radical which was found to be delocalised throughout the ligand backbone. Solid state Vis/NIR and EPR spectroelectrochemical experiments on the frameworks were used to probe the optical properties of the accessible redox states and their relative stabilities, as well as the charge transfer interactions which were generated upon infiltration of electron acceptor guests. These studies provide a basis for the application of electroactive frameworks in functional electronic and optical devices, where knowledge of the properties of the distinct redox states and their interconversion is essential.


Anh Tran, Emma Watson, Trent Conroy, Luke Dowman, Andrew Giltrap and Richard Payne* et al

Professor Richard Payne

Prof Richard Payne

Posted 10 March 2017
Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis
Nature Communications, 8, 14414, 2017

Abstract:
Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.