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SDG 12

The 'absolute existence' of phlogiston: the losing party's point of view.
07 November 2011
University of Sydney

Gal, Ofer;Boantza, Victor

Long after its alleged demise, phlogiston was still presented, discussed and defended by leading chemists. Even some of the leading proponents of the new chemistry admitted its ‘absolute existence’. We demonstrate that what was defended under the title ‘phlogiston’ was no longer a particular hypothesis about combustion and respiration. Rather, it was a set of ontological and epistemological assumptions and the empirical practices associated with them. Lavoisier’s gravimetric reduction, in the eyes of the phlogistians, annihilated the autonomy of chemistry together with its peculiar concepts of chemical substance and quality, chemical process and chemical affinity. The defence of phlogiston was the defence of a distinctly chemical conception of matter and its appearances, a conception which rejected the chemist’s acquaintance with details and particularities of substances, properties and processes and his skills of adducing causal relations from the interplay between their complexity and uniformity.
Folding of dinuclear platinum anticancer complexes within the cavity of para-sulphonatocalix[4]arene
25 July 2013
University of Sydney

Brown, Sarah D.;Plumb, Jane A.;Johnston, Blair F.;Wheate, Nial J.

The binding of three dinuclear platinum complexes, where the bridging ligand of the complexes is N,N0- (alkane-1,n-diyl)diisonicotinamide (n = 4, 6 or 8 for butane, hexane and octane, respectively) to the macrocycle para-sulphonatocalix[4]arene (sCX[4]) has been studied by 1H nuclear magnetic resonance (NMR) spectroscopy and molecular modelling. The NMR spectra show two important features, large upfield shifts of the methylene proton resonances of up to 1.8 ppm, which clearly places them within the shielding environment of the macrocycle’s cavity, and a loss of chemical symmetry of the metal complexes with extra resonances observed upon sCX[4] binding. Molecular models of the platinum–sCX[4] host–guest complexes show significant folding of the metal complexes’ aliphatic chain and a non-symmetrical interaction with the macrocycle. One side of the metal complexes forms three hydrogen bonds to sCX[4], whereas the opposite side of the metal complexes forms just one hydrogen bond, giving rise to the loss of chemical symmetry in the 1H NMR spectra. As the dinuclear platinum complexes are model anticancer drugs, the effect of sCX[4] binding was investigated in vitro in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-line A2780cp70. Whilst the free metal complexes are a magnitude of order more active than cisplatin in the A2780 cell line, they are all highly cross-resistant with cisplatin in the A2780cp70 line. Binding by sCX[4] has little affect on the metal complexes’ cytotoxicity in the sensitive cell line, but has a large effect in the resistant cell line. The two shortest metal complexes become less active when bound by sCX[4], whereas the longest metal complex becomes more cytotoxic.
Cisplatin-Tethered Gold Nanoparticles That Exhibit Enhanced Reproducibility, Drug Loading, and Stability: a Step Closer to Pharmaceutical Approval?
17 July 2014
University of Sydney

Craig, Gemma E.;Brown, Sarah D.;Lamprou, Dimitrios A.;Graham, Duncan;Wheate, Nial J.

Gold nanoparticles (AuNPs) can be used as delivery vehicles for platinum anticancer drugs, improving their targeting and uptake into cells. Here, we examine the appropriateness of different-sized AuNPs as components of platinum-based drug-delivery systems, investigating their controlled synthesis, reproducibility, consistency of drug loading, and stability. The active component of cisplatin was tethered to 25, 55, and 90 nm AuNPs, with the nanoparticles being almost spherical in nature and demonstrating good batch-to-batch reproducibility (24.37 ± 0.62, 55.2 ± 1.75, and 89.1 ± 2.32 nm). The size distribution of 25 nm AuNPs has been significantly improved, compared with a previous method that produces polydispersed nanoparticles. Attachment of platinum to the AuNP surface through a poly(ethylene glycol) (PEG) linker exhibits an increase in the drug loading with increasing particle size: 25 nm (815 ± 106 drug molecules per AuNP), 55 nm (14216 ± 880), and 90 nm (54487 ± 15996). The stability of the naked, PEGylated, and platinum-conjugated nanoparticles has been examined over time under various conditions. When stored at 4 °C, there is minimal variation in the diameter for all three AuNP sizes; variation after 28 days for the 25 nm AuNPs was 2.4%; 55 nm, 3.3%; and 90 nm, 3.6%. The 25 nm AuNPs also demonstrate minimal changes in UV−visible absorbance over the same time period.
How Pharmaceutical Industry Employees Manage Competing Moral Commitments
18 August 2014
University of Sydney

Lipworth, W;Montgomery, K;Little, M

The pharmaceutical industry has been criticised for pervasive misconduct. These concerns have generally resulted in increasing regulation. While such regulation is no doubt necessary, it tends to assume that everyone working for pharmaceutical companies is equally motivated by commerce, without much understanding of the specific views and experiences of those who work in different parts of the industry. In order to gain a more nuanced picture of the work that goes on in the “medical affairs” departments of pharmaceutical companies, we conducted 15 semi-structured interviews with professionals working in medical departments of companies in Sydney, Australia. We show that this group of pharmaceutical professionals are committed to their responsibilities both to patients, research participants, and the public and to their companies. Despite the discrepancies between these commitments, our participants did not express much cognitive dissonance, and this appeared to stem from their use of two dialectically related strategies, one of which embraces commerce and the other of which resists the commercial imperative. We interpret these findings through the lens of institutional theory and consider their implications for pharmaceutical ethics and governance. Keywords: Qualitative research; Social values; Pharmaceutical industry; Pharmaceutical ethics
Rules of Engagement: Journalists’ attitudes to industry influence in health news reporting.
29 August 2014
University of Sydney

Morrell, B;Forsyth, R;Lipworth, W;Kerridge, I;Jordens, C

Health-related industries use a variety of methods to influence health news, including the formation and maintenance of direct relationships with journalists. These interactions have the potential to subvert news reporting such that it comes to serve the interests of industry in promoting their products, rather than the public interest in critical and accurate news and information. Here we report the findings of qualitative interviews conducted in Sydney, Australia, in which we examined journalists’ experiences of, and attitudes towards, their relationships with health-related industries. Participants’ belief in their ability to manage industry influence and their perceptions of what it means to be unduly influenced by industry raise important concerns relating to the psychology of influence and the realities of power relationships between industry and journalists. The analysis also indicates ways in which concerned academics and working journalists might establish more fruitful dialogue regarding the role of industry in health-related news and the extent to which increased regulation of journalist-industry relationships might be needed.
Current ethical issues in synthetic biology: Where should we go from here?
26 November 2014
University of Sydney

Newson, A.J.

Synthetic Biology (SynBio) is an emerging scientific field which has quickly established momentum and visibility. Although no single definition of SynBio prevails, the field broadly encompasses the application of engineering principles to biology; re-designing biological materials and using them as new substrates to create products and entities not otherwise found in nature. This paper first reviews SynBio, highlighting the novel aspects of this technology. It then synthesises ethical issues highlighted in the literature to date and makes some initial claims that research on the ethical aspects of SynBio should: avoid creating a new sub-type of bioethics, concentrate on novel concepts and problems and be situated within a context of cooperative inter-disciplinary investigation. Keywords: Synthetic biology, ethical issues, regulation, creating life.
A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery
21 January 2016
University of Sydney

Kennedy, Alan R.;Florence, Alastair J.;McInnes, Fiona J.;Wheate, Nial J.

Single crystal and powder X-ray diffraction have been used to examine the host–guest complex of cucurbit[7]uril (CB[7]) and the model dinuclear platinum anticancer complex trans-[{PtCl(NH3)2}2μ-dpzm]2+ (di-Pt, dpzm= 4,4′-dipyrazolylmethane). The single crystal structure shows that the host–guest complex forms with the di-Pt dpzm ligand within the CB[7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB[7] carbonyls. Each host–guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]–di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB[7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB[7] and the CB[7]–di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160 °C. The DSC results showed that the free dpzm ligand melts between 186 and 199 °C, with a standard enthalpy of fusion of 27.92 kJ mol−1. As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290 °C. Encapsulation by CB[7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 °C.
A sensitive and specific β-alanyl aminopeptidase-activated fluorogenic probe for the detection of Pseudomonas aeruginosa
13 April 2016
University of Sydney

Váradi, Linda;Hibbs, David E.;Orenga, Sylvain;Babolat, Michèle;Perry, John D.;Groundwater, Paul W.

We report the synthesis of the sensitive and specific fluorogenic self-immolative substrate 8b, which is hydrolzyed by β-alanyl aminopeptidase (BAP), resulting in a 1,6-elimination and the release of the highly fluorescent hydroxycoumarin 6b. This fluorophore 6b is retained within bacterial colonies, so has potential for the detection of P. aeruginosa (a BAP producer); it also has potential in liquid media due to the rapid and strong signal release from the substrate 8b, and lack of self-quenching or photobleaching.
Biological variation and reference change values of feline plasma biochemistry analytes.
19 April 2016
University of Sydney

Baral, Randolph M.;Dhand, Navneet K.;Freeman, Kathleen P.;Krockenberger, Mark B.;Govendir, Merran

This is the first report concerning biological variation and reference change values of feline plasma biochemistry components in the peer-reviewed literature. Biological variation refers to inherent physiological variation of analytes. The ratio of individual biological variation to group biological variation is referred to as an analyte's index of individuality. This index determines the suitability of an analyte to be assessed in relation to population- or subject-based reference intervals. A subject-based reference interval is referred to as a reference change value or critical difference, and is calculated from individual biological variation. Fourteen cats were sampled for plasma biochemistry analysis once weekly for 6 weeks. Samples were stored and then tested at the same time. Results were assessed in duplicate and coefficients of variation for each analyte were isolated to distinguish variation within each subject, between all subjects and by the analyser. From these results, an index of individuality and reference change values were determined for each analyte. Five plasma biochemistry analytes (alkaline phosphatase, alanine aminotransferase, cholesterol, creatinine and globulin) had high individuality and, therefore, subject-based reference intervals are more appropriate; only one analyte (sodium) had low individuality, indicating that population-based reference intervals are appropriate. Most analytes had intermediate individuality so population-based reference intervals should be assessed in relation to subject-based reference intervals. The results of this study demonstrate high individuality for most analytes and, therefore, that population-based reference intervals are of limited utility for most biochemical analytes in cats.
A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of Piroxicam.
28 April 2016
University of Sydney

Lai, Felcia;Du, Jonathan J.;Williams, Peter A.;Váradi, Linda;Baker, Daniel;Groundwater, Paul W.;Overgaard, Jacob;Platts, James A.;Hibbs, David E.

Experimental charge density distribution studies of two polymorphic forms of piroxicam, β- piroxicam (1) and piroxicam monohydrate (2), were carried out via high-resolution single crystal X-ray diffraction experiments and multipole refinement. The asymmetric unit of (2) consists of two discrete piroxicam molecules, (2a) and (2b), and two water molecules. Geometry differs between (1) and (2) due to the zwitterionic nature of (2) which results in the rotation of pyridine ring around the C(10)–N(2) bond by approximately 180°. Consequently, the pyridine and amide are no longer co-planar and (2) forms two exclusive, strong hydrogen bonds, H(3) …O(4) and H(2) …O(3), with bond energy of 66.14 kJ mol-1 and 112.82 kJ mol- 1 for (2a), 58.35 kJ mol-1 and 159.51 kJ mol-1 for (2b) respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified on calculation of atomic charges in the zwitterion shows the formally positive charge of the pyridyl nitrogen is redistributed over the whole of the pyridine ring instead of concentrated at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazinecarboxamide moiety. Multipole derived lattice energy for (1) is -304 kJ mol-1 and that for (2) is -571 kJ mol-1, which is in agreement with the experimentally determined observations of higher solubility and dissolution rates of (1) compared to (2).
An analysis of the experimental and theoretical charge density distributions of the piroxicam-saccharin co-crystal and its constituents
02 May 2016
University of Sydney

Du, Jonathan J.;Váradi, Linda;Williams, Peter A.;Groundwater, Paul W.;Overgaard, Jacob;Platts, James A.;Hibbs, David E.

Experimental and theoretical charge density analyses of piroxicam (1), saccharin (2) and their 1:1 co-crystal complex (3) have been carried out. Electron density distribution (EDD) was determined through the use of high-resolution single crystal X-ray diffraction and the data were modelled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. A method for optimising the core density refinement of sulfur atoms is discussed, with emphasis on the reduction of residual electron density that is typically associated with this atom. The asymmetric unit of complex (3) contains single molecules of saccharin and the zwitterionic form of piroxicam. These are held together by weak interactions (hydrogen bonds, π-π and van der Waals interactions), ranging in strength from 4 to 160 kJmol-1, working together to stabilise the complex;. analysis of the molecular electrostatic potential (MEP) of the complexes showed electron redistribution within the cocrystal, facilitating the formation of these generally weak interactions. Interestingly, in the zwitterionic form of piroxicam, the charge distribution reveals that the positive and negative charges are not associated with the formal charges normally associated with this description, but are distributed over adjacent molecular fragments. The use of anisotropic displacement parameters (ADPs) for hydrogen atoms in the multipole model was also investigated but no improvement in the quality of the topological analysis was found.
High lethality and minimal variation after acute self-poisoning with carbamate insecticides in Sri Lanka – implications for global suicide prevention
07 June 2016
University of Sydney

Lamb, Thomas;Selvarajah, Liza R.;Mohamed, Fahim;Jayamanne, Shaluka;Gawarammana, Indika;Mostafa, Ahmed;Buckley, Nicholas A.;Roberts, Michael S.;Eddleston, Michael

Highly hazardous organophosphorus (OP) insecticides are responsible for most pesticide poisoning deaths. As they are removed from agricultural practice, they are often replaced by carbamate insecticides of perceived lower toxicity. However, relatively little is known about poisoning with these insecticides. METHODS: We prospectively studied 1288 patients self-poisoned with carbamate insecticides admitted to six Sri Lankan hospitals. Clinical outcomes were recorded for each patient and plasma carbamate concentration measured in a sample to confirm the carbamate ingested. FINDINGS: Patients had ingested 3% carbofuran powder (719), carbosulfan EC25 liquid (25% w/v, 389), or fenobucarb EC50 liquid (50% w/v, 127) formulations, carbamate insecticides of WHO Toxicity Classes Ib, II, and II, respectively. Intubation and ventilation was required for 183 (14.2%) patients while 71 (5.5%) died. Compared with carbofuran, poisoning with carbosulfan or fenobucarb was associated with significantly higher risk of death [carbofuran 2.2%; carbosulfan 11.1%, OR 5.5 (95% CI 3.0-9.8); fenobucarb 6.3%, OR 3.0 (1.2-7.1)] and intubation [carbofuran 6.1%; carbosulfan 27.0%, OR 5.7 (3.9-8.3); fenobucarb 18.9%, OR 3.6 (2.1-6.1)]. The clinical presentation and cause of death did not differ markedly between carbamates. Median time to death was similar: carbofuran 42.3 h (IQR 5.5-67.3), carbosulfan 21.3 h (11.5-71.3), and fenobucarb 25.3 h (17.3-72.1) (p = 0.99); no patients showed delayed onset of toxicity akin to the intermediate syndrome seen after OP insecticide poisoning. For survivors, median duration of intubation was 67.8 h (IQR 27.5-118.8) with no difference in duration between carbamates. Reduced GCS at presentation was associated with worse outcome although some patients with carbosulfan died after presentation with normal GCS. CONCLUSIONS: We did not find carbamate insecticide self-poisoning to vary markedly according to the carbamate ingested although the case fatality varied according to the concentration and formulation of the insecticide. Carbamate poisoning did not appear to be much less toxic than poisoning with some liquid OP insecticide formulations, e.g., chlorpyrifos EC40, that we have previously noted in these same hospitals (Lancet 2005, 366:1452-1459; QJM 2006, 99:513-522). Replacement of WHO Class II Toxicity OP insecticides in agriculture with high-strength liquid carbamate formulations may not substantially reduce case fatality after pesticide poisoning and, therefore, global suicide rates.
Vicinal Disulfide Constrained Cyclic Peptidomimetics: a Turn Mimetic Scaffold Targeting the Norepinephrine Transporter
21 June 2016
University of Sydney

Brust, Andreas;Wang, Ching-I. A.;Daly, Norelle L.;Kennerly, Joe;Sadeghi, Mahsa;Christie, Macdonald J.;Lewis, Richard J.;Mobli, Mehdi;Alewood, Paul F.

Loopy peptides: Peptide turn mimetics of a clinically relevant norepinephrine reuptake inhibitor were developed employing a high-throughput synthesis approach to generate peptide thioesters, with subsequent cyclization through native chemical ligation. The vicinal disulfide constrained cyclic peptidomimetics (see scheme) show high structural and functional similarity to the parent peptide, though with superior metabolic stability.
Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic
21 June 2016
University of Sydney

Gori, Alessandro;Wang, Ching-I A.;Harvey, Peta J.;Rosengren, K. Johan;Bhola, Rebecca F.;Gelmi, Maria L.;Longhi, Renato;Christie, Macdonald J.;Lewis, Richard J.;Alewood, Paul F.;Brust, Andreas

The design of disulfide bond mimetics is an important strategy for optimising cysteine-rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4-disubstituted-1,2,3-triazole bridge, are described. Sequential copper-catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.
Themed Section: Opioids New Pathways to Functional Selectivity
22 June 2016
University of Sydney

Christie, M.J.;Connor, M;Traynor, J.R.

"LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2"
Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.
22 June 2016
University of Sydney

Wan, J;Bhola, R.F.;Jha, P;Brust, A;Mobil, M;Lewis, R.J.;Christie, M.J.;Alewood, P.F.

Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter.
2-methyl-4-chlorophenoxyacetic acid and bromoxynil herbicide death.
28 July 2016
University of Sydney

Berling, I;Buckley, Nicholas A.;Downes, M.;Isbister, GK.

CASE REPORT: We report a fatal case of a 37 year old gentleman who ingested a MCPA/bromoxynil co-formulation herbicide. Although clinically well on initial examination, our patient declined dramatically over his 18 h admission with increasing CO2 production, hyperthermia and metabolic derangement to eventually die from cardiac asystole 20 h post ingestion. Two hours after ingestion the MCPA concentration was 83.9 μg/mL and bromoxynil concentration was 137 μg/mL. DISCUSSION: The patients' mechanism of death appeared to be uncoupling of oxidative phosphorylation, excess CO2 production and hyperthermia. There is limited knowledge on the acute toxicity of these herbicides, in particular bromoxynil, and this case highlights the relentless progression of severe toxicity in humans.
Loading of a Phenanthroline-Based Platinum(II) Complex onto the Surface of a Carbon Nanotube via pi–pi Stacking
11 October 2016
University of Sydney

Houston, Stephanie;Venkataramanan, Natarajan;Suvitha, Ambigapathy;Wheate, Nial

Stacking of the metal complex [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2þ (56MESS) onto the surface of two different fullerenes, a carbon nanotube (CNT), and a C60-buckyball was examined. The metal complex forms a supramolecular complex with multi-walled CNTs but not with buckyballs. Binding of 56MESS to the CNTs is highly efficient (90 %) but can be further stabilized by the addition of the surfactant, pluronic F-127, which resulted in a loading efficiency of 95 %. Molecular modelling shows that binding of 56MESS to the CNT is supported by the large surface area of the fullerene, whereas the more pronounced curvature and lack of a flat surface on the buckyball affects the ability of 56MESS to form bonds to its surface. The loading of 56MESS onto the CNT is via p–p stacking from the metal complex phenanthroline ligand and C–H p bonding fromthe diaminocyclohexane ligand. 56MESS has 13 critical bonding points with the CNT, eight of which are p–p stacking bonds, but the metal complex forms only seven bonds with the buckyball. In addition, the loading of 56MESS onto the CNT results in a charge transfer of 0.111 eV; however, charge transfer is almost negligible for binding to the buckyball.
The Deadly Business of an Unregulated Global Stem Cell Industry
31 March 2017
University of Sydney

Lysaght, T;Lipworth, W;Hendl, T;Kerridge, I;Munsie, M;Waldby, C;Stewart, C

In 2016, the Office of the State Coroner of New South Wales released its report into the death of an Australian woman, Sheila Drysdale, who had died from complications of an autologous stem cell procedure at a Sydney clinic. In this report, we argue that Mrs Drysdale's death was avoidable, and it was the result of a pernicious global problem of an industry exploiting regulatory systems to sell unproven and unjustified interventions with stem cells.
Fluorinated synthetic anion carriers: experimental and computational insights into transmembrane chloride transport
07 February 2019
University of Sydney

Spooner, Michael J.;Li, Hongyu;Marques, Igor;Costa, Pedro M.R.;Wu, Xin;Howe, Ethan N.W.;Busschaert, Nathalie;Moore, Stephen J.;Light, Mark E.;Sheppard, David N.;Gale, Philip A.

A series of fluorinated tripodal tris-thioureas function as highly active anion transporters across lipid bilayers and cell membranes. Here, we investigate their mechanism of action using anion transport assays in cells and synthetic vesicles and molecular modelling of transporter–lipid interactions. When compared with non-fluorinated analogues, fluorinated compounds demonstrate a different mechanism of membrane transport because the free transporter cannot effectively diffuse through the membrane. As a result, in H+/Cl cotransport assays, fluorinated transporters require the presence of oleic acid to form anionic oleate complexes for recycling of the transporter, whereas non-fluorinated analogues readily diffuse through the membrane as free transporters and show synergistic transport with the proton transporter gramicidin. Molecular dynamics simulations revealed markedly stronger transporter–lipid interactions for fluorinated compounds compared with non-fluorinated analogues and hence, higher energy barriers for fluorinated compounds to cross the membrane as free transporters. With use of appropriate proton transporters to ensure measurement of the correct rate-limiting steps, the transport rates determined in synthetic vesicle assays show excellent agreement with the anion transport rates determined in cell- based assays. We conclude that integration of computational and experimental methods provides a strategy to optimise transmembrane anion transporter design for biomedical applications.
Dissecting the chloride–nitrate anion transport assay
07 February 2019
University of Sydney

Yang, Yufeng;Wu, Xin;Busschaert, Nathalie;Furuta, Hiroyuki;Gale, Philip A.

A systematic study of chloride vs. nitrate selectivity across six anion transporters has revealed a good correlation between the selectivities of their anion binding and membrane transport properties. This work reveals the limitations of the chloride–nitrate exchange assay and shows how new approaches can be used to measure anion uniport.
Indole-based perenosins as highly potent HCl transporters and potential anti-cancer agents
07 February 2019
University of Sydney

Jowett, Laura A.;Howe, Ethan N.W.;Soto-Cerrato, Vanessa;Van Rossom, Wim;Pérez-Tomás, Ricardo;Gale, Philip A.

Prodigiosin is one of the most potent anion transporters in lipid bilayer membranes reported to date. Inspired by the structure of this natural product, we have recently designed and synthesised a new class of H+/Cl− cotransporters named ‘perenosins’. Here we report a new library of indole-based perenosins and their anion transport properties. The new transporters demonstrated superior transmembrane transport efficiency when compared to other indole-based transporters, due to favourable encapsulating effects from the substituents on the perenosin backbone. Anion transport assays were used to determine the mechanism of chloride transport revealing that the compounds function as ‘strict’ HCl cotransporters. Cell viability studies showed that some compounds specifically trigger lateonset cell death after 72 h with a unique correlation to the position of alkyl chains on the perenosins. Further investigations of cell death mechanism showed a mixture of cell cycle arrest and apoptosis was responsible for the observed decrease in cell viability.
Anion receptor chemistry: Highlights from 2016
07 February 2019
University of Sydney

Gale, Philip A.;Howe, Ethan N.W.;Wu, Xin;Spooner, Michael J.

This review covers recent advances in anion receptor chemistry from 2016, including developments in self-assembly, sensing, anion separation, transport, catalysis and fundamental advances in anion recognition systems.
Cyclic peptide unguisin A is an anion receptor with high affinity for phosphate and pyrophosphate
07 February 2019
University of Sydney

Ariawan, A. Daryl;Webb, James E.A.;Howe, Ethan N.W.;Gale, Philip A.;Thordarson, Pall;Hunter, Luke

Unguisin A (1) is a marine-derived, GABA-containing cyclic heptapeptide. The biological function of this flexible macrocycle is obscure. Here we show that compound 1 lacks any detectable activity in antimicrobial growth inhibition assays, a result that runs contrary to a previous report. However, we find that 1 functions as a promiscuous host molecule in a variety of anion-binding interactions, with high affinity particularly for phosphate and pyrophosphate. We also show that a series of rigidified, backbone-fluorinated analogues of 1 displays altered affinity for chloride ions.
Fluorinated tripodal receptors for potentiometric chloride detection in biological fluids
07 February 2019
University of Sydney

Pankratova, Nadezda;Cuartero, Maria;Jowett, Laura A.;Howe, Ethan N.W.;Gale, Philip A.;Bakker, Eric;Crespo, Gastón A.

Fluorinated tripodal compounds were recently reported to be efficient transmembrane transporters for a series of inorganic anions. In particular, this class of receptors has been shown to be suitable for the effective complexation of chloride, nitrate, bicarbonate and sulfate anions via hydrogen bonding. The potentiometric properties of urea and thiourea-based fluorinated tripodal receptors are explored here for the first time, in light of the need for reliable sensors for chloride monitoring in undiluted biological fluids. The ion selective electrode (ISE) membranes with tren-based tris-urea bis(CF3) tripodal compound (ionophore I) were found to exhibit the best selectivity for chloride over major lipophilic anions such as salicylate (log K = + 1.0 Cl Sal pot −/ − ) and thiocyanate (log K = + 0.1 Cl SCN pot −/ − ). Ionophore I-based ISEs were successfully applied for chloride determination in undiluted human serum as well as artificial serum sample, the slope of the linear calibration at the relevant background of interfering ions being close to Nernstian (49.8 ± 1.7 mV). The results of potentiometric measurements were confirmed by argentometric titration. Moreover, the ionophore I-based ISE membrane was shown to exhibit a very good long-term stability of potentiometric performance over the period of 10 weeks. Nuclear magnetic resonance (NMR) titrations, potentiometric sandwich membrane experiments and density functional theory (DFT) computational studies were performed to determine the binding constants and suggest 1:1 complexation stoichiometry for the ionophore I with chloride as well as salicylate.
Fluorescent squaramides as anion receptors and transmembrane anion transporters
07 February 2019
University of Sydney

Bao, Xiaoping;Wu, Xin;Berry, Stuart N.;Howe, Ethan N.W.;Chang, Young-Tae;Gale, Philip A.

A series of squaramide-based anion transporters functionalised with the 1,8-naphthalimide fluorophore has been developed for improved ionophoric activity and fluorescent imaging in cells.
Anion transport and supramolecular medicinal chemistry
07 February 2019
University of Sydney

Gale, Philip A.;Davis, Jeffery T.;Quesada, Roberto

New approaches to the transmembrane transport of anions are discussed in this review. Advances in the design of small molecule anion carriers are reviewed in addition to advances in the design of synthetic anion channels. The application of anion transporters to the potential future treatment of disease is discussed in the context of recent findings on the selectivity of anion transporters.
Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes
07 February 2019
University of Sydney

Dias, Christopher M.;Li, Hongyu;Valkenier, Hennie;Karagiannidis, Louise E.;Gale, Philip A.;Sheppard, David N.;Davis, Anthony P.

Ortho-Phenylene bis-ureas serve as anionophores in cells expressing halide-sensitive yellow fluorescent protein, as well as in synthetic vesicles. Activities can reach high levels, and are strongly dependent on the deliverability of the transporters.
A tripodal tris-selenourea anion transporter matches the activity of its thio- analogue but shows distinct selectivity
07 February 2019
University of Sydney

Spooner, Michael J.;Gale, Philip A.

We report the synthesis of a tripodal tris-selenourea transporter scaffold. The Cl− and NO− 3 transport activity of the compound has been compared extensively with the analogous oxo- and thiourea compounds. We found that the selenourea demonstrates remarkably similar transport efficacy and mechanistic properties to the equivalent thiourea, but demonstrates flipped selectivity for Cl− over NO−3.
Polymer Nanowires with Highly Precise Internal Morphology and Topography
19 February 2019
University of Sydney

Pelras, Théophile;Mahon, Clare S.;Nonappa;Ikkala, Olli;Gröschel, André H.;Müllner, Markus

The construction of precise soft matter nanostructures in solution presents a challenge. A key focus remains on the rational design of func-tionalities to achieve the high morphological complexity typically found in biological systems. Advances in controlled polymerisations and self-assembly increasingly allow approaches towards complex hierarchical nanomaterials. By combining tailor-made cylindrical polymer brushes, block copolymers and interpolyelectrolyte complexation-driven self-assembly, we demonstrate a facile construction of uniformly compartmentalised and topographically structured polymeric nanowires in aqueous media. The approach offers a modular avenue in pro-gramming the internal morphology of polymer nanowires by varying the block copolymer composition and topology.
Structural and magnetic properties of the osmium double perovskites Ba2-xSrxYOsO6
20 February 2019
University of Sydney

Kayser, Paula;Injac, Sean;Kennedy, Brendan J;Vogt, Thomas;Avdeev, Maxim;Maynard-Casely, Helen;Zhaoming, Zhang

The crystal and magnetic structures of double perovskites of the type Ba2-xSrxYOsO6 have been studied by synchrotron X-ray and neutron powder diffraction methods, bulk magnetic susceptibility measurements and X-ray absorption spectroscopy. The structures were refined using a combined neutron and synchrotron data set and are based on ordered array of corner sharing YO6 and OsO6 octahedra, with the Ba/Sr cations being completely disordered. The structure evolves from cubic to monoclinic as the Sr content is increased, due to the introduction of cooperative tilting of the octahedra. Bulk magnetic susceptibility measurements demonstrate the oxides are all antiferromagnets. The decrease in symmetry results in a, non-linear, increase in the Neel temperature. Low temperature neutron diffraction measurements of selected examples show these to be type-I antiferromagnets. X-ray absorption spectra collected at the Os L3- and L2-edges confirm the Os is pentavalent in all cases, and there is no detectable change in the covalency of the Os cation as the A-cation changes. Analysis of the L3:L2 branching ratio shows that the spin-orbit coupling is constant and insignificant across the series.
Multi-scale Structural Analysis of the A-site and Oxygen Deficient Perovskite Sr11Mo4O2
21 February 2019
University of Sydney

King, Graham;Avdeev, Maxim;Qasim, Ilyas;Zhou, Qingdi;Kennedy, Brendan J

The long range average crystal structure, as well as the short and medium range structural features, of the A-site deficient and oxygen deficient perovskite Sr11Mo4O23 have been determined. Rietveld refinement of synchrotron X-ray and neutron powder diffraction data show that this compound is cubic with space group Fd-3m and a lattice parameter of a = 16.4108 Å. These findings contradict earlier reports of a tetragonal crystal structure. Sr11Mo4O23 appears to be isostructural with Ba11W4O23, except that the disordered coordination environment around one of the Mo sites seems to be a mixture of octahedral and square pyramidal instead of octahedral and tetrahedral. The short and medium range structural features have been inspected using the neutron pair distribution function (PDF). Short range correlations between the oxygen polyhedra surrounding the Mo(2) atom exist to avoid short O–O contacts. A model has been constructed which contains such correlations and is verified by reverse Monte Carlo (RMC) modeling of the PDF. The RMC refinements also give the distribution of inter-atomic distances in this compound which reveals how the various atomic positions are correlated and over what length scales. These results are important for understanding the ionic conduction pathways.
Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux
18 March 2019
University of Sydney

Zhang, Shaoyi;Wang, Yan;Xie, Wei;Howe, Ethan N.W.;Busschaert, Nathalie;Sauvat, Allan;Leduc, Marion;Gomes-da-Silva, Ligia C.;Chen, Guo;Martins, Isabelle;Deng, Xiaxing;Maiuri, Luigi;Kepp, Oliver;Soussi, Thierry;Gale, Philip A.;Zamzami, Naoufal;Kroemer, Guido

Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores block autophagic flux in spite of the fact that they activate the pro-autophagic transcription factor EB (TFEB) coupled to the inhibition of the autophagy-suppressive mTORC1 kinase activity. Two synthetic chloride transporters (SQ1 and SQ2) caused a partially TFEB-dependent relocation of the autophagic marker LC3 to the Golgi apparatus. Inhibition of TFEB activation using a calcium chelator or calcineurin inhibitors reduced the formation of LC3 puncta in cells, yet did not affect the cytotoxic action of SQ1 and SQ2 that could be observed after prolonged incubation. In conclusion, the squaramide-based synthetic chloride transporters studied in this work (which can also dissipate pH gradients) are probably not appropriate for the treatment of cystic fibrosis yet might be used for other indications such as cancer.
Promises and Pitfalls of Metal Imaging in Biology
29 March 2019
University of Sydney

New, Elizabeth J;Wimmer, Verena C;Hare, Dominic J

A picture may speak a thousand words, but if those words fail to form a coherent sentence there is little to be learned. As cutting-edge imaging technology now provides us the tools to decipher the multitude of roles played by metals and metalloids in molecular, cellular and developmental biology, as well as health and disease, it is time to reflect on the advances made in imaging, the limitations discovered, and the future of a burgeoning field. In this Perspective, the current state-of-the-art is discussed from a self-imposed contrarian position, as we not only highlight the major advances made of the years but use them as teachable moments to zoom in on challenges that remain to be overcome. We also describe the steps being taken towards being able to paint a completely undisturbed picture of cellular metal metabolism, which is, metaphorically speaking, the Holy Grail of the discipline.
Investigating the Influence of Steric Hindrance on Selective Anion Transport
03 April 2019
University of Sydney

Jowett, Laura A.;Ricci, Angela;Wu, Xin;Howe, Ethan N.W.;Gale, Philip A.

A series of symmetrical and unsymmetrical alkyl tren based tris-thiourea anion transporters were synthesised and their anion binding and transport properties studied. Overall, increasing the steric bulk of the substituents resulted in improved chloride binding and transport abilities. Including a macrocycle in the scaffold enhanced the selectivity of chloride transport in the presence of fatty acids, by reducing the undesired H+ flux facilitated by fatty acid flip-flop. This study demonstrates the benefit of including
Visible Light-Driven MADIX Polymerisation via a Reusable, Low-Cost and Non-Toxic Bismuth Oxide Photocatalyst
23 April 2019
University of Sydney

Hakobyan, Karen;Gegenhuber, Thomas;McErlean, Christopher S.P.;Müllner, Markus

The continuous amalgamation of photocatalysis into existing reversible deactivation radical polymerisation processes has initiated a rapidly propagating area of polymer research in recent years. We introduce bismuth oxide (Bi2O3) as a heterogeneous photocatalyst for polymerisations, operating at room temperature with visible light. We demonstrate formidable control over degenerative chain-transfer polymerisations, such as macromolecular design by interchange of xanthate (MADIX) and reversible addition-fragmentation chain transfer (RAFT) polymerisation. We achieved narrow molecular weight distributions and attribute the excellent temporal control to a photo-induced electron transfer (PET) process. This methodology was employed to synthesise diblock copolymers combining differently activated monomers. The Bi2O3 catalyst system has the additional benefits of low toxicity, reusability, low-cost, and ease of removal from the reaction mixture.
Aspect-ratio-dependent interaction of molecular polymer brushes and multicellular tumour spheroids
23 April 2019
University of Sydney

Müllner, Markus;Yang, Kylie;Kaur, Amandeep;New, Elizabeth Joy

Polymer nanoparticles based on molecular polymer brushes allow precise and independent tailoring of nanoparticle characteristics. This enables the synthesis of soft hydrophilic polymer particles with matching composition and surface chemistry where only the aspect-ratio is varied. PEGylated brush nanoparticles revealed that brush nanorods exhibit higher association and penetration into multicellular tumour spheroids compared to their spherical or filamentous counterparts.
Self-assembly of diblock molecular polymer brushes in the spherical confinement of nanoemulsion droplets
23 April 2019
University of Sydney

Steinhaus, Andrea;Pelras, Theophile;Chakroun, Ramzi;Gröschel, André H.;Müllner, Markus

Understanding the self-assembly behavior of polymers of various topologies is key to a reliable design of functional polymer materials. Self-assembly under confinement conditions emerges as a versatile avenue to design polymer particles with complex internal morphologies while simultaneously facilitating scale-up. However, only linear block copolymers have been studied to date, despite the increasing control over macromolecule composition and architecture available. This study extends the investigation of polymer self-assembly in confinement from regular diblock copolymers to diblock molecular polymer brushes (MPBs). Block-type MPBs with polystyrene (PS) and polylactide (PLA) compartments of different sizes are incorporated into surfactant-stabilised oil-in-water (chloroform/water) emulsions. The increasing confinement in the nanoemulsion droplets during solvent evaporation directs the MPBs to form solid nano/microparticles. Microscopy studies reveal an intricate internal particle structure, including interpenetrating networks and axially-stacked lamellae of PS and PLA, depending on the PS/PLA ratio of the brushes.
Synthesis and applications of compartmentalised molecular polymer brushes
23 April 2019
University of Sydney

Pelras, Theophile;Mahon, Clare S.;Müllner, Markus

Polymer science is rapidly advancing towards the precision-construction of synthetic macromolecules of formidable complexity. Beyond the impressive advances in control over polymer composition and uniformity enabled by the living polymerisation revolution, the introduction of compartmentalisation within polymer architectures can elevate their functionality beyond that of their constituent parts, offering immense potential for the production of tailor-made nanomaterials. Here, we discuss synthetic routes to complex molecular brushes with discrete chemical compartments and highlight their potential in the development of advanced materials with applications in nanofabrication, optics and functional materials.
Supramolecular methods: the chloride/nitrate transmembrane exchange assay
01 May 2019
University of Sydney

Jowett, Laura A.;Gale, Philip A.

The chloride/nitrate anion exchange assay is one of the most common methods of measuring chloride transport across lipid bilayers. In this methods paper, we provide a step-by-step procedure for using this assay based on ion selective electrodes and highlight the advantages and limitations of this approach in assessing the transmembrane chloride transport capability of anionophores.
Dichotomous well-defined nanostructure with weakly arranged ion packing explains the solvency of pyrrolidinium acetate
24 May 2019
University of Sydney

Jiang, Haihui Joy;Imberti, Silvia;Atkin, Rob;Warr, Gregory

Pyrrolidinium ionic liquids, especially pyrrolidinium acetate (PyrrAc), have demonstrated outstanding capacity for extracting lignin from biomass, as electrolytes for fuel cells and lithium ion batteries and as solvents for acid-catalysed reactions. In this work we show that the unusual liquid nanostructure of PyrrAc is the key to its versatility as a solvent compared to other ionic liquids. Neutron diffraction with multiple H/D isotopic substitutions reveals that the bulk nanostructure of PyrrAc is a bicontinuous network of interpenetrating polar and apolar domains. However, the arrangement of groups in both domains is strikingly different from that found in other ionic liquids. In the apolar regions, the pyrrolidinium rings are highly intercalated and disordered, with no preferred alignment between adjacent pyrrolidinium rings, which distinguishes it from both π−π stacking seen in imidazolium or pyridinium ionic liquids, and the tail-tail bilayer-like arrangements in linear alkylammonium ionic liquids. The H-bond network within the polar domain extends only to form finite clusters, with long bent H-bonds to accommodate electrostatics. Therefore, while PyrrAc unquestionably has well defined amphiphilic nanostructure, the disordered arrangement of groups in the polar and apolar domains enables it to accommodate a wide variety of solutes. The combination of well-defined polar/apolar nanostructure, but disordered arrangements of groups within domains, is therefore the origin of PyrrAc’s capacity for lignin extraction and as an electrolyte.
Effect of Deep Eutectic Solvent Nanostructure on Phospholipid Bilayer Phases
24 May 2019
University of Sydney

Bryant, Saffron Jade;Atkin, Rob;Warr, Gregory

Phospholipids are shown by solvent penetration experiments to form lamellar phases and sponta-neously spawn vesicles in a wide range of deep eutectic solvents (DESs) composed of alkylammoni-um halide salts and glycerol or ethylene glycol, which are shown to be nanostructured by X-ray scat-tering. In contrast with molecular solvents, the chain melting temperature of each phospholipid, which determines the stability of the swellable bilayer phase, depends on the structure of the cation, anion and molecular H-bond donor that constitute the DES. Chain melting is most sensitive to the length of the alkyl chain of the cation, which is partitioned between apolar domains in the bulk, nanostructured DES and those within the lipid bilayer. This is moderated by the structures of the an-ion and the molecular hydrogen bond donor, which determine the extent of polar/apolar segregation in the bulk liquid.
Effect of Protic Ionic Liquid Nanostructure on Phospholipid Vesicle Formation
27 May 2019
University of Sydney

Bryant, Saffron Jade;Wood, Kathleen;Atkin, Rob;Warr, Gregory

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 implica-tions for the use of ionic liquids in soft and biological materials and for biopreservation, and demon-strates 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 in-crease with phospholipid acyl chain length, paralleling behaviour in aqueous systems.
Continuous negative-to-positive tuning of thermal expansion achieved by controlled gas sorption in porous coordination frameworks
29 May 2019
University of Sydney

Auckett, Josie E.;Barkhordarian, Arnold A.;Ogilvie, Stephen H.;Duyker, Samuel G.;Chevreau, Hubert;Peterson, Vanessa K.;Kepert, Cameron J.

Control of the thermomechanical properties of functional materials is of great fundamental and technological significance, with the achievement of zero or negative thermal expansion behavior being a key goal for various applications. A dynamic, reversible mode of control is demonstrated for the first time in two Prussian blue derivative frameworks whose coefficients of thermal expansion are tuned continuously from negative to positive values by varying the concentration of adsorbed CO2. A simple empirical model that captures site-specific guest contributions to the framework expansion is derived, and displays excellent agreement with the observed lattice behaviour.
Increasing spin crossover cooperativity in 2D Hofmann-type materials with guest molecule removal
29 May 2019
University of Sydney

Zenere, Katrina A.;Duyker, Samuel G.;Trzop, Elzbieta;Collet, Eric;Chan, Bun;Doheny, Patrick W.;Kepert, Cameron J.;Neville, Suzanne M.

Molecule-based spin state switching materials that display ambient temperature transitions with accompanying wide thermal hysteresis offer an opportunity for electronic switching, data storage, and optical technologies but are rare in existence. Here, we present the first 2D Hofmann-type materials to exhibit the elusive combination of ambient temperature spin crossover with wide thermal hysteresis (ΔT = 50 and 65 K). Combined structural, magnetic, spectroscopic, and theoretical analyses show that the highly cooperative transition behaviours of these layered materials arise due to strong host–host interactions in their interdigitated lattices, which optimises long-range communication pathways. With the presence of water molecules in the interlayer pore space in the hydrated phases, competing host–host and host–guest interactions occur, whilst water removal dramatically increases the framework cooperativity, thus affording systematic insight into the structural features that favour optimal spin crossover properties.
Kamlet-Taft Solvation Parameters of Solvate Ionic Liquids
17 June 2019
University of Sydney

Dolan, Andrew;Sherman, Dylan;Atkin, Rob;Warr, Gregory

The Kamlet-Taft solvent parameters of solvate ionic liquids (SILs) prepared from lithium salts with glyme and glycol ligands have been determined. The dipolarity/polarizibilities (π*) are high, similar to those found in conventional ionic liquids. The H-bond basicities (β) depend strongly on the anion. The H-bond acidities (α) are high in both glyme and glycol SILs, indicating that the lithium is acting as a H-bond donor site. ‘Poor’ SILs have glyme rich and salt rich regions, in these liquids the π* and β values are almost identical to the parent glyme or glycol, and the α values are determined by the salt alone.
Scattering from Ionic Liquids
17 June 2019
University of Sydney

Murphy, Thomas;Atkin, Rob;Warr, Gregory

Research into the properties and applications of ionic liquids (ILs) has accelerated over the last few decades, driven principally by the advanced reaction kinetics and specificity they offered for synthesis and catalysis. ILs display many highly desirable properties, including high electrical and thermal conductivities and wide electrochemical windows, all of which can be tuned by altering the nature of their constituent ions. The discovery that ILs mediate surfactant self-assembly increased interest further. X-ray and neutron scattering are powerful tools for elucidating structure in both simple and complex, mesostructured liquids that were soon applied to IL-based systems. Early work revealed that many IL solvents are themselves nanostructured, and comprise distinct polar and apolar domains produced by the solvophobic segregation of alkyl moieties. Over the last decade scattering techniques have been used to characterise the nanostructure of a diverse range of ILs. Recently, nanostructure changes in ILs produced by the dissolution of salts, polymers, small molecules and amphiphiles have begun to be elucidated. X-ray and neutron scattering have, and will continue to, play a fundamental role in understanding structure-property relationships in IL-based systems.
Hydroquinone-Based Anion Receptors for Redox-Switchable Chloride Binding
12 July 2019
University of Sydney

McNaughton, Daniel A.;Fu, Xiaochen;Lewis, William;D'Alessandro, Deanna M.;Gale, Philip A.

A series of chloride receptors has been synthesized containing an amide hydrogen bonding site and a hydroquinone motif. It was anticipated that oxidation of the hydroquinone unit to quinone would greatly the diminish chloride binding a nity of these receptors. A conformational switch is promoted in the quinone form through the formation of an intramolecular hydrogen bond between the amide and the quinone carbonyl, which blocks the amide binding site. The reversibility of this oxidation process highlighted the potential of these systems for use as redox-switchable receptors. 1H-NMR binding studies confirmed stronger binding capabilities of the hydroquinone form compared to the quinone; however, X-ray crystal structures of the free hydroquinone receptors revealed the presence of an analogous inhibiting intramolecular hydrogen bond in this state of the receptor. Binding studies also revealed interesting and contrasting trends in chloride a nity when comparing the two switch states, which is dictated by a secondary interaction in the binding mode between the amide carbonyl and the hydroquinone/quinone couple. Additionally, the electrochemical properties of the systems have been explored using cyclic voltammetry and it was observed that the reduction potential of the system was directly related to the expected strength of the internal hydrogen bond.
Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations
26 August 2019
University of Sydney

Marques, Igor;Costa, Pedro M.R.;Miranda, Margarida Q.;Busschaert, Nathalie;Howe, Ethan N.W.;Clarke, Harriet J.;Haynes, Cally J.E.;Kirby, Isabelle L.;Rodilla, Ananda M.;Pérez-Tomás, Ricardo;Gale, Philip A.;Félix, Vítor

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N–H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical monosquaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured.
New Insights into the Anion Transport Selectivity and Mechanism of Tren-based Tris-(thio)ureas
26 August 2019
University of Sydney

Jowett, Laura A.;Howe, Ethan N.W.;Wu, Xin;Busschaert, Nathalie;Gale, Philip A.

The anion transport properties of a series of previously reported tren-based anionophores have been revisited using new assays designed to measure anion uniport. This study provides new insights into the transport mechanism and selectivity of this important class of transporters. Specifically, we report the chloride and nitrate transport selectivity of these systems and quantify sulfate transport to determine EC50 values for sulfate transport for the first time. Two new assays were developed to study bicarbonate transport allowing accurate quantification of chloride/bicarbonate exchange.
Effect of cholesterol on the dipole potential of lipid membranes
04 September 2019
University of Sydney

Clarke, Ronald J.

The membrane dipole potential, ψd, is an electrical potential difference with a value typically in the range 150 – 350 mV (positive in the membrane interior) which is located in the lipid headgroup region of the membrane, between the linkage of the hydrocarbon chains to the phospholipid glycerol backbone and the adjacent aqueous solution. At its physiological level in animal plasma membranes (up to 50 mol%), cholesterol makes a significant contribution to ψd of approximately 65 mV; the rest arising from other lipid components of the membrane, in particular phospholipids. Via its effect on ψd, cholesterol may modulate the activity of membrane proteins. This could occur through preferential stabilization of protein conformational states. Based on its effect on ψd, cholesterol would be expected to favour protein conformations associated with a small local hydrophobic membrane thickness. Via its membrane condensing effect, which also produces an increase in ψd, cholesterol could further modulate interactions of polybasic cytoplasmic extensions of membrane proteins, in particular P-type ATPases, with anionic lipid headgroups on the membrane surface, thus leading to enhanced conformational stabilization effects and changes to ion pumping activity.
Cholesterol depletion inhibits Na+,K+-ATPase activity in a near-native membrane environment
10 September 2019
University of Sydney

Garcia, Alvaro;Lev, Bogdan;Hossain, Khondker R.;Gorman, Amy;Diaz, Dil;Pham, T. H. Nguyen;Cornelius, Flemming;Allen, Toby W.;Clarke, Ronald J.

Cholesterol’s effects on Na+,K+-ATPase reconstituted in phospholipid vesicles have been extensively studied. However, previous studies have reported both cholesterol-mediated stimulation and inhibition of Na+,K+-ATPase activity. Here, using partial reaction kinetics determined via stopped-flow experiments, we studied cholesterol’s effect on Na+,K+-ATPase in a near-native environment in which purified membrane fragments were depleted of cholesterol with methyl-β-cyclodextrin (mβCD). The mβCD-treated Na+,K+-ATPase had significantly reduced overall activity and exhibited decreased observed rate constants for ATP phosphorylation (ENa+3 → E2P, i.e. phosphorylation by ATP and Na+ occlusion from the cytoplasm) and K+ deocclusion with subsequent intracellular Na+ binding (E2K+2 → E1Na+3). However, cholesterol depletion did not affect the observed rate constant for K+ occlusion by phosphorylated Na+,K+-ATPase on the extracellular face and subsequent dephosphorylation (E2P → E2K+2). Thus, partial reactions involving cation binding and release at the protein’s intracellular side were most dependent on cholesterol. Fluorescence measurements with the probe eosin indicated that cholesterol depletion stabilizes the unphosphorylated E2 state relative to E1, and the cholesterol depletion-induced slowing of ATP phosphorylation kinetics was consistent with partial conversion of Na+,K+-ATPase into the E2 state, requiring a slow E2 → E1 transition before the phosphorylation. Molecular dynamics simulations of Na+,K+-ATPase in membranes with 40 mol% cholesterol revealed cholesterol interaction sites that differ markedly among protein conformations. They further disclosed state-dependent effects on membrane shape, with the E2 state being likely disfavored in cholesterol-rich bilayers relative to the E1P state because of a greater hydrophobic mismatch. In summary, cholesterol extraction from membranes significantly decreases Na+,K+-ATPase steady-state activity.
Membrane accessibility of glutathione
10 September 2019
University of Sydney

Garcia, Alvaro;Eljack, Nasma D.;Sani, Marc-Antoine;Separovic, Frances;Rasmussen, Helge H.;Kopec, Wojciech;Khandelia, Himanshu;Cornelius, Flemming;Clarke, Ronald J.

Regulation of the ion pumping activity of the Na+,K+-ATPase is crucial to the survival of animal cells. Recent evidence has suggested that the activity of the enzyme could be controlled by glutathionylation of cysteine residue 45 of the β-subunit. Crystal structures so far available indicate that this cysteine is in a transmembrane domain of the protein. Here we have analysed via fluorescence and NMR spectroscopy as well as molecular dynamics simulations whether glutathione is able to penetrate into the interior of a lipid membrane. No evidence for any penetration of glutathione into the membrane was found. Therefore, the most likely mechanism whereby the cysteine residue could become glutathionylated is via a loosening of the -β subunit association, creating a hydrophilic passageway between them to allow access of glutathione to the cysteine residue. By such a mechanism, glutathionylation of the protein would be expected to anchor the modified cysteine residue in a hydrophilic environment, inhibiting further motion of the β-subunit during the enzyme’s catalytic cycle and suppressing enzymatic activity, as has been experimentally observed. The results obtained, therefore, suggest a possible structural mechanism of how the Na+,K+-ATPase could be regulated by glutathione.
The voltage-sensitive dye RH421 detects a Na+,K+-ATPase conformational change at the membrane interface
10 September 2019
University of Sydney

Garcia, Alvaro;Promod, Pratap R.;Lupfert, Christian;Cornelius, Flemming;Jacquemin, Denis;Lev, Bogdan;Allen, Toby W.;Clarke, Ronald J.

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.
Fatty Acid Fueled Transmembrane Chloride Transport
22 October 2019
University of Sydney

Howe, Ethan N.W.;Gale, Philip A.

Generation of chemical gradients across biological membranes of cellular compartments is a hallmark of all living systems. Here we report a proof-of-concept prototype transmembrane pumping system in liposomes. The pump uses fatty acid to fuel chloride transport, thus generating a transmembranechloride gradient. Addition of fatty acid to phospholipid vesicles generates a transmembrane pH gradient (pHin < pHout), and this electrochemical H+ potential is harnessed by an anionophore to drive chloride efflux via H+/Cl− cotransport. Further addition of fatty acid efficiently fuels the system to continuously drive chloride transport against the concentration gradient, up to [Cl−] 65 mM | [Cl−] 100 mM, and is 1400 times more efficient than using an in out +− external fuel. Based on our findings from dissecting the H /Cl flux process with the use of different liposomal fluorescence assays, and supported by additional liposome-based 13C NMR and DLS studies; we proposed that the presence of an anionophore can induce asymmetric distribution of fatty acid, and contribute to another Cl− flux mechanism in this system.
Voltage-Switchable HCl Transport Enabled by Lipid Headgroup–Transporter Interactions
22 October 2019
University of Sydney

Wu, Xin;Small, Jennifer R.;Cataldo, Alessio;Withecombe, Anne M.;Turner, Peter;Gale, Philip A.

Synthetic anion transporters that facilitate transmembrane H+/Cl- symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low-to-modest H+/Cl- symport activity and their mechanism of action remains less well understood. We report a chloride-selective tetraurea macrocycle that has a record-high H+/Cl- symport activity similar to that of prodigiosin and most importantly demonstrates unprecedented voltage-switchable transport properties that are linked to the lack of uniport activity. By studying the anion binding affinity and transport mechanisms of four other anion transporters, we show that the lack of uniport and voltage-dependent H+/Cl@ symport originate from strong binding to phospholipid headgroups that hampers the diffusion of the free transporters through the membrane, leading to an unusualH+/Cl- symport mechanism that involves only charged species. Our work provides important mechanistic insights into different classes of anion transporters and a new approach to achieve voltage-switchability in artificial membrane transport systems.
Tetraurea Macrocycles: Aggregation-Driven Binding of Chloride in Aqueous Solutions
22 October 2019
University of Sydney

Wu, Xin;Wang, Patrick;Turner, Peter;Lewis, William;Catal, Osman;Thomas, Donald S.;Gale, Philip A.

Artificial receptors that recognize anionic species via non-covalent interactions have a wide range of biomedical, industrial, and environmental applications. A major challenge in this area of research is to achieve high-affinity and selective anion binding in aqueous media. So far, only a few examples of receptors capable of strong (>105 M 1) anion binding in solutions containing >50% water are available, and none show selectivity for chloride. We report here the discovery of a D4h-symmetric fluorinated tetraurea macrocycle that fulfils this function owing to its unique self-assembly properties. The macrocycle has a strong tendency to self-associate into columnar aggregates via intermolecular hydrogen bonds and aromatic stacking. In aqueous solutions, macrocycle aggregation generates solvent-shielding and size-selective binding pockets favorable for hydrogen bonding with chloride. As a result, micromolar affinity and highly selective chloride binding have been achieved with this simple small molecule (MW < 700) in 60 vol % water/acetonitrile.
Mimicking the Wettability of the Rose Petal using Self-assembly of Waterborne Polymer Particles
21 November 2019
University of Sydney

Telford, Andrew Michael;Hawkett, B.S.;Such, C.;Neto, Chiara

In this work, we present a novel platform to synthesize polymeric “raspberry” particles and explore their use to fabricate surfaces with low wettability and high water adhesion, resembling the properties of naturally occurring surfaces such as the rose petal. The raspberry particles were obtained by layer-by-layer self-assembly of 850 nm core polystyrene particles bearing surface carboxylate groups and corona nanoparticles of different sizes and polymers (polystyrene, poly(para-fluorostyrene) or poly(2,3,4,5,6- penta-fluorostyrene), also bearing surface carboxylates), interleaved with positively charged poly(ally amine) hydrochloride.The raspberry particles were then bound together by covalent coupling of the carboxylate groups with the amine groups of the polymeric interlayer. The films produced by drop-casting the raspberry particles exhibited static water contact angles between ∼135° and ∼146°, depending on the nature of the corona, hysteresis of ∼135° and high adhesion of water droplets. Since all particles were synthesized from scratch by surfactant free emulsion polymerization in air and every step of the protocol was performed in water, this platform is up-scalable and environmentally friendly.
Liquid-like ionic diffusion in solid bismuth oxide revealed by coherent quasielastic neutron scattering
21 November 2019
University of Sydney

Wind, Julia;Mole, Richard A;Yu, Dehong;Ling, Chris D

The exceptional oxide-ionic conductivity of the high-temperature phase of bismuth oxide gives rise to a characteristic “quasielastic” broadening of its neutron scattering spectrum. We show that the oscillating form of this broadening can be fit using a modified version of a jump-diffusion model previously reserved for liquid ionic conductors. Fit parameters include a quantitative jump distance and a semi-quantitative diffusion coefficient. In the present case, the results show that diffusion is isotropic (liquid-like) even though some directions present shorter oxygen-vacancy distances, an insight corroborated by computational dynamics simulations. More broadly, the results show for the first time that quasielastic neutron scattering can be directly analyzed to yield quantitative insights into the atomic-scale mechanisms of solid-state ionic conduction, even when the diffusing species is a coherent neutron scatterer such as oxygen. This shows its power as a tool for studying functional solid-state materials, notably for solid-oxide fuel cells and, potentially, lithium-ion batteries.
Local structure adaptations and oxide ionic conductivity in the Type III stability region of (1–x)Bi2O3∙xNb2O5
21 November 2019
University of Sydney

Wind, Julia;Sharma, Neeraj;Yaremchenko, Aleksey A;Kharton, Vladislav V;Blom, Douglas A;Vogt, Thomas;Ling, Chris D

Starting from a previously published stoichiometric model for the commensurate Type III phase in the (1–x)Bi2O3∙xNb2O5 system, Bi94Nb32O221 (x = 0.254), we have developed a crystal-chemical model of this phase across its solid-solution range 0.20 ≤ x ≤ 0.26. After using annular dark-field scanning transmission electron microscopy to identify the metal sites that support non-stoichiometry, we show that the maximum possible range of that non-stoichiometry is 0.198 ≤ x ≤ 0.262, perfectly consistent with the experimental result. Inter-site cation defects on these sites provide some local coordinative flexibility with respect to the surrounding oxygen sublattice, but not enough to create continuous fluorite-like channels like those found in the high-temperature incommensurate Type II phase. This explains the reduced oxide-ionic conductivity of Type III compared to Type II at all temperatures and compositions, regardless of which phase is thermody-namically stable under those conditions. The solid-solution model shows that oxygen disorder and vacancies are both re-duced as x increases, which also explains why Type III becomes relatively more stable, and why oxide ionic conductivity decreases, as x increases.
Rational design of a commensurate (3+3)-D modulated structure within the fast-ion conducting stabilized δ-Bi2O3 series
22 November 2019
University of Sydney

Wind, Julia;Polt, Julia;Zhang, Zhaoming;Blom, Douglas A;Vogt, Thomas;Withers, Ray L;Ling, Chris D

We report the systematic design, preparation, and characterization of the first commensurate member of the oxide-ionic conducting, (3 + 3)-D modulated, Type II phases of doped δ-Bi2O3. The incommensurate Type II modulation vector ε was previously described as continuously variable, but high-resolution synchrotron X-ray powder diffraction data show that close to the composition Bi23CrNb3O45, it “locks in” to ε = 1/3. The space group of the resulting 3 × 3 × 3 fluorite-type supercell was found to be F4̅3m by selected-area electron diffraction, and the structure was solved and Rietveld-refined against neutron powder diffraction data in conjunction with local structural information from X-ray absorption spectroscopy, high-resolution transmission electron microscopy, and ab initio geometry optimization calculations. The result unambiguously validates the crystal-chemical model of the Type II phases as being based on the local ordering of oxygen around transition metals M into tetrahedral clusters of MO6 octahedra and isolated MO4 tetrahedra, separating relatively disordered fluorite-type regions that facilitate the highest oxide-ionic conduction among transition metal-doped δ-Bi2O3 phases.
Robust grafting of PEG-methacrylate brushes from polymeric coatings
28 November 2019
University of Sydney

Telford, A.M.;Meagher, L.;Neto, Chiara

A study is presented of the grafting of poly(ethylene glycol)methyl ether methacrylate (PEGMA) from polymeric macroinitiator films to form well-defined polymer brushes, using activators generated/regenerated by electron transfer (AGET/ARGET) atom transfer radical polymerization (ATRP). Polymer brush coatings can potentially be obtained on surfaces of virtually any shape and composition, because of the ease of conformal casting of the anchoring macroinitiator film. Polymer brush coatings are synthesized in a robust way, as ARGET and AGET ATRP require little to no deoxygenation and make use of stable catalysts. The monomer, catalyst, ligand and reducing agent concentrations, the amount and type of initiating moiety in the anchoring films, and the choice of solvents are optimized, resulting in control over the rate of reaction, and the molecular weight of poly(PEGMA). The best conditions are determined for the formation of a poly(PEGMA) brush with high grafting density, controlled thickness and “living” ends available for post-functionalization.
Micropatterned Surfaces for Atmospheric Water Condensation via Controlled Radical Polymerization and Thin Film Dewetting
28 November 2019
University of Sydney

Wong, I.;Teo, G.H.;Neto, Chiara;Thickett, S.C.

Inspired by an example found in nature, the design of patterned surfaces with chemical and topographical contrast for the collection of water from the atmosphere has been of intense interest in recent years. Herein we report the synthesis of such materials via a combination of macromolecular design and polymer thin film dewetting to yield surfaces consisting of raised hydrophilic bumps on a hydrophobic background. RAFT polymerization was used to synthesize poly(2-hydroxypropyl methacrylate) (PHPMA) of targeted molecular weight and low dispersity; spin-coating of PHPMA onto polystyrene films produced stable polymer bilayers under appropriate conditions. Thermal annealing of these bilayers above the glass transition temperature of the PHPMA layer led to complete dewetting of the top layer and the formation of isolated PHPMA domains atop the PS film. Due to the vastly different rates of water nucleation on the two phases, preferential dropwise nucleation of water occurred on the PHPMA domains, as demonstrated by optical microscopy. The simplicity of the preparation method and ability to target polymers of specific molecular weight demonstrate the value of these materials with respect to large-scale water collection devices or other materials science applications where patterning is required.
Tunable Nanopatterns via the Constrained Dewetting of Polymer Brushes
28 November 2019
University of Sydney

Lee, T.;Hendy, S.C.;Neto, Chiara

Coarse-grained molecular dynamics simulations were used to investigate the mor- phology and dynamics of nano-patterns formed by grafted polymer brushes on a non- adsorbing substrate as a result of constrained dewetting. As a good solvent is made to gradually evaporate, polymer brushes with low to moderate grafting density collapse into discrete nano-sized aggregates, with di erent types of nano-patterns possible, in- cluding pancake micelles and holey layers. The type of pattern, the size and number of features, and their dynamics depend on the grafting density of the polymer brush and amount of good solvent adsorbed. The nal pattern morphology depends primarily on the total amount of material adsorbed to the surface, including both polymer and solvent. This result suggests the possibility for the use of polymer brushes as surfaces with reversibly tunable nano-patterns.
Protein Micropatterns by PEG Grafting on Dewetted PLGA Films
28 November 2019
University of Sydney

Ghezzi, Manuel;Thickett, S.C.;Telford, A.M.;Easton, C.D.;Meagher, L.;Neto, Chiara

The ability to control protein and cell positioning on a microscopic scale is crucial in many biomedical applications, such as single cell studies. We have developed and investigated the grafting of poly(ethylene glycol) (PEG) brushes onto poly(D,L-lactide-co-glycolide) (PLGA) thin films, which can be micro-patterned by exploiting their spontaneous dewetting on top of polystyrene (PS) films. Dense PEG brushes with excellent protein repellence were achieved on PLGA by using cloud point grafting conditions, and selective adsorption of proteins on the micro-patterned substrates was achieved by exploiting the different affinity protein adsorption onto the PEG brushes and the PS holes. PEG-grafted PLGA films showed better resistance against spontaneous degradation in buffer than bare PLGA films, due to passivation by the thin PEG coating. The simplicity of dewetting and subsequent grafting approaches, coupled with the ability to coat and pattern non-planar substrates give rise to possible applications of PEG-grafted PLGA films in single cell studies and cell cultures for tissue engineering.
Guiding the Dewetting of Thin Polymer Films by Colloidal Imprinting
28 November 2019
University of Sydney

Ghezzi, Manuel;Wang, P-Y.;Kingshott, P.;Neto, Chiara

Micropatterned surfaces are important in many biomedical and bioengineering applications, such as the development of biosensors. An approach for the creation of ordered surface patterns, fabricated combining colloidal crystals, consisting of ordered layers of micrometric particles, with dewetting of bilayers of thin polymer fi lms is introduced. The produced patterns are both topographical and chemical in nature, consisting of ordered arrays of microscale holes imprinted in a polymer fi lm, with tunable size. The spontaneous dewetting of the polymer fi lm enables this tunability, with a maximum sevenfold increase in lateral size of the holes and sixfold increase in depth from imprinting to coalescence with neighboring holes. Polymer dewetting and layer inversion are seen to compete during the annealing of the polymer bilayers, and the optimal conditions for hole growth are identifi ed. An indepth investigation highlights the effects of UV-ozone treatment on the longrange ordering of the colloidal crystals and on preventing the dewetting of the imprinted bilayers. Ordered patterns of different size and depth are produced over large areas by tuning of the colloidal crystal assembly, UV surface treatment and dewetting conditions. Potential applications of the micropatterns produced in the present work include microarrays for single cell studies and biosensors.
Chain Collapse and Interfacial Slip of Polystyrene Films in Good/ Nonsolvent Vapor Mixtures
28 November 2019
University of Sydney

Al-Khayat, O.;Geraghty, K.;Shou, K.;Nelson, A.;Neto, Chiara

We investigated the dynamics and morphology of dewetting of metastable polystyrene films (thickness 75− 500 nm) cast on silicon substrates, upon exposure to vapors of a mixture of toluene, a good solvent, and ethanol, a nonsolvent. Adding more than 2 wt % ethanol to the saturated toluene environment resulted in a dramatic increase in dewetting rate, an increase in the contact angle of polymer droplets and hole rims on the substrate, and extensive fingering leading to droplet shedding. Films preannealed close to Tg before exposure to the solvent vapors showed markedly slower dewetting. We conclude that in the presence of a good/nonsolvent mixture the polymer chains transition to a globule conformation, which leads to larger interfacial slip, lower viscosity, and significant elastic stress. The slip length derived in the presence of ethanol vapor is close to the values obtained for polystyrene on hydrophobized silicon. As the dewetting process is so significantly boosted by exposure to mixed toluene/ethanol vapors, polystyrene films as thick as 520 nm could be dewetted.
Patterned chemisorption of proteins by thin polymer film dewetting
29 November 2019
University of Sydney

Lim, S.K.;Perrier, S.;Neto, Chiara

The covalent attachment of proteins and their patterning on surfaces are important in the bio-medical industry, for use in applications such as bio-sensing and biocompatible medical devices. In this work, proteins are chemisorbed by reaction of their amine groups to glutaraldehyde- and carboxylic acid-functionalised surfaces, within patterns obtained by the dewetting of thin polystyrene films. The proof of principle is shown that consecutive attachment of proteins within the same pattern is possible using this method.
Zero-point energy conservation in classical trajectory simulations: Application to H2CO
03 December 2019
University of Sydney

Lee, Kin Long Kelvin;Quinn, Mitchell S;Kolmann, Stephen J;Kable, Scott H;Jordan, Meredith j T

A new approach for preventing zero-point energy (ZPE) violation in quasi-classical trajectory (QCT) simulations is presented and applied to H2CO “roaming” reactions. Zero-point energy may be problematic in roaming reactions because they occur at or near bond dissociation thresholds and these channels may be incorrectly open or closed depending on if, or how, ZPE has been treated. Here we run QCT simulations on a “ZPE-corrected” potential energy surface defined as the sum of the molecular potential energy surface (PES) and the global harmonic ZPE surface. Five different harmonic ZPE estimates are examined with four, on average, giving values within 4 kJ/mol—chemical accuracy—for H2CO. The local harmonic ZPE, at arbitrary molecular configurations, is subsequently defined in terms of “projected” Cartesian coordinates and a global ZPE “surface” is constructed using Shepard interpolation. This, combined with a second-order modified Shepard interpolated PES, V, allows us to construct a proof-of-concept ZPE-corrected PES for H2CO, Veff, at no additional computational cost to the PES itself. Both V and Veff are used to model product state distributions from the H + HCO ! H2 + CO abstraction reaction, which are shown to reproduce the literature roaming product state distributions. Our ZPE-corrected PES allows all trajectories to be analysed, whereas, in previous simulations, a significant proportion was discarded because of ZPE violation. We find ZPE has little effect on product rotational distributions, validating previous QCT simulations. Running trajectories on V, however, shifts the product kinetic energy release to higher energy than on Veff and classical simulations of kinetic energy release should therefore be viewed with caution.
The Good the Bad and the Slippery: A Tale of Three Solvents in Polymer Film Dewetting
04 December 2019
University of Sydney

Al-Khayat, Omar;Hong, Jun Ki;Geraghty, Kieran;Neto, Chiara

We investigated the dynamics and morphology of dewetting of bilayers of thin polymer films, made of a top poly(4-vinylpyridine) (P4VP) film on a polystyrene film on silicon substrates, upon exposure to vapors of binary and ternary mixtures of ethanol, acetone, and water, respectively a good solvent, a poor solvent, and a nonsolvent for P4VP. The composition of the vapor mixtures affected dramatically dewetting rate, dewetting dynamics and the morphology of the dewetted features, with vapor mixtures leading always to much higher dewetting rates than both pure solvent vapors and thermal annealing. We identified the role that each of the solvent vapors plays in the mixture, and concluded that water and acetone induce a transition of the polymer chains to a globule conformation reducing viscosity and modify the interfacial energies, two effects that strongly drive the dewetting. In an acetone environment, dewetting further speeds up, under the effect of a lubricated flow.
Waterborne all-polymeric colloidal 'raspberry' particles with controllable hydrophobicity and water droplet adhesion properties
04 December 2019
University of Sydney

Telford, Andrew M.;Easton, Chris D.;Hawkett, Brian S.;Neto, Chiara

Wepresent a superhydrophobic coating made fromwaterborne, all-polymeric ‘raspberry’ particles, composed of a micrometric spherical core decorated with a corona of nanometric spherical particles. As-cast particles produced hydrophobic coatings that were highly adhesive to almost-spherical droplets of water, resembling the properties of some types of rose petals. The coatings could be made slippery to spherical water droplets, like the lotus leaf, by surface activation with air plasma followed by reaction with an alkyl-trichlorosilane. The silanisation of films of latex particleswas investigated on two model surfaces (a flat polystyrene film and a monolayer of polystyrene waterborne microparticles) by X-ray photoelectron spectroscopy and water contact angle measurements, and applied to our recently-developed ‘raspberry’ particles to produce a superhydrophobic coating.
Control of nanoparticle formation using the constrained dewetting of polymer brushes
04 December 2019
University of Sydney

Lee, Thomas;Hendy, Shaun C.;Neto, Chiara

We have used coarse-grained molecular dynamics simulations to investigate the use of pinned micelles formed by the constrained dewetting of polymer brushes to act as a template for nanoparticle formation. The evaporation of a thin film containing a dissolved solute from a polymer brush was modeled to study the effect of solubility, concentration, grafting density, and evaporation rate on the nucleation and growth of nanoparticles. Control over particle nucleation could be imposed when the solution was dilute enough such that particle nucleation occurred following the onset of constrained dewetting. We predict that nanoparticles with sizes on the order of 1 nm to 10 nm could be produced from a range of organic molecules under experimentally accessible conditions. This method could allow the functionality of organic materials to potentially be imparted onto surfaces without the need for synthetic modification of the functional molecule, and with control over particle size and aggregation, for application in the preparation of surfaces with useful optical, pharmaceutical, or electronic properties.
High Glass Transition Temperature Fluoropolymers for Hydrophobic Surface Coatings via RAFT Copolymerization
04 December 2019
University of Sydney

Rowe, M.;Teo, G.;Horne, J.;Al-Khayat, Omar;Neto, Chiara;Thickett, Stuart C.

The preparation of polymer thin films or surface coatings that display a static water contact angle .958 often requires hierarchical roughness features or surface functionalization steps. In addition, inherently hydrophobic polymers such as fluoropolymers often possess low glass transition temperatures, reducing their application where thermal stability is required. Herein, the first reported synthesis of 2,3,4,5,6-pentafluorostyrene (PFS) and N-phenylmaleimide (NMI) via reversible addition–fragmentation chain-transfer (RAFT)-mediated free radical polymerization is presented, with a view towards the preparation of inherently hydrophobic polymers with a high glass transition temperature. A suite of copolymers were prepared and characterized, and owing to the inherent rigidity of the maleimide group in the polymer backbone and p–p interactions between adjacent PFS and NMI groups, very high glass transition temperatures were achieved (up to 1808C). The copolymerization of N-pentafluorophenylmaleimide was also performed, also resulting in extremely high glass transition temperature copolymers; however, these polymers did not exhibit characteristics of being under RAFT control. Thin films of PFS-NMI copolymers exhibited a static contact angle ,1008, essentially independent of the amount of NMI incorporated into the polymer.
Functional patterned coatings by thin polymer film dewetting
06 December 2019
University of Sydney

Telford, Andrew M.;Thickett, S.C.;Neto, Chiara

An approach for the fabrication of functional polymer surface coatings is introduced, where micro-scale structure and surface functionality are obtained by means of self-assembly mechanisms. We illustrate two main applications of micro-patterned polymer surfaces obtained through dewetting of bilayers of thin polymer films. By tuning the physical and chemical properties of the polymer bilayers, micropatterned surface coatings could be produced that have applications both for the selective attachment and patterning of proteins and cells, with potential applications as biomaterials, and for the collection of water from the atmosphere. In all cases, the aim is to achieve functional coatings using approaches that are simple to realize, use low cost materials and are potentially scalable.
Using Click Chemistry to Tune the Properties and the Fluorescence Response Mechanism of Structurally Similar Probes for Metal Ions
13 December 2019
University of Sydney

Ast, Sandra;Kuke, Stefanie;Rutledge, Peter J;Todd, Matthew H

Four cyclam-based fluorescent molecular probes were prepared using ‘click’ chemistry and investigated to determine the effect of the triazole connectivity and fluorophore substitution on photophysical properties and metal ion response mechanism. The ligands’ fluorescence is turned on in the presence of Zn(II) but varies in intensity depending on the solvent; the highest signal changes are found in MeCN. Complexation with Cu(II) leads to fluorescence quenching, but only in the aqueous solvent, where the triazole is involved in coordination of the metal. The length of the pendant triazole arm influences the ligand field around pentacoordinated Cu(II) yielding a distorted square planar coordination geometry in the ligands with an ethylene linker. The quantum yield (QY) of the emission intensity can be tuned by the triazole substitution, resulting in increases in QY of more than one order of magnitude (ligand 1 vs. 3). Changing the fluorophore opens up alternative radiative processes, leading to phosphorescence-like behaviour in coumarin probe 2. Steady state fluorescence emission spectra of the free ligands and their respective Cu(II) complexes in a ‘glass environment’ reveal two different inherent fluorescent quenching mechanisms. In the free ligands an electron transfer deactivates the excited chromophore, while in the Cu(II)-complexes it is energy transfer that results in complete quenching of the ligands’ emission.
Selective displacement of a scorpionand triazole ligand from metallocyclam complexes visualised using NMR spectroscopy.
13 December 2019
University of Sydney

Wong, Joseph;Proschogo, Nicholas;Todd, Matthew H;Rutledge, Peter J

Target-activated metal complexes (TAMCs) – complexes that remain benign until reaching a specific biomolecular target, binding to which then affects 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 metal-cyclam 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 at zinc(II). Triazole displacement may be visualised by monitoring the 1H NMR resonance of the single triazole C–H proton environment. Using 2H NMR 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 stripping of the metal ion from the complex.
The Pseudoproline Approach to Peptide Cyclization
17 December 2019
University of Sydney

Jolliffe, Katrina A.

The development of efficient methods for the synthesis of cyclic peptides is of interest because of the many potential applications of this class of molecule. Pseudoprolines are derived from serine, threonine, and cysteine and can be used as traceless turn-inducers to facilitate the cyclization of a wide range of linear peptide precursors. The incorporation of a pseudoproline into the peptide to be cyclized generally results in a cyclization reaction that proceeds more quickly and with higher yield than that of an analogous sequence without the pseudoproline. Installation of a pseudoproline at the C-terminal position of a linear peptide sequence has also been shown to eliminate any epimerization of this residue during the reaction. Following pseudoproline-mediated cyclization, these turn-inducers can be removed on treatment with acid in a similar manner to other protecting groups to provide the native peptide sequence, and in the case of cysteine-derived pseudoprolines, the resulting cysteine can be readily converted into alanine through desulfurization. These traceless turninducers have been successfully used in the synthesis of cyclic peptides containing either serine, threonine, cysteine or alanine residues.
Pyrophosphate recognition and sensing in water using bis[zinc(II)dipicolylamino]-functionalized peptides
17 December 2019
University of Sydney

Jolliffe, Katrina A.

Phosphate oxoanions and phosphorylated biomolecules (such as nucleotides, lipids, and proteins) play key roles in a wide range of biological processes. The ability to selectively detect these ions in the presence of each other has numerous applications in biochemistry and biomedicine. However, receptors and sensors that can discriminate between polyphosphate species with high selectivity and in biologically relevant conditions are rare. In this Account, we show how peptides (both cyclic and linear) can be used to position two zinc(II)dipicolylamine [Zn(II)DPA] binding sites in an appropriate arrangement to provide selective binding of pyrophosphate (PPi) in the presence of other polyphosphate species, including ATP, and in complex media such as cell growth buffer. The use of peptide scaffolds to position the Zn(II)DPA anion binding sites allowed the synthesis of small receptor libraries in which the arrangement of the two binding sites could be subtly altered to evaluate the factors affecting both binding selectivity and affinity for PPi. We altered a number of structural elements including peptide length, cyclic peptide ring size, amino acid composition, the positioning of the binding sites with respect to one another, and the relative stereochemistry of the peptides. Backbone modified cyclic peptides based on the Lissoclinum class of natural products were initially employed to provide an added degree of preorganization to the receptors, although it was subsequently found that short, flexible bis[Zn(II)DPA]-functionalized linear peptides are also effective scaffolds for selective pyrophosphate recognition. The peptidic receptors were successfully employed for the detection of PPi in aqueous media by indicator displacement assays using both colorimetric and fluorescent indicators, with the best compounds able to bind to PPi selectively in both cell growth media and artificial urine and also allow the accurate determination of PPi concentrations in physiologically relevant ranges (micromolar concentrations) in these complex media. Improved pyrophosphate selectivity was observed upon increasing the complexity of the media from HEPES buffer to cell growth media (Krebs saline). Pyrophosphate sensors in which a fluorescent indicator was covalently attached to either a linear or cyclic peptide scaffold through a flexible linker were then constructed. When the Zn(II)DPA binding sites and the indicator were suitably placed with respect to one another on the peptide scaffold, these ‘intramolecular indicator displacement assays’ showed improved selectivity for PPi over other polyphosphate anions, such as ATP, when compared to the intermolecular indicator displacement assays. This observation provides the basis for the design and application of future PPi sensors in biochemistry and biomedicine.
Sulfate selective recognition using neutral dipeptide anion receptors in aqueous solution
17 December 2019
University of Sydney

Elmes, Robert B. P.;Yuen, Karen K. Y.;Jolliffe, Katrina A.

The synthesis of six small peptide anion receptors based on thiourea and squaramide recognition moieties is described. These new receptors bind to tetrahedral sulfate anions with remarkable affinity and selectivity in aqueous solution as shown by NMR spectroscopy. Molecular modelling suggests that selectivity is mediated by a hydrogen bond network incorporating the amide backbone protons in a manner similar to that found in the sulfate-binding protein.
Expanding the breadth of 4-amino-1,8-naphthalimide photophysical properties through substitution of the naphthalimide core
17 December 2019
University of Sydney

Leslie, Kathryn G.;Jacquemin, Denia;New, Elizabeth J.;Jolliffe, Katrina A.

Fluorescent sensors that illuminate specific molecules and chemical events allow the selective and sensitive study of the cellular environment. At the centre of this technology lies the fluorescent reporter molecule, and it is therefore crucial to provide a breadth of fluorophores with varying photophysical and biological behaviour. 4-Amino-1,8- naphthalimides are commonly employed in fluorescent sensors, but the narrow range of structural derivatives limits versatility of application. Here we report the synthesis and investigation of a set of twelve 4-amino-1,8-naphthalimides bearing an additional substituent on the aromatic core. Photophysical characterisation and time-dependent density functional theory studies provided insights into the structure– photophysical property relationships of these derivatives, which show an expanded range of emission wavelengths and other photophysical properties. These compounds could all be visualised within cells by confocal microscopy, showing cytoplasmic or lipid droplet localisation. Our studies have demonstrated that simple structural modification of 4-amino-1,8-naphthalimides provides derivatives with considerable breadth of behaviour that lend valuable versatility to the design of fluorescent sensors.
Anion Recognition By Cyclic Peptides
17 December 2019
University of Sydney

Elmes, Robert B. P.;Jolliffe, Katrina A.

Anion binding selectivity can often be controlled by judicious arrangement of recognition moieties around an anion of interest. Indeed, nature takes advantage of large peptides/proteins to provide highly efficient and selective anion receptors using a small number of amino acid building blocks placed in a precise arrangement. Cyclic peptides are ideal synthetic scaffolds to position binding residues in a similarly preorganised manner as their synthetic versatility and rigidified structure allows precise control over their size and shape. This review summarises the recent use of such cyclic peptide scaffolds as receptors for various anionic species.
Quantum Chemical Prediction of Equilibrium Acidities of Ureas, Deltamides, Squaramides and Croconamides
18 December 2019
University of Sydney

Ho, Junming;Zwicker, Vincent E.;Jolliffe, Katrina A.

Robust quantum chemical methods are employed to predict the pKas of several families of dual hydrogen-bonding organocatalyts/anion receptors, including deltamides and croconamides as well as their thio-derivatives. The average accuracy of these predictions is about 1 pH unit, and allow for a comparison of the acidity between classes of receptors and for quantitative studies of substituent effects. These computational insights further explain the relationship between pKa and chloride anion affinity of these receptors that will be important for designing future anion receptors and organocatalysts.
Deltamides and croconamides: Expanding the range of dual H-bond donors for selective anion recognition.
18 December 2019
University of Sydney

Zwicker, Vincent E.;Yuen, Karen K. Y.;Smith, David G.;Ho, Junming;Qin, Lei;Turner, Peter;Jolliffe, Katrina A.

Dual H-bond donors are widely used as recognition motifs in anion receptors. We report the synthesis of a library of dual H-bond receptors, incorporating the deltic and croconic acid derivatives, termed deltamides and croconamides, respectively, and a comparison of their anion binding affinities (for monovalent species) and Brønsted acidities to those of the well-established urea and squaramide dual H-bond donor motifs. For dual H-bonding cores with identical substituents, the trend in Brønsted acidity is croconamides> squaramides>deltamides>ureas, with the croconamides found to be 10–15 pKa units more acidic than the corresponding ureas. In contrast to the trends displayed by ureas, deltamides and squaramides, N,N’-dialkyl croconamides displayed higher binding affinity to chloride than the N,N’-diaryl derivatives, which was attributed to partial deprotonation of the N,N’-diaryl derivatives at neutral pH. A number of differences in anion binding selectivity were observed upon comparison of the dual H-bond cores. Whereas the squaramides display similar affinity for both chloride and acetate ions, the ureas have significantly higher affinity for acetate than chloride ions and the deltamides display higher affinity for dihydrogenphosphate ions than other oxoanions or halides. These inherent differences in binding affinity could be exploited in the design of anion receptors with improved ability to discriminate between monovalent anions.
Selective sensing of pyrophosphate in physiological media using zinc(II)dipicolylamino-functionalised peptides
18 December 2019
University of Sydney

Zwicker, Vincent E.;Long, Benjamin M.;Jolliffe, Katrina A.

A series of linear peptide based anion receptors, in which the distance between the bis[zinc(II)dipicolylamine] binding sites and the peptide backbone was varied systematically, was prepared and their anion binding ability was investigated using indicator displacement assays. Shortening the distance between the binding site and the peptide backbone was found to enhance both the receptor affinity and selectivity for pyrophosphate over other organic polyphosphate anions in Krebs buffer with the maximum selectivity and affinity observed with a spacer length of two methylene units. The suitability of these receptors for the determination of pyrophosphate concentrations in Krebs buffer and in artificial urine was examined.
Fluorescent and colorimetric chemosensors for pyrophosphate
18 December 2019
University of Sydney

Lee, Songyi;Yuen, Karen K. Y.;Jolliffe, Katrina A.;Yoon, Juyoung

Pyrophosphate anions play key roles in various biological and chemical processes. During the last few years, many exciting results have emerged regarding the development of fluorescent and colorimetric sensors for this biologically important species. In this review, we will cover the fluorescent and colorimetric chemosensors developed for the detection of pyrophosphate (PPi) since 2010.
Amino acid-based squaramides for anion recognition
19 December 2019
University of Sydney

Elmes, Robert B. P.;Jolliffe, Katrina A.

Eight receptors 1–8 comprising an L-lysine scaffold modified at N- and C-termini with aliphatic alkyl chains and N,N0-alkyl amides, respectively, and bearing squaramide moieties on the amino acid side chain were synthesised by a combination of solid- and solution-phase chemistries and shown to complex various anions in 0.5%H2Oin dimethyl sulfoxide-d6 solution. All of the receptors were found to bind SO22 4 ; Cl2, AcO2 and BzO2 via hydrogen-bond or acid–base interactions with the squaramide protons; however, 1 was found to bind to SO22 4 via hydrogen bonds formed between the anion and both the squaramide and amideNHmoieties. Moreover, modification of both the N- and C-termini of the amino acids with different alkyl substituents had a negligible effect on their anion-binding properties while simultaneously conferring lipophilicities in a range that is optimal for molecules to behave as ‘drug-like’ systems as defined by Lipinski’s rule of five. The results of this study demonstrate the versatility of such amino acid receptors as building blocks in the field of anion recognition.
Triazole–containing zinc(II)dipicolylaminefunctionalised peptides as highly selective pyrophosphate sensors in physiological media
19 December 2019
University of Sydney

Zwicker, Vincent E.;Liu, Xuejian;Yuen, Karen K. Y.;Jolliffe, Katrina A.

A small family of linear bis[zinc(II)dipicolylamine] (bis[Zn(II)-DPA])-functionalised peptidic anion receptors has been prepared where the Zn(II)-DPA binding sites have been installed via either a reductive amination reaction or a copper(I)- catalysed azide-alkyne cycloaddition reaction. The latter reaction connects the Zn(II)-DPA binding site and the peptide backbone through a 1,2,3-triazole linkage. Subsequent anion binding studies using indicator displacement assays were conducted to elucidate the effect of the triazole linker on the anion-binding properties of these novel receptors and it was found that the triazole-containing receptors exhibited stronger affinity and slightly improved selectivity for pyrophosphate over adenosine triphosphate and adenosine diphosphate compared to the analogous receptors which did not bear the triazole linker.
Supramolecular beta-cyclodextrin adducts of boron-rich DNA metallointercalators containing dicarba-closo-dodecaborane
19 December 2019
University of Sydney

Ching, H. Y. Vincent;Clarke, Ronald J.;Rendina, Louis M.

A chiral, isomeric series of novel boron-rich PtII metallointercalators ([PtL2(phen)](NO3)2: L = (x)-(1,y-closo-carboran-1-yl)pyrid-z-ylmethanol: x = R, S; y = 7, 12; z = 3, 4) wre prepared and fully characterized. By means of variable-temperature NMR spectroscopy, different combinations of Δ-head-to-tail, head-to-head, and Λ-head-to-tail rotamers were identified, and the free energies of activation for Pt–N bond rotation were determined for the pyrid-4-yl complexes with ΔG‡307 = 16.1 ± 0.3 kcal mol–1 and ΔG‡325 = 16.2 ± 0.5 kcal mol–1 for the 1,7-carboranyl derivative and ΔG‡307 = 16.4 ± 0.5 kcal mol–1 and ΔG‡325 = 16.2 ± 0.5 kcal mol–1 for the 1,12-carboranyl derivative. The corresponding 2:1 host–guest β-cyclodextrin (β-CD) adducts ([PtL2(phen)·2β-CD](NO3)2) were also prepared and fully characterized by high resolution electrospray ionization mass spectrometry and 2D-1H{11B} nuclear Overhauser enhancement spectroscopy and rotating-frame Overhauser effect spectroscopy NMR experiments. The interaction of the novel supramolecular adducts with calf thymus DNA was investigated by means of linear dichroism, ultraviolet-visible spectroscopy, thermal denaturation, and isothermal titration calorimetry experiments which revealed a bimodal binding regime with DNA intercalation favored at low [drug]/[DNA] ratios, while at higher drug loading, surface aggregation was observed. Furthermore, the data were also consistent with some degree of dissociation of the β-CD host–guest adducts upon DNA binding. When we used a single binding-site model, interpreted as a weighted average of all of the possible equilibrium interactions, the compounds showed high affinity for ct-DNA with Kassoc ranging from (1.3 ± 0.1) × 105 M–1 to (5.7 ± 0.4) × 105 M–1. In general, the overall DNA-binding behavior was enthalpically driven with a minor or unfavorable entropic component, which is consistent with the thermodynamics of an intercalation-dominated process. A higher degree of DNA intercalation was observed for the R-isomer in the pyrid-3-yl compounds, and the opposite trend was observed in the case of pyrid-4-yl derivatives.
Synchrotron X-ray fluorescence studies of a bromine-labelled cyclic RGD peptide interacting with individual tumor cells
19 December 2019
University of Sydney

Sheridan, Erin J.;Austin, Christopher J. D.;Aitken, Jade B.;Vogt, Stefan;Jolliffe, Katrina A.;Harris, Hugh H.;Rendina, Louis M.

The first example of synchrotron X-ray fluorescence imaging of cultured mammalian cells in cyclic peptide research is reported. The study reports the first quantitative analysis of the incorporation of a bromine-labelled cyclic RGD peptide and its effects on the biodistribution of endogenous elements (for example, K and Cl) within individual tumor cells.
Syntheses and reductions of C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes
20 December 2019
University of Sydney

Kahlert, Jan;Böhling, Lena;Brockhinke, Andreas;Stammler, Hans-Georg;Neumann, Beate;Rendina, Louis M.;Low, Paul J.;Weber, Lothar;Fox, Mark A.

Two C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes, 1-(BMes2)-2-R-1,2-C2B10H10 (1, R = H, 2, R = Ph), were synthesised by lithiation of 1,2-dicarba-closo-dodecaborane and 1-phenyl-1,2-dicarba-closo-dodecaborane, respectively, with n-butyllithium and subsequent reaction with fluorodimesitylborane. These novel compounds were structurally characterised by X-ray crystallography. Compounds 1 and 2 are hydrolysed on prolonged exposure to air to give mesitylene and boronic acids 1-(B(OH)2)-2-R-1,2-C2B10H10 (3, R = H, 4, R = Ph respectively). Addition of fluoride anions to 1 and 2 resulted in boryl-carborane bond cleavage to give dimesitylborinic acid HOBMes2. UV absorption bands at 318–333 nm were observed for 1 and 2 corresponding to local π–π*-transitions within the dimesitylboryl groups while visible emissions at 541–664 nm with Stokes shifts of 11[thin space (1/6-em)]920–16[thin space (1/6-em)]170 cm−1 were attributed to intramolecular charge transfer transitions between the mesityl and cluster groups. Compound 2 was shown by cyclic voltammetry to form a stable dianion on reduction. NMR spectra for the dianion [2]2− were recorded from solutions generated by reductions of 2 with alkali metals and compared with NMR spectra from reductions of 1,2-diphenyl-ortho-carborane 5. On the basis of observed and computed 11B NMR shifts, these nido-dianions contain bowl-shaped cluster geometries. The carborane is viewed as the electron-acceptor and the mesityl group is the electron-donor in C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes.
Site-specific synthesis of a hybrid boron-graphene salt
20 December 2019
University of Sydney

Kahlert, Jan U.;Austin, Christopher J. D.;Hall, Andrew J.;Rawal, Aditya;Hook, James M.;Rendina, Louis M.;Choucair, Mohammad

We report the first example of an ionic graphene salt containing boron. An anionic charge is introduced to the graphene surface by means of 7,8-nido-[C2B9H11]− carborane clusters covalently and electronically bound to the graphene lattice, and this new material was isolated as its Cs+ salt.
Efficient radiosynthesis of a [18F]-phosphonium salt containing closo-carborane
20 December 2019
University of Sydney

Ioppolo, Joseph A.;Giboureau, Nicolas;Bhadbhade, Mohan;Morrison, Daniel E.;Kassiou, Michael;Rendina, Louis M.

An efficient synthesis of an 18F-labelled phosphonium salt containing closo-carborane is described. The preparation of this salt was attempted using both single-step and two-step protocols, with greater success found for the latter. An X-ray structure for the unlabelled 19F salt is also presented.
Carborane functionalization of the aromatic network in chemically-synthesized graphene
20 December 2019
University of Sydney

Kahlert, Jan U.;Rawal, Aditya;Hook, James M.;Rendina, Louis M.;Choucair, Mohammad

The conjugated aromatic system of graphene was used to trap the reactive, boron-rich 1,2-carborane cluster. Functionalization of the graphene surface was confirmed by solid-state MAS 11B NMR spectroscopy and quantified by X-ray photoelectron spectroscopy. This work represents the first confirmed example of direct functionalization of a graphene lattice with carboranes.
Molecular Recognition of an Adenine Derivative by Organoplatinum(II) Complexes with Hydrogen-Bonding Functionality
20 December 2019
University of Sydney

Crisp, Michael G.;Kavianpour, Poya;Rendina, Louis M.

The first examples of adenine binding by isomeric organoplatinum(II) complexes bearing H-bonding nicotinic and isonicotinic acid ligands are reported. Notably, a subtle switching of the H-bonding functionality from the 3- to 4-position of the pyridyl ring leads to a significant change in both the strength of association and the site of adenine binding.
Total Synthesis of Glycinocins A−C
24 April 2020
University of Sydney

Corcilius, Leo;Elias, Nabiha T.;Ochoa, Jessica L.;Linington, Roger G.;Payne, Richard J.

The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics structurally related to the clinically approved daptomycin. Herein, we describe a divergent total synthesis of glycinocins A–C, which differ in the structure of a branched α,β-unsaturated fatty acyl moiety. The three natural products exhibited calcium-dependent antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MICs ranging from 5.5 to 17 μM.
Synthetic Studies Toward the Skyllamycins: Total Synthesis and Generation of Simplified Analogues
24 April 2020
University of Sydney

Giltrap, Andrew M.;Haeckl, F. P. Jake;Kurita, Kenji L.;Linington, Roger G.;Payne, Richard J.

Herein, we report our synthetic studies toward the skyllamycins, a highly modified class of nonribosomal peptide natural products which contain a number of interesting structural features, including the extremely rare α-OH-glycine residue. Before embarking on the synthesis of the natural products, we prepared four structurally simpler analogues. Access to both the analogues and the natural products first required the synthesis of a number of nonproteinogenic amino acids, including three β-OH amino acids that were accessed from the convenient chiral precursor Garner’s aldehyde. Following the preparation of the suitably protected nonproteinogenic amino acids, the skyllamycin analogues were assembled using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. To access the natural products (skyllamycins A–C) the synthetic route used for the analogues was modified. Specifically, linear peptide precursors containing a C-terminal amide were synthesized via solid-phase peptide synthesis. After cleavage from the resin the N-terminal serine residue was oxidatively cleaved to a glyoxyamide moiety. The target natural products, skyllamycins A–C, were successfully prepared via a final step cyclization with concomitant formation of the unusual α-OH-glycine residue. Purification and spectroscopic comparison to the authentic isolated material confirmed the identity of the synthetic natural products.
Peptide Ligation–Desulfurization Chemistry at Arginine
11 May 2020
University of Sydney

Malins, Lara R.;Cergol, Katie M.;Payne, Richard J.

The utility of a new β‐thiol arginine building block in ligation–desulfurization chemistry has been demonstrated through reactions and kinetic studies with a range of peptide thioesters. Application of the method is highlighted by a one‐pot, kinetically controlled, rapid ligation to generate a 7 kDa MUC1 glycopeptide.
Rapid Additive-Free Selenocystine–Selenoester Peptide Ligation
12 May 2020
University of Sydney

Mitchell, Nicholas J.;Malins, Lara R.;Liu, Xuyu;Thompson, Robert E.;Chan, Bun;Radom, Leo;Payne, Richard J.

We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins.
Risk and Financial Management of COVID-19 in Business, Economics and Finance
18 June 2020
University of Sydney

Chang, Chia-Lin;McAleer, Michael;Wong, Wing-Keung

The SARS-CoV-2 coronavirus that causes the COVID-19 disease led to the most significant change in the world order over the past century, destabilizing the global economy and financial stock markets, the world’s economy, social development, business, risk, financial management and financial markets, among others. COVID-19 has generated great uncertainty, and dramatically affected tourism, travel, hospitality, supply chains, consumption, production, operations, valuations, security, financial stress and the prices of all products, including fossil fuel and renewable energy sources. This Editorial introduces a Special Issue of the Journal of Risk and Financial Management (JRFM) on the “Risk and Financial Management of COVID-19 in Business, Economics and Finance”. This Special Issue will attract practical, state-of-the-art applications of mathematics, probability and statistical techniques on the topic, including empirical applications. This paper investigates important issues that have been discussed in tourism, global health security and risk management in business as well as the social and medical sciences.
One‐Pot Ligation–Oxidative Deselenization at Selenocysteine and Selenocystine
19 June 2020
University of Sydney

Mitchell, Nicholas J.;Kulkarni, Sameer S.;Malins, Lara R.;Wang, Siyao;Payne, Richard J.

The use of native chemical ligation at selenocysteine (Sec) residues with peptide thioesters and additive‐free selenocystine ligation with peptides bearing phenyl selenoesters, in concert with one‐pot oxidative deselenization chemistry, is described. These approaches provide a simple and rapid method for accessing native peptides with serine in place of Sec at the ligation junction. The efficiency of both variants of the one‐pot ligation–oxidative deselenization chemistry is probed through the synthesis of a MUC5AC‐derived glycopeptide.

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