School of Chemistry Research Booklet - UOW Faculty of Science ...

School of Chemistry Research Booklet

Contact for further information A/Professor Stephen Wilson Head, School of Chemistry University of Wollongong Wollongong NSW 2522 Australia

Telephone (Local) (International) Facsimile (Local) International e-mail School Administrative Assistant (email) website

02 4221 3509 61 2 4221 3509 02 4221 4287 61 2 4221 4287 [email protected] [email protected]; http://www.uow.edu.au/science/chem

TABLE OF CONTENTS

Introduction and Welcome Research Facilities Research Strengths Research Interests Associate Professor Jennifer L Beck Dr Simon Bedford Associate Professor Stephen Blanksby Dr Carolyn T Dillon Professor Nick Dixon Professor David Griffith Associate Professor Marc in het Panhuis Dr Dianne Jolley Associate Professor Paul Keller Dr Michael Kelso Dr Garry Mockler Dr Clare Murphy Associate Professor Aaron Oakley Dr Glennys O’Brien Professor William Price Professor Stephen Pyne Associate Professor Stephen Ralph Dr Chris Richardson Dr Danielle Skropeta Dr Adam Trevitt Associate Professor Stephen Wilson Dr Haibo Yu Major Equipment

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INTRODUCTION AND WELCOME W

elcome to the School of Chemistry at the University of Wollongong, NSW. Our School is currently one of the larger Chemistry based Schools in Australia with a national and international reputation for excellence in teaching and research. There is a close nexus between our research and teaching programs where much of our undergraduate program is informed by our research. The School has particular internationally recognized research strengths in biomolecular science and medicinal chemistry, materials chemistry and environmental chemistry. The School has around 55 Academic staff, including research only personnel and approximately 50 PhD students. In addition, there is about 20 staff engaged in research support positions, giving over 120 staff members dedicated to research projects and outcomes. The School of Chemistry at UOW has been consistently successful over a number of years in attracting funding for its work from both competitive Government sources such as the Australian Research Council (ARC), National Health and Medical Research Council (NHMRC) and other agencies and from Industrial sources, through collaborative linkages and direct contract research. More details of research funding are given later in this publication but we give here a list illustrating the range of collaborative partners we are involved with: AMRAD, ANSTO, AstraZeneca, Avexa, BHP Billiton, BlueScope Steel, Cochlear, CSIRO, CRC Cochlear Implants, CRC SmartPrint, CRC IMST, CRC Polymers, Defence Science and Technology Organisation (DSTO), School of Primary Industry, Glaxo, and Rio Tinto.

Research Facilities The School has modern equipment and facilities for research and teaching. Particularly important are state-of-the-art facilities in mass spectrometry (including high resolution electrospray, LC/ion trap/MS, LC/MS, GC/MS and MALDI), NMR spectroscopy (300 MHz, 2 x 500 MHz and access to both an 800 MHZ Brucker Spectrometer at ANU and a 600 MHz at UNSW), an electrochemical surface mapping facility, FTIR spectroscopy, various CD UV-vis spectrometers and an extensive range of other analytical equipment. The School also has strong capabilities in computer-aided molecular modelling.

Research Strengths The School has active research programs in both pure and applied chemistry. These programs are concentrated into four partly overlapping areas: • Bio-organic/Medicinal Chemistry • Structural Determination of Biomolecules and Protein Biochemistry • Environmental Chemistry • Intelligent Polymers and Electromaterials Science An integral and interconnecting component of each of four major programs is the exploitation of the School’s analytical/instrumental expertise and equipment. The pages of the brochure contain details of the research carried out within the School. If you would like further information please contact the research group concerned directly (details given for each group). Alternatively, if you require more information of a general nature, please contact me at the email address below. Best Wishes Stephen Wilson Head, School of Chemistry

email: [email protected]

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RESEARCH INTERESTS

A/Professor Jennifer L. Beck email: [email protected]

Mass Spectrometry of Proteins and DNA Research in the Beck laboratory is aimed at solving problems in biochemistry using biophysical techniques, in particular mass spectrometry. There are three major areas of research: (1)

Investigations of protein-protein and protein-DNA interactions within the bacterial replisome. The replisome is the dynamic assembly of proteins, DNA and cofactors (metal ions, nucleotides) that functions to replicate the chromosome. Although the components of the Escherichia coli replisome are known, little is known about the order of assembly and contact points between binding partners. Some of these questions can be addressed using mass spectrometry. The projects aim to test the limits of mass spectrometry and (in collaboration with Prof Nick Dixon) to uncover new information about chromosome replication.

(2)

Higher order DNA structures: fundamentals and drug targeting. The classical, familiar model of DNA structure elucidated by Watson and Crick is a double-stranded helix made up of chemical units that consist of a sugar phosphate backbone attached to various sequences of purine and pyrimidine bases (the genome sequence). In order for the information stored in the sequence to be read and eventually expressed in the vast range of normal (e.g. metabolism) and abnormal (e.g. growth of cancer cells) life processes, the DNA must interact with many cofactors and proteins that catalyse the chemical reactions that drive these processes. Therefore, proteins with different roles must recognise specific regions of the DNA. This molecular recognition is possible, in part, because some DNA sequences elicit interactions among atoms within the DNA structure that alter its shape from that of the familiar double helix (duplex). Some sequences predispose DNA towards higher order structures such as quadruplexes (four strands) and triplexes (three strands), while some sequences cause significant deviations of the “normal” double helical (B-form) DNA resulting in Z-DNA. Z-DNA differs from B-DNA in a number of ways including that it is a left-handed, rather than a right-handed helix. In this project, mass spectrometry is used as a major tool in conjunction with other techniques such as circular dichroism spectrophotometry, X-ray crystallography and ion mobility mass spectrometry to understand the interactions between the various DNA structures and potential chemotherapeutic agents.

(3)

Recently, project (2) has expanded to include efforts to define the activity and substrates of the enzyme, telomerase. Telomeres are guanosine-rich regions at the ends of eukaryote chromosomes that fold to form quadruplex DNA. These non-coding regions are thought to protect the chromosomes. When cells replicate, the DNA polymerase assembly cannot copy the telomeric ends so that the telomeres shorten with each round of replication. When the telomeres reach a critical short length, the cells are targeted for apoptosis. This is one mechanism that confers mortality to normal somatic cells. The lengths of telomeres and the mechanisms that affect this are thought to underlie certain diseases and the aging process. In contrast, in germ cells and cancer cells, telomerase is more active/expressed and telomere lengths are maintained. This is one mechanism which

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“immortalizes” cancer cells. It is thought that ligands which interfere with the actions of telomerase might be leads for anticancer drugs. In collaboration with the Children’s Medical Research Institute (Drs Tracy Bryan and Scott Cohen, CMRI, U Sydney) the Beck group and other staff of the School of Chemistry (Drs Stephen Ralph, Aaron Oakley, Michael Kelso and Emeritus Professor John Bremner) are investigating the types of DNA structures which are substrates of telomerase. It is only by understanding the enzymology of telomerase that progress will be made towards understanding its roles in disease, cancer and aging. The group has formed the University Research Network: Molecular Interactions in Telomeres: Clues to Cell Immortality and Cancer (http://research.uow.edu.au/miitn/index.html). (4)

Development of simple mass spectrometry-based methods for analysis of clinically important plasma proteins. Plasma, the extracellular matrix of the blood, is the most frequently analysed clinical sample. It contains “classical” plasma proteins such as albumin (small molecule transport), transferrin (iron transport), immunoglobulins (antibodies), and blood clotting proteins such as fibrinogen and prothrombin. Additionally, there are other proteins that normally function inside cells but are released into the plasma as a result of cell damage or death. These include proteins that are markers of myocardial infarction such as creatinine kinase or myoglobin. Also important are foreign proteins that derive from infectious or parasitic organisms. To 2002, there were 289 proteins that had been detected in plasma, of which 117 are clinical analytes. The most abundant of these proteins, albumin, is 1010 times more abundant than the least abundant, interleukin 6 (indicator of inflammation or infection).1 Detection of medium-low abundance proteins therefore requires efficient, rapid removal of abundant proteins that may interfere with analyses. In this project the research to be carried out will result in development of simple, relatively low-cost techniques for fractionating plasma proteins of diagnostic importance, and analysing the fractions containing subsets of proteins within the dynamic range of modern electrospray ionisation mass spectrometers.

Selected publications: 1. Gornall, K. C., Samosorn, S., Tanwirat, B., Suksamrarn, A., Bremner, J. B., Kelso, M. J., and Beck, J. L. A mass spectrometric investigation of novel quadruplex DNA-selective berberine derivatives, Chem. Commun. (Cambridge, U. K.) 46, 6602-6604. 2. Kelso, C., Rojas, J. D., Furlan, R. L. A., Padilla, G., and Beck, J. L. (2009) Characterisation of anthracyclines from a cosmomycin D-producing species of Streptomyces by collisionally-activated dissociation and ion mobility mass spectrometry, Eur. J. Mass Spectrom. 15, 73-81. 3. Alonso, H., Blayney, M. J., Beck, J. L., and Whitney, S. M. (2009) Substrate-induced Assembly of Methanococcoides burtonii D-Ribulose-1,5-bisphosphate Carboxylase/Oxygenase Dimers into Decamers, J. Biol. Chem. 284, 33876-33882. 4. Kelso, C., Tillott, V., Rojas, J. D., Furlan, R. L. A., Padilla, G., and Beck, J. L. (2008) Mass spectrometric investigation of the DNA-binding properties of an anthracycline with two trisaccharide chains, Archives of Biochemistry and Biophysics 477, 348-355. 5. Watt, S. J., Urathamakul, T., Schaeffer, P. M., Williams, N. K., Sheil, M. M., Dixon, N. E., and Beck, J. L. (2007) Multiple oligomeric forms of Escherichia coli DnaB helicase revealed by electrospray ionisation mass spectrometry, Rapid Communications in Mass Spectrometry 21, 132-140. 6. Beck, J. L., Urathamakul, T., Watt, S. J., Sheil, M. M., Schaeffer, P. M., and Dixon, N. E. (2006) Proteomic dissection of DNA polymerization, Expert Review of Proteomics 3, 197-211. 7. Gupta, R; Hamdan, SM; Dixon, NE; Sheil, MM; Beck, JL. Application of electrospray ionization mass spectrometry to study the hydrophobic interaction between the epsilon and theta subunits of DNA polymerase III. Protein Sci., 13: 2878-2887, 2004. 8. Beck, JL; Ambahera, S; Yong, SR; Sheil, MM; de Jersey, J; Ralph, SF. Direct observation of covalent adducts with Cys34 of human serum albumin using mass spectrometry. Anal. Biochem., 325: 326-336, 2004. 9. Kapur, A; Beck, JL; Brown, SE; Dixon, NE; Sheil, MM. Use of electrospray ionization mass spectrometry to study binding interactions between a replication terminator protein and DNA. Protein Sci., 11: 147-157, 2002.

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Dr Simon Bedford email: [email protected]

Science Education Research My research interests lie within the field of chemical education, and in the learning and teaching of science. I carry out research that looks into both the pedagogical aspects of this learning and also the practice of teaching science. In recent work, that has meant looking at providing the best modes of feedback to learners so that they can improve their own learning and understanding of a particular topic. This has involved comparing and contrasting various methods to see which is the most effective in a scientific teaching and learning environment. In addition to this, research has been carried out in supporting the quantitative aspects of science education and the teaching of tacit chemical topics; in particular context based learning and some problem driven learning so that the subject matter becomes more in tune with what the learner is already familiar with have been applied. A holistic approach has been used when dealing with these topics, so that blended resources have been produced that engage with the learner and facilitate the teacher. In this way e-learning methodologies have been used sparingly and only where they give significant benefits to the teaching and learning process. Key areas where this has been applied are the blended learning programme of study on Mathematics for Pharmacologists, a HEFCE and RSC funded Chemistry For Our Future project, and an Organic Retrosynthetic strategy course. Several collaborative research projects with Dr. Glennys O’Brien are currently being developed and expanded upon. Research students have been employed to develop interactive and context based video animations in order to support the teaching of CHEM101/102 courses and the engineering foundation course CHEM103. We are looking at the best way to support learners that enter with a wide variation in science qualifications (HSC, Bridging Course and SC only) and yet have similar exit learning objectives to reach in order to progress onto their chosen degree progammes. In particular we are investigating how group work and peer support strategies (POGIL©: http://www.pogil.org/) can be best implemented to maximise the learning experience for all. In this way learners construct their own understanding and knowledge is personalised to their specific needs. We are also looking ‘down stream’ at the issues learners have when progressing on Chemistry and related degree programmes especially the growing number of ‘misconceptions’ and poor skill base (arrow pushing, stereochemistry) they have that hinder success and employment. Suggested Research Topics for Future Prospective Honours students: Quantitative Chemistry (e.g Peer support for mathematics in context) Technology Enhanced Teaching (e.g Mobile Learning) Problem Based Learning (e.g Exploring cognitive load theory) Misconceptions and unlearning the past (e.g Why teacher does not always know best) Selected Publications • •

S. B. Bedford, and J. Mason, Holding a Mirror Up to Work Based Learning, Assessment and Feedback; ASET Placement and Employability Professionals’ Conference – University of Lancaster, Conference paper, September, 2009. S. B. Bedford, and R. Roshan, The Mathematics problem solved- Mathematics and statistical help for scientists, International Conference on Variety in Chemistry Education, The University of Manchester, Manchester, Conference

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Proceedings, October 2009. •

S. B. Bedford, and C. Gibson, Technology Supported Learning, International Society for the Scholarship of Teaching and Learning Conference, ISSOTL, Edmonton, Alberta Canada, DC, 16-19th October 2008 (Conference proceedings).

•

S. B. Bedford, and G. J. Price, Shaping the Future of Maths & Stats in Higher Education, MSOR Conference Proceedings Lancaster University. 8th and 9th September 2008.

•

S. B. Bedford, and C. Martin, The swings and roundabouts of placement learning: The erosion and enhancement of skills and knowledge; ASET Placement and Employability Professionals’ Conference – Silver Jubilee Event, University of Wales in Cardiff, Conference paper, September, 2007, and ASET Placement & Employability Professionals Publication (ISBN 978-0-9542231-7-5).

•

S. B. Bedford, and G. J. Price, A Study into the use of computer aided assessment to enhance formative assessment during the early stages of undergraduate chemistry courses; International Computer Assisted Assessment, Loughborough, Conference paper (ISSN 0-9539572-6-8), July, 2007.

•

S. B. Bedford, and J. Mason, How to impart tacit knowledge – Blending Chess and chemistry; International Bended Learning Conference, University of Hertfordshire, Conference paper, June, 2007 (ISBN: 978-1-902806-81-5), and New Directions in the Teaching of Physical Sciences, Volume 3, October 2007 (ISSN 1740-9888).

•

S. B. Bedford, and S. Legg, Maintaining quality feedback in the face of increasing student numbers; The 2nd International Science Learning and Teaching conference, Keele University, Conference paper, June, 2007 (ISSN 9781-905788-39-2) and Assessment & Evaluation in Higher Education, Published by School of Education, University of Bath, 2007, The Tertiary Educational Group Conference, Keele University, Keele, August 2006, (ISBN: 978-0-85404298-2).

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A/Professor Stephen Blanksby email: [email protected] Mass spectrometry (MS): applications and fundamentals The mass spectrometry user resource and research facility (MSURRF) at UoW has a range of sophisticated instrumentation for the detection and characterization of molecular species based on their mass/charge ratio. These state-of-the-art technologies can be employed for applications as diverse as determining the lipid profile of cellular membranes in biological tissue samples or probing the oxidation products from weathered colorbond® roofing panels! In addition to these analytical applications, the mass spectrometer provides the ideal gas phase “test tube” for probing the structure and reactivity of molecular ions and neutral radicals. Applications: Lipid mass spectrometry My group is currently involved in the rapidly expanding field of lipidomic research. Using modern MS techniques we are able to observe subtle changes in the lipid composition of cell membranes. These changes in the membrane lipid profile can associated with a range of factors including; diet, exercise, illness or age. For example, in collaboration with Dr Todd Mitchell and Prof. Roger Truscott (University of Sydney) we are using MS to search for changes in the lipid profile of the human lens that may be associated with age and the onset of cataract or presbyopia. In addition to studies of biological samples we are also working toward improved methods for the structural characterization and the quantification of phospholipids by electrospray ionization MS. We have several ongoing projects that aim to provide a better understanding of the underlying mechanisms of lipid ionization, fragmentation and oxidation in the mass spectrometer. We have recently developed a new technique for chemically induced fragmentation of lipids using ozone that determines the position of double bonds in lipids. Applications: keeping colorbond® colourful In collaboration with Dr Philip Barker at Bluescope Steel Research we are using the complementary technologies of electron spin resonance (ESR), electrospray ionization mass spectrometry (ESI-MS) and a new technique known as desorption electrospray ionization mass spectrometry (DESI-MS) to elucidate oxidation processes that occur within the polymer coating of Bluescope’s flagship sheet steel product, colorbond®. ESR readily identifies free radicals formed by these oxidation processes, while ESI-MS and DESI-MS provide structural information about both radical and non-radical species formed by these processes. These studies are directed towards improving the longevity of colorbond® under the harsh oxidizing conditions encountered on the typical Australian roof!

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Fundamentals: perxoyl radicals and peroxide anions in the gas phase The advantage of gas phase studies, using mass spectrometers, over traditional “wet-chemistry” is that the former allow us to understand the fundamental reactivity of ions and molecules without interference from either solvent or counter-ions. Furthermore, some critically important ions and molecules are so reactive that they can only be studied in the isolation of the vacuum inside the mass spectrometer. The results of these fundamental studies contribute to our understanding of complex applied problems in biological, atmospheric, and combustion chemistries. Using the latest in ion-trap mass spectrometry equipment (the ThermoFinnigan LTQ) and nanosecond laser technology we are developing a range of methods for producing distonic peroxyl radical ions in the gas phase using electrospray ionization. Distonic anions have a separated charge and radical center and can thus act as “charge tagged radicals” where the charge does not significantly perturb the reactivity of the radical but simply provides us with a convenient handle with which to isolate it in the ion trap mass spectrometer. We are currently investigating methods for reacting our charge tagged peroxyl radicals with a range of neutral substrates in the gas phase. This new methodology will provide unique insight into the chemistry of peroxyl radicals in the gas phase and thus the role of peroxyl radical intermediates in combustion and atmospheric processes. This work is being carried out in collaboration with Dr Adam Trevitt (UoW) and Professor Richard O’Hair (University of Melbourne) and is supported by the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology. Selected Publications 1.

2.

3. 4.

5. 6.

7. 8.

Ellis, S. R., Wu, C., Deeley, J. M., Zhu, X., Truscott, R. J. W., in het Panhuis, M., Cooks, R. G., Mitchell, T. W., Blanksby, S. J. “Imaging of Human Lens Lipids by Desorption Electrospray Ionization Mass Spectrometry” Journal of the American Society for Mass Spectrometry 2010, in press (accepted 3/9/2010). Poad, B. L. P., Pham, H. T., Thomas, M. C., Nealon, J. R., Campbell, J. L., Mitchell, T. W. and Blanksby, S. J. “Ozone-induced dissociation on a modified tandem linear ion-trap: observations of different reactivity for isomeric lipids” Journal of the American Society for Mass Spectrometry 2010, in press (accepted 18/8/2010). Deeley, J. M., Hankin, J. A., Friedrich, M. G., Murphy, R. C., Truscott, R. J. W., Mitchell, T. W. and Blanksby, S. J. “Sphingolipid distribution changes with age in the human lens” Journal of Lipid Research 2010, 51(9), 2753-2760. Lowe, T. A., Paine, M. R. L., Marshall, D. L., Hick, L. A., Boge, J. A., Barker, P. J. and Blanksby, S. J. ”Structural identification of hindered amine light stabilisers in coil coatings using electrospray ionisation tandem mass spectrometry” Journal of Mass Spectrometry 2010, 45(5), 486-495. Taylor, I. F., Blanksby, S. J., Colbran, S. B. and Willett, G. D. “Production and isolation of ligated metal(IV)-oxo ions by tandem mass spectrometry” Rapid Communications in Mass Spectrometry 2010, 24(8), 1142-1146. Saville, J. T., Zhao, Z., Willcox, M. D. P., Mitchell, T. W. and Blanksby, S. J. “Detection and quantification of phospholipids and cholesterol in contact lens deposits: the effect of contact lens material and lens care solution.” Investigative Ophthalmology and Visual Science 2010, 51(6), 2843-2851. Blanksby, S. J. and Mitchell, T. W., “Advances in mass spectrometry for lipidomics”. Annual Reviews of Analytical Chemistry 2010, 3, 433–65 . Kirk, B. B., Harman, D. G. and Blanksby, S. J. “Direct Observation of the Gas Phase Reaction of the Cyclohexyl Radical with Dioxygen Using a Distonic Radical Ion Approach”. Journal of Physical Chemistry A 2010, 114, 1446– 1456.

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Dr Carolyn T. Dillon email: [email protected]

Bioinorganic and Medicinal Chemistry Research interests of the Dillon laboratory include studies of the modes of action of metal and metalloid containing anticancer and anti-inflammatory agents for the design and synthesis of more effective drugs. Techniques include: • Microprobe X-ray fluorescence (XRF) mapping of cells performed at the Advanced Photon Source in Chicago and the Australian Synchrotron; • X-ray absorption spectroscopy (XAS) performed at the Photon Factory in Tsukuba, Japan and the Australian Synchrotron; • Infrared Microspectroscopy of cells at the Australian Synchrotron; • Mass spectrometry; • Gel electrophoresis assays; • Cell assays; • Graphite Furnace Atomic Absorption Spectroscopy; • Electron microscopy.

Determining the Intracellular Targets of Arsenic Anti-Cancer Drugs As2O3 (marketed as Trisenox) is used clinically for the treatment of relapsed acute promyelocytic leukemia resulting in cure rates of 80-85%. Following its success, arsenic is rapidly emerging as a potential treatment of other forms of cancer with a number of arsenic compounds currently undergoing clinical trials. The underlying factor that appears to be crucial to the success of arsenic anti-cancer drugs is their multi-faceted mechanisms of toxicity towards cancer cells. While most anti-cancer drugs act by targeting DNA and enzymes involved in DNA synthesis, arsenic has been aptly described as an anti-cancer missile with multiple warheads as it also induces toxicity through interactions with a number of critical enzymes and proteins, including mitochondrial ANT and tubulin. Currently we are investigating the biomolecular interactions of arsenic trioxide and its metabolites with each of these targets to assess their importance in arsenic-induced anti-cancer action. This project will probe the intracellular interactions of arsenic compounds currently undergoing clinical trials and the metabolites of Trisenox. Studies will be performed to determine whether the anti-cancer activity results from direct interactions of arsenic with proteins, DNA or the production of radicals. The project will use mass spectrometry (MS), infrared (IR) spectroscopy, electron spin resonance (ESR) spectroscopy, confocal microscopy, and DNA gel electrophoresis. Design and Synthesis of New Arsenic Anti-Cancer Drugs. While As complexes are gaining notoriety as anti-cancer drugs, one of the main drawbacks of their use is their toxicity, which arises from their indiscriminate toxicity in vivo. Importantly, however, subtle differences occur between normal cells and tumour cells. For example, it is well established that the greater bioenergetic requirements of transformed cells over normal cells results in a more rapid uptake of glucose to satisfy the requirements of increased glycolysis. In this project, the

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logical incorporation of glucose moieties into arsenic compounds is being utilized as a selective targeting strategy for producing arsenic anti-cancer drugs. Similarly, the coordination of arsenic to “tumour-homing peptides”, that are recognised by and incorporated into tumour cells, is also being studied. Ideally, the incorporation of these peptides and glucose ligands into arsenic compounds should improve patient efficacy and at the same time reduce adverse side-effects. Consequently, the synthesis, stabilities, cellular metabolism/reactivities and selectivity of such arsenic compounds in and to tumour cells is being investigated to determine if the “targeting devices” remain bound to the arsenic and furthermore, whether they aid in delivering arsenic to the tumour cells. Techniques include basic inorganic syntheses, purification and characterization (nmr, UV/Vis and mass spectrometry) techniques, and cell culture assays. Chemistry and Bioavailability of Manganese in Arc Welding Fume Collaborators: Brian Monaghan, John Norrish, Huijun Li, Faculty of Engineering, UOW Concern about manganese exposure in welders has been highlighted by recent litigation linking manganese from welding fume with manganism and Parkinsons disease However, it is clear that there is insufficient scientific data to predict the exposure or bioavailability of this substance. Despite this, severe restrictions on exposure have been foreshadowed that could significantly impede engineering fabrication in Australia. As such it is imperative to perform studies that will overcome the existing deficiencies in the current knowledge of manganese bioavailability to allow a clear, unbiased assessment of the health risk. The aim of this proposal is to correlate welding fume composition with Mn bioavailability information obtained under normal steel welding conditions. The bioavailability of Mn will be studied by determining the dissolution of the welding particulates in simulated lung and gastric fluids.. The solutions will be analysed by graphite furnace atomic absorption spectrometry which is capable of detecting ppb Mn concentrations. In addition, human lung cells (grown in cell culture) will be exposed to welding particulates (various weights and extracted solutions, obtained from different welding procedures). The samples will be analysed by GFAAS and microprobe XRF akin to previously published methods of Dillon. Selected Publications 1. Dillon, C. T.; Lay, P. A.; Kennedy, B. J.; Stampfl, A. P. J.; Cai, Z.; Ilinski, P.; Rodrigues, W.; Legnini, D. G., Lai, B. and Maser, J. Hard X-ray microprobe studies of chromium(VI)-treated V79 Chinese hamster lung cells: intracellular mapping of the biotransformation products of a chromium carcinogen. J. Biol. Inorg. Chem. 2002, 7, 640-645. 2. Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Zhou, Q.; Davies, N. M.; Biffin, J. R. and Regtop, H. L. Gastrointestinal damage, anti-inflammatory activity and superoxide dismutase activity of copper and zinc complexes of the anti-inflammatory drug, indomethacin. Chem. Res. Toxicol. 2003, 16, 28-37. 3. Levina, A.; Codd, R.; Dillon, C. T.; Lay, P. A. Chromium in biology: nutritional aspects and toxicology. Prog. Inorg. Chem., 2003, 51, Chapter 2, 145-250. 4. Hall, M. D.; Dillon, C. T.; Zhang, M.; Beale, P.; Cai, Z.; Lai, B.; Stampfl, A. P. J.; Hambley, T. W. The Cellular Distribution and Oxidation State of Platinum(II) and Platinum(IV) Antitumour Complexes in Cancer Cells. J. Biol. Inorg. Chem., 2003, 8, 726-732. 5. Waern, J.B.; Dillon, C.T.; Harding, M. M. Organometallic anticancer agents: cellular uptake and cytotoxicity studies on thiol derivatives of the antitumour agent molybdocene dichloride. J Med Chem. 2005, 48, 2093-2099. 6. Munro, K.L.; Mariana, A.; Klavins, A.I.; Foster, A.J.; Lai, B.; Vogt, S.; Cai, Z.; Harris, H.H.; Dillon, C.T. Microprobe XRF mapping and XAS investigations of the intracellular metabolism of arsenic for understanding arsenic-induced toxicity. Chem. Res. Toxicol. 2008, 21, 1760-1769. 7. Munro, K.L.; Bambery, K.R.; Carter, E.A.; Puskar, L.; Tobin, M.J.; Wood, B.R. Dillon, C.T.; Synchrotron radiation infrared microspectroscopy of arsenic induced changes to intracellular biomolecules in live leukemia cells. Vib. Spec., 2010, 53, 39-44.

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Professor Nicholas E Dixon email: [email protected]

Some proteins are enzymes that promote chemical reactions; others provide molecular switches that control metabolic and developmental processes through precise interactions with other proteins, nucleic acids and other ligands. The chemistry that governs the specificity and strength of interactions of proteins with substrates, inhibitors, nucleic acids, and other proteins is being explored in three complementary research programs. Molecular Motors in the Escherichia coli Replisome The first program concerns the thirty or so different proteins in the model bacterium Escherichia coli that collaborate to replicate the DNA of its chromosome prior to cell division. DNA replication is a very good model system to study protein–protein and protein–nucleic acid interactions because the proteins act together in a giant nucleoprotein assembly called the replisome, to make perfect copies of the chromosome. The replisome comprises three interacting molecular motors, the DNA helicase (DnaB) that separates the two DNA strands, and the two DNA polymerases (Pol III holoenzyme) that simultaneously make copies of them at the replication fork. Interactions among the proteins are dynamic and are often mediated by flexible intrinsically unstructured regions within the protein subunits. In this program, we use molecular genetics to engineer rich sources of the proteins and to produce mutant derivatives and segments of them, and conventional enzymology, DNA synthesis and protein interaction assays to study protein function. This program is supported by the work of many local, national and international collaborators, in areas as diverse as protein X-ray crystallography, ESR and high-field NMR spectroscopy, mass spectrometry, electron microscopy, computational methods and single-molecule techniques. These methods are used to further understand the structures of the individual proteins, and to relate their structures to how they work and interact with each other and with DNA in the various processes that occur as the replisome functions. Antibacterial Drug Targets in Bacterial DNA Replication Some bacterial pathogens have acquired resistance to almost all known antibacterial drugs in current clinical use, leaving limited options available for treatment of some patients with serious bacterial infections. Since correct function of the replisome is essential for survival of bacteria, it may represent a good target for discovery and development of new

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antimicrobial drugs that prevent DNA replication in pathogens. We have begun to translate our extensive knowledge of E. coli DNA replication to studies of replisome structure and function in bacterial pathogens, to validate conserved sites of enzymatic activity and protein-protein interactions as targets for new antibacterial drug discovery and development. We have been focusing especially on species from the genus Acinetobacter, a Gram-negative bacterial pathogen that is emerging as a common cause of serious multi-drug resistant infections, especially in hospitals. New Protein Technologies Our third research program has complementary objectives. A suite of new techniques in protein chemistry is being developed, including methods for in vitro evolution of new protein functions, in vitro synthesis of proteins on a preparative scale, including methods for site-specific incorporation of unnatural amino acids, library methods for precise location of boundaries between distinct folded domains in larger proteins, measurements of distances between pairs of amino acid residues in protein complexes to facilitate structure prediction, and stabilisation of small protein domains by end-to-end cyclisation of their polypeptide chains. New methods based on protein mass spectrometry are also being exploited to map protein interaction interfaces in macromolecular protein and protein-DNA complexes, and the extraordinarily stable interaction between a replication terminator protein and its DNA recognition sequence is being used to develop devices for ultrasensitive diagnostics. Used together, these techniques are helping to overcome some of the bottlenecks in rapid determination of protein structures and functions, and to study the fundamental chemistry that underpins the relationship between the structure, folding, stability and functions of proteins. Selected Publications 1.

Elvin, C.M., Carr, A.G., Huson, M.G., Maxwell, J.M., Pearson, R.D., Vuocolo, T., Liyou, N.E., Wong, D.C.C., Merritt, D.J. & Dixon, N.E. (2005) Synthesis and properties of crosslinked recombinant pro-resilin. Nature, 437, 999–1002.

3.

Pintacuda, G., Park, A.Y., Keniry, M.A., Dixon, N.E. & Otting, G. (2006) Lanthanide labeling offers fast NMR approach to 3D structure determinations of protein–protein complexes. Journal of the American Chemical Society, 128, 3696–3702.

4.

Mulcair, M.D., Schaeffer, P.M., Oakley, A.J., Cross, H.F, Neylon, C., Hill. T.M. & Dixon, N.E. (2006) A molecular mousetrap determines polarity of termination of DNA replication in E. coli. Cell, 125, 1309–1319.

5.

Jergic, S., Ozawa, K., Su, X.-C., Scott, D.D., Williams, N.K., Hamdan, S.M., Crowther, J.A., Otting, G. & Dixon, N.E. (2007) The unstructured C-terminus of the τ subunit of Escherichia coli DNA polymerase III holoenzyme is the site of interaction with the α subunit. Nucleic Acids Research, 35, 2813–2824.

6.

Tanner, N.A., Hamdan, S.M., Jergic, S., Loscha, K.V., Schaeffer, P.M., Dixon, N.E. & van Oijen, A.M. (2008) Singlemolecule studies of fork dynamics in Escherichia coli DNA replication. Nature Structural & Molecular Biology, 15, 170–176.

7.

Ozawa, K., Jergic, S., Park, A.Y., Dixon, N.E. & Otting, G. (2008) The proofreading exonuclease subunit ε of Escherichia coli DNA polymerase III is tethered to the polymerase subunit α via a flexible linker. Nucleic Acids Research, 36, 5074–5082.

8.

Dixon, N.E. (2009) DNA Replication: Prime-time looping. Nature, 462, 854–855.

9.

Morin, I., Dixon, N.E. & Schaeffer, P.M. (2010) Ultrasensitive detection of antibodies using a new Tus-Ter-lock immunoPCR system. Molecular BioSystems, 6, 1173–1175.

10.

Robinson, A., Brzoska, A.J., Turner, K.M., Withers, R., Harry, E.J., Lewis, P.J. & Dixon, N.E. (2010) Essential biological processes of an emerging pathogen: DNA replication, transcription and cell division in Acinetobacter spp. Microbiology & Molecular Biology Reviews, 74, 273–297.

11.

Potapov, A., Yagi, H., Huber, T., Jergic, S., Dixon, N.E., Otting, G. & Goldfarb, D. (2010) Nanometer-scale distance measurements in proteins using Gd3+ spin labeling. Journal of the American Chemical Society, 132, 9040–9048.

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Professor David Griffith email: [email protected]

Atmospheric Chemistry and Spectroscopy See also Dr. Stephen Wilson, Dr. Clare Murphy Our research in atmospheric chemistry is concerned with measurements and interpretation of atmospheric trace gas composition and the exchange of trace gases between the atmosphere, biosphere and geosphere. These studies are aimed at a better understanding of the budgets, sources and sinks of trace gases important in atmospheric chemistry, the greenhouse effect, climate change, stratospheric ozone chemistry and ultraviolet radiation. These gases include CO2, CH4, N2O, CO, O3, NH3, NO, NO2, water vapour and many others. Current foci and specific examples include: • exchange of trace gases with soils, animals and agricultural environments •

Especially methane from livestock and nitrous oxide from soils

• spectroscopic measurement of isotopic composition in trace gases •

Using isotopic fractionation to trace the sources and sinks of trace gases – nitrous oxide, methane, carbon dioxide, water vapour

• solar spectroscopy for ground-based remote sensing of atmospheric composition •

Tracing biomass burning emissions and estimating their atmospheric impacts

•

Global carbon dioxide measurements and modelling

• global satellite-based measurements of carbon dioxide , including the Japanese Greenhouse gas Observing Satellite (GOSAT) and NASA’s future Orbiting Carbon Observatory (OCO-2) This research involves a strong component of development of novel applications of spectroscopy (especially FTIR spectroscopy) for measurements of atmospheric trace gas composition and fluxes. The main areas of development are: • Long path, low-resolution FTIR spectroscopy for simultaneous high precision analysis of trace gases in air. The technique is being used for example at the Cape Grim clean air monitoring station in Tasmania, at the CSIRO trace gas analysis laboratory (GASLAB), and at the campus in Wollongong to determine concentrations and sources of CO2, CH4, N2O and CO. • A high precision FTIR spectrometer is used together with micrometeorological sampling methods to measure fluxes of greenhouse gases (CO2, CH4, N2O) from the earth’s surface, in particular from agricultural environments and landfills. This work involves extensive collaboration with the CSIRO. • Very high resolution solar FTIR spectroscopy is used for ground-based remote sensing of atmospheric composition at Wollongong and Darwin as part of two global networks – The Total Carbon Column Observing Network (TCCON, http://www.tccon.caltech.edu) and the Network for Detection of Stratospheric Change (NDACC, http://www.ndsc.ncep.noaa.gov/). The former focuses on high accuracy measurements of CO2 and other greenhouse gases, the latter on a wider range including stratospheric ozoneThis work is combined with parallel measurements of

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solar ultraviolet and visible spectra and UV radiation (Dr. Stephen Wilson). Recent and current work is also focused on using remote sensing to quantify biomass burning emissions to the atmosphere (Dr. Clare Murphy).. • We have pioneered the use of high resolution FTIR spectroscopy as a new technique for isotopic analysis of atmospheric trace gases. There are several applications where the FTIR-based method provides complementary information to that from conventional analysis by mass spectrometry. These include distinguishing isotopicallysubstituted species of similar mass and structural isomers such as 15N14N16O + 14N15N16O, or 13CH4 + CH3D. Selected Publications 1. Griffith, D. W. T. (2002). FTIR measurements of atmospheric trace gases and their fluxes. Handbook of Vibrational Spectroscopy. J. M. Chalmers and P. R. Griffiths, John Wiley & Sons. 4: 2823-2841. 2. Turatti, F., D.W.T. Griffith, S.R. Wilson, M.B. Esler, T. Rahn, H. Zhang, G. Blake, and M. Wahlen, Positionally dependent 15N fractionation factors in the photolysis of N2O determined by high resolution FTIR spectroscopy, Geophys. Res. Lett., 27 (16), 2489-2492, 2000. 3. Griffith, D.W.T., Toon, G.C., Sen, B., Blavier, J.-F., and Toth, R.A., 2000. Vertical profiles of nitrous oxide isotopomer fractionation measured in the stratosphere. Geophysical Research Letters, 27 (16), 2485-2488. 4. Esler, M.B., D.W.T. Griffith, S.R. Wilson, and L.P. Steele, Precision trace gas analysis by FT-IR spectroscopy, Anal. Chem., 72 (1), 206-215 and 216-221, 2000. 5. Griffith, D.W.T., and B. Galle, Flux measurements of NH3, N2O and CO2 using dual beam FTIR spectroscopy and the flux-gradient technique, Atmos. Environ., 34 (7), 1087-1098, 2000. 6. Leuning, R., S.K. Baker, I.M. Jamie, C.H. Hsu, L. Klein, O.T. Denmead, and D.W.T. Griffith, Methane emission from free ranging sheep: a comparison of two measurement methods, Atmos. Environ., 33 (9), 1357-1365, 1999. 7. Griffith, D.W.T., N.B. Jones, and W.A. Matthews, Interhemispheric ratio and annual cycle of carbonyl sulfide (OCS) total column from ground based solar FTIR spectra, J. Geophys. Res., 103 (D7), 8447-8454, 1998. 8. Griffith, D.W.T., Synthetic calibration and quantitative analysis of gas phase infrared spectra, Applied Spectroscopy, 50 (1), 59-70, 1996.

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Associate Professor and ARC Future Fellow Marc in het Panhuis email: [email protected] Soft Materials Research Marc’s research is focused on the fabrication, characterization and exploitation of soft, conducting and biocompatible materials for bio-medical applications. In particular, a range of biopolymers (hydrocolloids), such as gellan gum and various carrageenans, are being actively explored by my research team as active components in novel hybrid materials linking them with conducting fillers such as conducting polymers and carbon nanotubes. These materials have exciting potential in applications such as tissue engineering and medical bionics. Pros and Cons of Carbon Nanotubes Carbon nanotubes (a.k.a. Buckminsterfullerenes) consist of sp2 hybridised carbon arranged into tubular structures, and have attracted enormous attention due to their phenomenal mechanical and electrical characteristics. These hollow cylinders can be produced with diameters ranging from ~ 0.4 nm (for single-walled carbon nanotubes, SWNT) to ~100 nm (for multi-walled carbon nanotubes, MWNT) and with length on the micrometer scale. Many researchers are attracted to carbon nanotubes (CNTs) due to their phenomenal values as is evident from the current publication rate of 30 articles per week (January-August 2010). However, it is not all that simple as carbon nanotubes suffer from a number of well-known disadvantages: (i) Standardisation, carbon nanotubes are not a standardised product, i.e. their properties and molecular structure depends on both the production method and manufacturer. For example, MWNT produced by the catalytic chemical vapour deposition have a significant lower level of graphitisation (ratio of sp2:sp3 hybridised C atoms as assessed from Raman spectroscopy) then those produced by the arc-discharge method; (ii) Controlled synthesis, (to the best of my knowledge) it is not possible to completely control the chemical and electrical properties of carbon nanotubes at the point of assembly (synthesis). At best the diameter range can be controlled during synthesis, yielding (during SWNT synthesis) a mixture of single-walled carbon nanotubes with semi-conducting and metallic properties; and (iii) Process-ability, carbon nanotubes are mostly produced with defects, impurities, embedded catalyst and are bundled (or aggregated). The disperse-ability of carbon nanotubes in most common solvents is rather limited due to their hydrophobic nature, but this can be improved through the use of dispersants such as surfactants and polymers. Carbon Nanotube Networks Accessing the phenomenal electrical properties of carbon nanotubes is essential for realising practical applications based on these fascinating structures. This requires organising carbon nanotubes into a material or a device, while taking into account that the level of graphitisation, and type of nanotubes (SWNT and MWNT) are all important factors to consider. Furthermore, it is well-know that the electrical properties of individual carbon nanotubes are superior to those of carbon nanotube networks (NN). The reported conductivity values for individual CNTs are in excess of 8x106 S/m. In contrast, typical conductivity values for NN are below 104 S/m, although this can be improved through chemical treatment. Single CNT device applications dictate fabrication of individual SWNT with specific electrical properties. For example, field effect transistor devices require semi-conducting SWNT, whereas interconnects require metallic SWNT. Reliable fabrication of individual SWNT remains an issue due to the inability to control chirality and therefore electronic properties during synthesis.

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Wet-processing Methods In contrast, NN can be reproducibly fabricated using various wet-processing methods involving vacuum filtration, evaporative casting, inkjet printing, and extrusion printing CNT dispersions. The advantage of a NN is that the influence of an individual CNT’s chirality is minimised, with the network containing both semi-conducting and metallic pathways. Hence, NN can serve as either semi-conducting channels or conducting sheets. These electrical properties combined with their flexible nature, make NN ideal for a number of potential applications such as solar cells, displays, touch screens, sensors and electronic paper. Challenges in Soft Materials Research: Development of Conducting Hydrogels Many great challenges for conducting composite materials still lie ahead. For example, implantable electronic devices such as sensors and drug delivery systems will require the development of conducting hydrogels. These composite materials need to satisfy a large number of requirements such as biocompatibility as well as high electrical conductivity. Achieving this involves incorporating conducting fillers such as conducting polymers and carbon nanotubes into hydrogels, which is not entirely straightforward. The unique electrical properties of CNTs combined with their low density and high aspect ratio may provide an advantage over other conducting fillers, but the CNTs biocompatibility story remains an outstanding issue. Selective Publications 1.

N. Songmee, P. Singjai and M. in het Panhuis, ‘Gel-carbon nanotube materials: the relationship between nanotube network connectivity and conductivity’, Nanoscale 2, 1740-1745 (2010).

2.

A. J. Granero, J.M. Razal, G.G. Wallace and M. in het Panhuis, ‘Conducting gel-fibres based on carrageenan, chitosan and carbon nanotubes’, Journal of Materials Chemistry 20, 7953-7956 (2010).

3.

C.J. Ferris and M. in het Panhuis, ‘Conducting bio-materials based on gellan gum hydrogels.’ Soft Matter 5, 34303437 (2009)

4.

C.J. Ferris and M. in het Panhuis, ‘Gel-carbon nanotube composites: the effect of carbon nanotubes on gelation and conductivity behaviour.’ Soft Matter 5, 1466-1473 (2009).

5.

J.A. Boge, L.J. Sweetman, M. in het Panhuis and S.F. Ralph, ‘The effect of preparation conditions and biopolymer dispersants on the properties of SWNT buckypapers’, Journal of Materials Chemistry 19, 9131-9140 (2009).

6.

A.J. Granero, J.M. Razal, G.G. Wallace, and M. in het Panhuis, ‘Spinning carbon nanotube-gel fibers using polyelectrolyte complexation’, Advanced Functional Materials 18, 3759-3764 (2008).

7.

M. in het Panhuis, A. Heurtematte, W.R. Small, and V.N. Paunov, ‘Inkjet printed water sensitive transparent films from natural gum-carbon nanotube composites’, Soft Matter 3, 840-843 (2007).

8.

W.R. Small and M. in het Panhuis, ‘Inkjet printing of transparent, electrically conducting single-wall carbon nanotube composites’, Small 3, 1500-1503 (2007).

9.

M. in het Panhuis, ‘Carbon nanotubes: enhancing the polymer building blocks for intelligent materials’, Journal of Materials Chemistry 16, 3598-3605 (2006).

10.

M. in het Panhuis, S. Gowrisanker, D.J. Vanesko, C.A. Mire, H. Jia, H. Xie, R.H. Baughman, I.H. Musselman, B.E. Gnade, G.R. Dieckmann and R.K. Draper, ‘Nanotube network transistors from peptide-wrapped single-walled carbon nanotubes’, Small 1, 820-823 (2005).

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Dr Dianne Jolley email: [email protected] Research area: Environmental chemistry and toxicology The behaviour of elements in key ecosystems (e.g., estuaries, wetlands, mangroves, soils) is a major issue in environmental research. Modern environmental research is adopting a holistic approach using a combination of information (e.g., biological indicators, sediment quality, speciation and modelling) to get a better understanding of the processes controlling the behaviour of critical elements. This often involves the analysis of complex mixtures of materials for a range of chemical species. Recent developments in instrumental technology will enable scientists to develop a greater understanding of trace elements in animals, plants, water, sediment, and gaseous environments (e.g., using isotopic signatures). Most previous studies have examined only compositional aspects of these systems, with limited attempts being made to determine the pathways of the elements through the systems. Information on trace element pathways will expand our understanding of element behaviour under differing conditions, including their bioavailability. As we gain a greater understanding of these pathways, scientists are in a better position to explain past environmental changes and to predict the environmental impacts of current human activities. Trace metals in particular are very interesting, as they may be essential or non-essential. Essential trace metals play a critical role in many biological systems, as they are required in minute amounts in order to sustain good health. For example, they are essential in the function of key enzymes in the stabilisation of proteins in nucleic acids, in energy conversion and transport, and in a variety of drug treatments (metallo- based anticancer agents, radiopharmaceuticals). In marine systems, some metals are structurally incorporated into animals, e.g., Zn in the jaws of nereid polychaetes (marine worms), Cu in the blood of molluscs and crustacea. Non-essential trace metals such as cadmium, mercury and lead have little known metabolic function. In addition, some trace metals are found in amino acids that actively incorporated into functioning proteins by specific tRNA molecules. These proteins are called metallo-proteins, and are important in the function of a variety of biological projects and organisms. The uptake of trace elements (e.g., Se) may also be used as a marker of environmental pollution. Studies of trace metal uptake in marine organisms require determination of the elements associated with different classes of proteins within the organism (e.g., proteins that will protect the organism from oxidative stress). All trace elements, both essential and non-essential may be toxic in excessive amounts. My research interests lie between the fields of Analytical and Environmental Chemistry, and Toxicology. Specifically I have interest in: • The development of new methods to investigate the uptake, metabolism and storage of metal species in aquatic biological systems; • The development/optimisation of techniques to determine the biologically available portion of toxic compounds in marine ecosystems (including diffusive gradients in thin films – DGT); • Environmental toxicology in aquatic systems, such as the investigation of chemically induced physiological changes in organisms (including reactive oxygen species, mitochondrial activity, and pH); • Determining the fate of chemicals both within the biotic and abiotic environment; Specific topics of current interest include: • Understanding mechanisms of toxicity: indentifying the physiological effects of toxic metals This research proposes to assess the level of cellular stress in cells exposed toxic levels of metals. We will

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•

•

•

investigate two species of algae (Phaeodactylum tricornutum and Dunaliella tertiolecta) chosen because of their differing sensitivities to metals. The research will reveal the “physiological” impact of toxic metals within algae using a combination of culturing techniques, toxic bioassays, flow cytometry (to count cells), and confocal microscopy. Cellular “stress” will be determined using commercially purchased molecular probes to measure reactive oxygen species (ROS); cellular mitochondrial membrane potential; cell acidity; the phases of the cell cycle (G1, S, G2, apoptotic); reduced glutathione (GSH); and chlorophyll-α autofluorescence (no probes required). Development of new methods to isolate and quantify different metal species in biological and abiotic samples (currently diffusive gradients in thin films (DGT) for anionic contaminants) Australia’s current sediment quality guidelines offer a “risk-based” approach in which sediments that exceed a guideline value for a specific contaminant will 'trigger' a tiered (step-wise) assessment framework. The framework for metals proceeds from assessing total concentrations (eg stron acid digestions followed by instrumental analysis), to biological availability of the contaminant, to biological effects (toxicity, ecology). However, the use of inadequate tools (or techniques) for assessing bioavailability frequently results in incorrect conclusions, e.g. ‘no impact’ when effects are clearly occurring to benthic organisms living within the sediment surface. This project will evaluate the diffuse gradients in thin films (DGT) technique in combination with sediment toxicity bioassays as robust laboratory and field tools for assessing metal bioavailability. Microalgae as a source of biodiesel: the potential for metal exposure to increase lipid concentrations in cells Many algal species have been found to grow rapidly and produce substantial amounts of triacylglycerol (TAG) or oil. It has long been postulated that algae could be employed as cell factories to produce oils and other lipids for biofuels (and other biomaterials). Research has shown that microalgae grown under unfavourable conditions (environmental stress) have altered their lipid metabolism in favour of the formation and accumulation of lipids, mainly in the form of TAG. This project aims to determine the effect of elevated metal concentrations on the lipid production of four indigenous marine microalgae. Previous research at UOW has shown that metals induce a suite of stress responses in microalgae, including the formation of cellular compartments that resemble lipid bodies. If these are lipid bodies, it will increase the total lipid production (as triacylglycerol) in microalgae, which would improve their efficiency as a source of biofuel. Copper in anti-fouling paints(fishing nets and boat hulls): sediment contamination and the effects on marine organisms

Selected Publications   1. Bennett W. W., Teasdale P.R., Panther, J.G., Welsh, D.T., and Jolley D.F. (in press). The development and evaluation of a diffusive gradient in a thin film (DGT) technique for the measurement of inorganic arsenic and selenium. Analytical Chemistry. doi 10.1021/ac101543 2. Angel, B.M., Simpson, S.L., Jolley, D.F. (in press) Toxicity to Melita plumulosa from intermittent and continuous exposures to dissolved copper. Environmental Toxicology and Chemistry. 3. Melville, F., Andersen, L.E., and Jolley, D.F. (2009). The Gladstone (Australia) oil spill – Impacts on intertidal areas: Baseline and six months post-spill. Marine Pollution Bulletin. 58: 263-271. 4. McKinnon J.G., Gribben P.E., Davis A.R., Jolley D.F. and Wright J.T. (2009). Differences in soft sediment macrobenthic assemblages invaded by Caulerpa taxifolia compared to un-invaded habitats. Marine Ecology Progress Series. 380: 59-71 (cited 3 times) 5. Levy J.L., Stauber J.L., Wakelin S.A., Jolley D.F. (2009). The effect of bacterial communities on the sensitivity of marine and freshwater microalgae to copper in toxicity bioassays. Chemosphere. 74: 1266-1274. DOI: 10.1016/j.chemosphere.2008.10.049 6. Threlfall, C.G., Jolley, D. F., Evershed, N., Goldingay, R., and Buttemer, W.A (2008) Do Green and Golden bell frogs (Litoria aurea) occupy habitats with fungicidal properties? Australian Zoologist. ISSN: 0067-2238. 34(3): 350-360 7. Levy, J.L., Angel B. M., Stauber J. L., Poon W. L., Cheng S. H, Jolley DF (2008) Uptake and internalisation of copper by three marine microalgae of differing sensitivities. Aquatic Toxicology. 89 :82-93. 8. Johnson H. L., Stauber, J. L., Adams, M. S., and Jolley, D. F. (2007). Copper and zinc tolerance of two tropical microalgae after copper acclimation. Environmental Toxicology. 22 (3) 234 – 244. (cited 5 times) 9. Atkinson, C. A.; Jolley, D. F.; Simpson, S. L. (2007) Effect of overlying water pH, dissolved oxygen, salinity and physical disturbance and metal release from Pb and Zn contaminated marine sediments. Chemosphere. 69, 1428 – 1437. 10. Simpson, S. L, Burston, V. L., Jolley, D. F., and Chau, K. (2006) Application of surrogate methods for assessing the bioavailability and bioaccumulation of PAHs in sediments to sediment ingesting organisms. Chemosphere 65 (11), 24012410 (cited 3 times)

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A/Professor Paul A Keller

e-mail: [email protected]

Organic and Medicinal Chemistry • Organic synthesis, including methodology development, with an emphasis on the asymmetric synthesis of sterically hindered systems, spiro compounds, and new fullerenyl derivatives. The synthesis of chiral heterocycles as ligands in reaction including diphosphines, diarsines and diamines. •

Drug Design and development targeting anti-infectives (HIV, Dengue Fever, Chikungunya virus, multidrug resistant bacteria) and drugs for the prevention of premature birth.

•

Natural product chemistry including the study of Antarctic moss as sententials for climate change, indigenous therapeutics from Indonesian and Bhutanese traditional medicines and the study of colours from Australian natives.

The Design of Helical Chiral Ligands for the Stereoselective Synthesis of Sterically Hindered Systems The biaryl unit is a privileged unit in small molecule drugs, i.e. it is a common moiety and is therefore a key component when designing new therapeutics. Despite the importance of the biaryl, stereoselective syntheses of the chiral versions atropisomeric biaryls – are surprisingly rare. We are developing the chiral synthesis of diphosphino, diarsino and diamino ligands for use in the Suzuki reaction based upon the concept of intermeshing (chiral) helices to direct the stereoselectivities. This project is a synthetic organic chemistry development project and students will be complementary interaction non-complementary interaction involved the development of state of the art design principles and modern synthetic organic chemistry Steric techniques and computer-aided molecular modelling (in collaboration with Prof Tim Clark, University of interacti Erlangen).

L* Drug Design and Development Anti-Viral Investigations We have a range of targets including anti-HIV, the Dengue virus and the Chikungunya virus. Importantly, we are looking for fundamental commonalities in viral targets and part of our work is to investigate potential new binding pockets which we predict would be present within some established viral targets. Further, we are trying to investigate the modes of action of our inhibitors with respect to some proposed complex binding and subsequent transport mechanisms. Multidrug Resistant Bacteria We are developing peptoid antibacterial compounds as therapeutics targeting drug sensitive and resistant strains of Clostridium difficile. This is a Gram-positive spore forming anaerobic bacterium found in the human gut and associated diseases (CDAD) include mild to severe diarrhoea which is often complicated by pseudomembranous colitis (inflammation of the colon) and is an increasing problem for hospitalised patients in the US, Canada and EU countries. Each year in the

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USA there are 400,000 cases with C. difficile associated diarrhoea. The cost burden to the US health care system from C. difficile infections and CDAD, is estimated as >$1.1 billion annually, with associated costs. These costs are expected to increase with the emergence of hypervirulent ribotypes. These infections are potentially significant health issues in Australia with its ageing population and the recent detection of the hypervirulent ribotype in Australia. The Fight for Life – Targeting the Prevention of Premature Birth Premature birth remains the greatest cause of death in babies in the Western world and a major consumer of health dollars. Corticotropin releasing hormone (CRH) has been implicated in the onset of labour in pregnancy and the “fight or flight” response, in addition to a large number of physiological disorders. Antagonists of CRH have been shown to delay the onset of labour in animal studies, however current available antagonists are unsuitable for therapeutic use. Our program involves the generation and development of new design principles through the construction of pharmacophores and novel molecular scaffolds aiming towards developing these more effective, placental permeable therapeutics. New Fullerene Chemistry and Supramolecular Structures as Potential Solar Cells Since its discovery, [60]-fullerene and its homologues have shown promise for exciting new developments and applications in medicinal chemistry and material science. However, an enhanced understanding of fullerenyl chemistry and reactivity is vital for the accurate prediction of chemical outcomes and its application to such uses. The aims of this project are to: • •

To synthesise new fullerene supramolecular structures for use as potential solar cells (in collaboration with Dr Nathalie Solladie, University of Toulouse). Develop new methods for the stereoselective and regioselective functionalisation of the fullerene surface to give optically active, multifunctionalised fullerenes,

•

Undertake mechanistic and computational studies to understand and predict the regiochemistry, reactivity and chemistry of C60 systems, and

•

Utilize this chemistry in the construction of simple nanomachines, using C60 fullerenes as templates, emulating biological processes.

H H

Ho O N

O

Ph 9

H H

O

1 17

O O

16

O Me

The Colours of Australian Nature In a curiosity driven project, we are interested in the chemical structure of the colours in some Australian native species. For example, Emu’s eggs are a dark blue colour and thus far, no one has identified the colour colouration in Bluebottles. Further, parrot feathers contain a variety of primary colours which are thus far unidentified.

Selected Publications 1. John B. Bremner, Paul A. Keller, Stephen G. Pyne, et. al, Combating Vancomycin- and Methicillin-resistant Bacteria: Novel Binaphthyl-based Small Dicationic Peptoids with Therapeutic Potential, Angew Chemie 2010, 537-540. 2. Mary J. Gresser , Steven M. Wales, Paul A. Keller, The Attempted Stereoselective Synthesis of Chiral 2,2'-Biindoline, Tetrahedron, 2010, 66, 6965-6976. 3. Abdel-Hamid, M. K.; Bremner, J. B.; Coates, J.; Keller, P. A.; Miländer, C.; Torkamani, Y. S.; Skelton, B. W.; White, A. H.; Willis, A. C.; Novel Spiro and Fused Heterocycles from the Allylation of Indigo through Domino Nucleophilic Reactions, 2009, Tetrahedron Lett. 50, 6947-6950. 4. Stevens, A. J.; Gahan, M. E.; Mahalingam, S.; Keller, P. A. The Medicinal Chemistry of Dengue Fever, J. Med. Chem. 2009, 52, 7911-7926. 5. Gamble, A. B.; Keller, P. A., Synthesis of Reaction-Ready 6,6′-Biindole and 6,6′-Biisatin via Palladium(II)-Catalysed Intramolecular C-H Functionalisation, Chem. Commun., 2010, 46, 4076 6. Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Garner, J.; Gresser, M. J.; Breuning, M. Modern Concepts for the Atropselective Synthesis of Axially Chiral Biaryls. Angew. Chem. 2005, 44, 5384-5427. 8. P. A. Keller, M. Bowman, K. H. Dang, S. P. Leach, R. Smith, A. McClusky, Pharmacophore Development for Corticotrophin Releasing Hormone: New Insights into Inhibitor Activity, J. Med Chem. 1999, 42, 2351-2357.

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Dr Michael Kelso email: [email protected] Inhibitors of uPA for the Prevention/Treatment of Breast Cancer Metastasis

The plasminogen activation system plays a key role in tumour invasion and metastasis as it is responsible for proteolysis of tissue barriers and modulation of cell adhesion and migration events. One of the key enzymes in this pathway is the Urokinase Type Plasminogen Activator (uPA) and inhibitors of this protease represent attractive targets for the treatment of metastatic disease, particularly in breast cancer. Amiloride is a safe, orally bioavailable K+-sparing diuretic drug that has been used for nearly 4 decades in the treatment of high blood pressure and fluid retention. Amiloride is also known to inhibit uPA with an IC50 in the low micromolar range and accumulating evidence shows that Amiloride demonstrates anti-metastatic activity in both in vitro experiments and in animal tumour models. This project aims to synthesise a series of analogues related to Amiloride in the search for a more potent and orally active uPA inhibitor which could be useful as a new drug for treating breast cancer metastasis. Cl

HN

H N NH2 O

R NH2

N

HN

N

X Y

NH2 O

NH2

Amiloride (weak uPA inhibitor)

H N

More potent uPA inhibitors derived from Amiloride

Tumour Selective Chemotherapy

Anti-cancer chemotherapy usually involves maximum tolerated doses of combinations of highly toxic antiproliferative agents that lack selectivity for tumours. Patients thus experience numerous side-effects during their treatment and there is clearly a need for more tumour-selective and safer drugs. This research program aims to investigate whether safer and more effective anti-cancer combination therapy can be produced by linking two anti-cancer agents with differing modes of action (angiogenesis inhibitor and cytotoxin) into a single inactive prodrug that is selectively cleaved to reveal the two active drugs only within the hypoxic regions of solid tumours. Inert Angiogenesis Inhibitor Cytotoxin Prodrug Bio-reductive cleavage only within hypoxic tumour environment + Inactive Inactive Angiogenesis Cytotoxin Inhibitor Hypoxia-cleavable Tether

Active Angiogenesis Inhibitor

Active Cytotoxin

Biofilm Dispersing Agents

Microbial biofilms are responsible for numerous human pathogenic infections. They tend to respond poorly to

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conventional antimicrobials and there are currently no drugs with useful anti-biofilm efficacy. Recent studies have shown that biofilm cultures can initiate programmed self-dispersion responses when exposed to endogenous quorum sensing molecules, hypoxic conditions or nitric oxide. These studies have exposed a novel anti-biofilm treatment strategy which uses drugs to first disperse biofilms into vulnerable planktonic cultures which are subsequently cleared by a combination of host immune defenses and conventional antibiotics. This program seeks to synthesise some novel biofilm dispersing agents (examples shown below) and evaluate their potential as new antibiotics for treating fatal P. aeruginosa respiratory biofilm infections that are prevalent in cystic fibrosis patients. Antimicrobial Photodynamic Therapy for Treating Drug-Resistant Bacterial Infections

Efflux of drugs from bacterial cells via membrane-bound Multidrug Resistance Pumps (MDRs) is a powerful mechanism that microorganisms use to resist a host of antibiotics. Co-administration of antibiotics with efflux pump inhibitors is showing promise as an innovative strategy for countering bacterial drug resistance. We have shown that an alternative strategy in which efflux pump inhibitors are covalently linked to antibiotics via noncleavable tethers also produces highly effective, dual-action antimicrobial hybrid molecules (e.g. SS14). Antimicrobial photodynamic therapy (PDT) uses harmless visible light to excite non-toxic photosensitizing dyes (e.g. phenothiazines) to high energy triplet states that are toxic to bacterial cells. PDT has recently been proposed as an alternative treatment for localized infections. Our collaborators recently discovered that phenothiazines are substrates for bacterial MDR’s, and that the use of efflux pump inhibitors potentiates the efficacy of PDT with phenothiaziniums by up to 100,000 times. This key finding suggests that PDT in the presence of efflux pump inhibitors could be useful for treating drug resistant bacterial infections. This research program aims to synthesise prototype hybrid molecules for use in PDT (example shown below) that combine phenothiazines with efflux pump inhibitors via non-cleavable tethers. Selected Publications

1. A Mass Spectrometric Investigation of Novel Quadruplex DNA-selective Berberine Derivatives. Gornall, K. C.; Samosorn, S.; Tanwirat, B.; Suksamrarn, A.; Bremner, J. B.; Kelso, M. J.; Beck, J. L. Chem. Commun. 2010, 46, 6602-6604. 2. Berberine−INF55 (5-Nitro-2-Phenylindole) Hybrid Antimicrobials: Effects of Varying the Relative Orientation of the Berberine and INF55 Components. Tomkiewicz, D.; Casadei, G.; Larkins-Ford, J.; Moy, T.I.; Garner, J.; Bremner, J. B.; Ausubel, F. M.; Lewis, K.; Kelso, M. J. Antimicrobial Agents and Chemother. 2010, 54(8), 3219-3224. 3. Structure–Activity Relationships of 2-aryl-1H-indole Inhibitors of the NorA Efflux Pump in Staphylococcus aureus. Ambrus, J. A.; Kelso, M. J.; Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis, K. Bioorg. Med. Chem. Lett. 2008, 18, 4294-4297. 4. Oxidative Coupling of Indoles Using Thallium (III) Trifluoroacetate. Keller, P. A.; Yepuri, N. R.; Kelso, M. J.; Mariani, M.; Skelton, B. W.; White, A. H. Tetrahedron, 2008, 64, 7787-7795. 5. Peptides and Small Molecules Targeting the Plasminogen Activation System: Towards Prophylactic AntiMetastasis Drugs for Breast Cancer. Tyndall, J. D. A.; Kelso, M. J.; Clingan, P.; Ranson, M. Recent Patents on Anti-Cancer Drug Discovery. 2008, 3, 1-13. 6. Synthesis of an Anthracyclinone Bearing an Unprecedented Aromatic Ring-Fused Bridgehead-Hydroxylated Bicyclo[3.1.1]heptanol. Kelso, C.; Beck, J.L.; Kelso, M.J. Tetrahedron Lett. 2007, 48, 7440-7443. 7. Structure-Activity Relationships of Alpha-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase. Hardouin C.; Kelso, M.J.; Romero, F.A.; Rayl, T.J; Leung, D.; Hwang, I.; Cravatt, B.F.; Boger, D.L. J. Med. Chem. 2007, 50(14), 3359-3368. 8. Catalytic Enantioselective Conjugate Addition of Carbamates. Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gomez-Bengoa, E.; Garcia, J-M. J. Am. Chem. Soc. 2004, 126 (30): 9188-9189.

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Dr Garry Mockler

email: [email protected] Model Compounds of Copper Proteins The structures and properties of model compounds of copper proteins are studied in order to better understand the functions, structures and properties of these metalloproteins which occur in biological systems. Galactose oxidase, which contains a type 1b copper atom, oxidizes a number of primary alcohols including galactose to the corresponding aldehydes. Model compounds of galactose oxidase are being synthesized and characterised and their reactions with sugars and alcohols are being investigated. Selected Publications 1. R J Butcher, G Diven, G Erickson, J Jasinski, G M Mockler, R Y Pozdniakov, E Sinn, Inorg. Chim. Acta., 239, 107-116 (1995) 2. Ray J, Butcher, Garry Mockler, Owen McKern, Acta Cryst, E59, m20– m22 (2003) 3. Ray J. Butcher, Garry Mockler, Owen McKern, Acta Cryst. E59, m61-m63 (2003)

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Dr Clare Murphy (Paton-Walsh) email: [email protected] (see also David Griffith and Steve Wilson) Research Interests

Atmospheric Composition, Chemistry & Climate The changing composition of the earth’s atmosphere is a matter of intense scientific research as we strive to understand details of the physical and chemical mechanisms that control our climate. Remote sensing spectrometers are used to study trace gases in the atmosphere by examining terrestrial atmospheric absorption lines in the spectra. These spectra may be recorded from the ground by coupling the spectrometer to a solar tracker and thereby recording the infrared spectrum from the Sun once it has passed through the Earth’s atmosphere. Complementary measurements are made by satellite-based spectrometers that record radiation emitted from the Earth or solar radiation scattered by the Earth’s atmosphere. Due to concerns about catastrophic climate change there are an increasing number of satellite-based sensors and measurements stations around the globe aimed at characterising the changing composition and chemistry of our atmosphere. Significant efforts are also underway to build models capable of capturing the complex chemical and dynamical changes within the atmosphere. The Centre for Atmospheric Chemistry at the UoW operates remote sensing spectrometers at Wollongong and at Darwin, that monitor the changing composition of the atmosphere and provide ground-truthing for a number of satellite-based instruments. We have strong ties to many other groups worldwide that use ground and satellite-based instruments (combined with chemical transport models) to learn about the cycles that control the exchange of gases between the Earth’s surface and its atmosphere and how these are changing under mans’ influence. Biomass Burning Bushfires are a major source of atmospheric trace gases and aerosols. Due to the variable nature of their occurrence, extent and intensity, bushfires are the largest contributor to the variability of the composition of the troposphere (lower atmosphere). Smoke and gases from Australian forest and savanna fires have a significant impact on air quality and atmospheric composition and chemistry across the Southern Hemisphere and globally. Despite their global significance, emissions from Australian fires are poorly characterised, so further research is needed in this area. Scientific Focus Areas: • The impact of biomass burning on the chemistry and composition of the troposphere.

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• Estimating emissions from vegetation fires using satellite measurements of aerosol optical depth. • Identifying and quantifying sources of gaseous pollutants to the atmosphere. Representative Publications: 1. Paton-Walsh, C., N. M. Deutscher, D. W. T. Griffith, B. W. Forgan, S. R. Wilson, N. B. Jones, and D. P. Edwards (2010), Trace gas emissions from savanna fires in northern Australia, Journal of Geophysical Research-Atmospheres, 115. 2. Paton-Walsh, C., L. K. Emmons, and S. R. Wilson (2010), Estimated total emissions of trace gases from the Canberra Wildfires of 2003: a new method using satellite measurements of aerosol optical depth & the MOZART chemical transport model, Atmospheric Chemistry and Physics, 10(12), 5739-5748. 3. de Laat, A. T. J., A. M. S. Gloudemans, H. Schrijver, I. Aben, Y. Nagahama, K. Suzuki, E. Mahieu, N. B. Jones, C. Paton-Walsh, N. M. Deutscher, D. W. T. Griffith, et al (2010), Validation of five years (20032007) of SCIAMACHY CO total column measurements using ground-based spectrometer observations, Atmos. Meas. Tech. Discuss., 3(4), 2891-2930. 4. Deutscher, N. M., D. W. T. Griffith, C. Paton-Walsh, and R. Borah (2010), Train-borne measurements of tropical methane enhancements from ephemeral wetlands in Australia, Journal of Geophysical ResearchAtmospheres, 115. 5. Griffith, D. W. T., S. D. Parkes, V. Haverd, C. Paton-Walsh, and S. R. Wilson (2009), Absolute Calibration of the Intramolecular Site Preference of N-15 Fractionation in Tropospheric N2O by FT-IR Spectroscopy, Analytical Chemistry, 81(6), 2227-2234. 6. Paton-Walsh, C., R. L. Mittermeier, W. Bell, H. Fast, N. B. Jones, and A. Meier (2008), An Intercomparison of Ground-Based Solar FTIR Measurements of Atmospheric Gases at Eureka, Canada, Journal of Atmospheric and Oceanic Technology, 25(11), 2028-2036. 7. Paton-Walsh, C., S. R. Wilson, N. B. Jones, and D. W. T. Griffith (2008), Measurement of methanol emissions from Australian wildfires by ground-based solar Fourier transform spectroscopy, Geophysical Research Letters, 35(8). 8. Paton-Walsh, C., N. Jones, S. Wilson, A. Meier, N. Deutscher, D. Griffith, R. Mitchell, and S. Campbell (2004), Trace gas emissions from biomass burning inferred from aerosol optical depth, Geophysical Research Letters, 31(5).

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A/Prof Aaron Oakley Email: [email protected]

Structural biology Living organisms contain proteins, DNA and other macromolecules that perform essential functions to maintain life. Obtaining structural information on these molecules can lead to a detailed understanding of their biological function. Practical outcomes include the design of drugs to bind to proteins that are involved in disease processes. My interest is in the determination of such structures through X-ray-based techniques, and the use of these structures in drug discovery. Proteins in DNA replication A long-standing collaboration with Prof Nick Dixon (School of Chemistry) seeks to structurally characterize the interaction of bacterial proteins that participate in DNA replication. We have recently determined the structural basis of the interaction between DnaG (the protein that lays down RNA primers on DNA) and SSB (that binds to singlestranded DNA). The SSB-peptide is shown at right bound on the surface of DnaG. Disruption of these interactions by small-molecule compounds designed to bind at these sites could inhibit DNA-replication in bacteria. Another protein we are targeting is the beta-clamp, a donut-shaped protein that slides along DNA and binds to several enzymes that copy and repair DNA. Enzymes in glutathione metabolism The cyclotransferases are a family of proteins that remove glutamate from various amino acids to form oxoproline and free collaboration with Prof Phil Board (JCSMR) we have structure of GGCT (shown at right) a cyclotransferase that gamma-glutamylcysteine. Gamma-glutamylcysteine is a

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glutathione synthesis. In patients with glutathione synthase defficiency, the inhibition of GGCT would block the degradation of gamma-glutamylcysteine and allow its accumulation to a level where it may partially substitute for glutathione in redox and detoxification reactions. Fragment screening Moving forward, we aim to use fragment-based screening to develop inhibitors that bind to the above proteins. FBS utilizes small molecule entities (too small to serve as drugs in their own right) as starting-points for drug discovery efforts. Fragment libraries are screened against the target using crystallography to visualize their mode of binding. The “fragments” are relatively small (MW <~250 Da). Fragment binding tends to be more promiscuous (less specific) than binding of a drug lead to its target since fragments lack the structural complexity necessary for highly specific binding. Although fragments tend to bind weakly (100 μM to mM) compared to leads, they provide an excellent starting point for lead development. When combined with medicinal chamistry (in collaboration with Dr Michael Kelso) it is hoped that promising leads will be developed.

Co-factor free oxygenases Oxygenases, enzymes that can catalyze reactions of “triplet” oxygen with “singlet” substrates are fascinating because of the spin-forbidden nature of the reaction. I recently contributed to a structural study on two enzymes (HOD and QDO), that catalyse these reactions. In collaboration with Dr Haibo Yu (school of chemistry), computational methods are being used to aid detailed mechanistic investigation of the reaction in these enzymes. Selected Publications: 1. Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimmBreschkin JL. Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses. J Med Chem. 2010 Sep 9;53(17):6421-31. 2. Oakley AJ, Coggan M, Board PG. Identification and characterization of gamma-glutamylamine cyclotransferase, an enzyme responsible for gamma-glutamyl-epsilon-lysine catabolism. J Biol Chem. 2010 Mar 26;285(13):9642-8. Epub 2010 Jan 28. 3. Steiner RA, Janssen HJ, Roversi P, Oakley AJ, Fetzner S. Structural basis for cofactor-independent dioxygenation of N-heteroaromatic compounds at the alpha/beta-hydrolase fold. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):657-62. Epub 2009 Dec 22. 4. Oakley AJ, Yamada T, Liu D, Coggan M, Clark AG, Board PG. The identification and structural characterization of C7orf24 as gamma-glutamyl cyclotransferase. An essential enzyme in the gammaglutamyl cycle. J Biol Chem. 2008 Aug 8;283(32):22031-42. Epub 2008 May 30. 5. Oakley AJ, Loscha KV, Schaeffer PM, Liepinsh E, Pintacuda G, Wilce MC, Otting G, Dixon NE. Crystal and solution structures of the helicase-binding domain of Escherichia coli primase. J Biol Chem. 2005 Mar 25;280(12):11495-504. Epub 2005 Jan 12.

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Dr Glennys O'Brien email: [email protected]

My current research interests lie in chemistry and science education, in particular understanding the barriers to students constructing their own knowledge and in developing their chemistry skills for a major in chemistry or application in their own chosen discipline. Because chemistry is a central and enabling science; most applied science disciplines require a first year level working knowledge of chemistry. This need is exacerbated by a general lack of preparation for university level mathematics as used in quantitative chemistry, and a lack of perception regarding the need for the "hard sciences" and mathematics in applied sciences impacting on student motivation. My current projects include the mapping of science subjects in a curriculum exploration at the subject level, to promote development of curricula which are perceived as coherent by students; and support students developing their knowledge across several subjects explicitly woven together. Tied to this project and built in response to a chronic need, mathematics support in contextualized problems has been developed as part of the University wide, ALTC supported "Return to Mathematics" project. This mathematics support project has two other parts: exploring the use of tablet technology in education and diagnosis of problem solving difficulties by screen and voice capture of student activity. Other project work covering development of specific learning objects is a collaboration with Dr Melanie Cameron and Learning Design staff, for development of online prelab activities based in a Flash environment and promoting active student participation by requiring a sequence of on screen and paper based activities. Developments within First Year Chemistry in collaboration with Dr Simon Bedford include the investigation of student activity within the tutorial – workshop setting, using adaptations of the "POGIL"© methodology to especially support students who enter the first year without completion of senior high school chemistry. Specific Projects: •

Investigating student activity during problem solving by capturing “think aloud” and writing using a tablet laptop. (In collaboration with Assoc Prof Sue Bennett, Faculty of Education)

•

Further development of tablet based methodologies for making learning objects.

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•

Student responses to specific learning activities in the problem based learning workshop environment.

Selected Publications: 1. O'Brien G, Jarrett L, Purser E and Brown C. (2010) Mapping Science Subjects: A Ground Up Approach. Uniserve Sci 2010, http://escholarship.library.usyd.edu.au/journals/index.php/IISME/issue/current 2. O'Brien G, Denny S and Tonini M. (2009) Using tablets to generate support resources for chemistry students struggling with mathematics. http://www.monash.edu/eeducation/atiec/presentations.html 3. O'Brien G and Cameron M. (2008). Prelaboratory activities to enhance the laboratory learning experience. http://sydney.edu.au/science/uniserve_science/pubs/procs/2008/080.pdf

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Professor William E Price email: [email protected] Research Interests My research interests are concerned primarily with physical properties, particularly mass transfer, in fluids and porous media such as polymers and foods. It spans both pure research, studying interactions in fluid mixtures and their effect on the properties and structure of the system and applied research targeted at specific, often industry-driven, goals. At present there are three areas in which these interests are being pursued: Analysis of trace pollutants in the environment With the current interest in water reuse, there is a need to analyse low levels of micropollutants in water and environmental water samples. I am currently focused at developing methodologies for the analysis of a number of classes of trace pollutants in waste water, many of them of anthropogenic origin. These include hormones, pharmaceuticals, pesticides, plasticizers, detergents and phytooestrogens. These need to be analysed at very low levels to ascertain their extent in waste water and determine the ability of tertiary treatment processes in removing them, to enable the water to be reused. I have a strong current collaboration with Dr. Long Ngheim, Faculty of Engineering, UoW who has complementary expertise in membrane separation techniques for water treatment and reuse. Selected Publications Kang, J. and W. E. Price (2009). "Occurrence of Phytoestrogens in Environmental Water and Wastewater Samples." J. Environmental Monitoring 11: 1477 - 1483. Kang, J., L. A. Hick, et al. (2007). "A fragmentation study of isoflavones in negative electrospray ionization by MSn ion trap mass spectrometry and triple quadrupole mass spectrometry." Rapid Communications in Mass Spectrometry 21: 857-868. Kang, J., L. A. Hick, et al. (2007). "Using calibrational approaches to compensate for remaining matrix effects in quantitative LC-ESI-MSn analysis of phytoestrogens in aqueous environmental samples " Rapid Communications in Mass Spectrometry 21: 4065-4072. Kang, J., W. E. Price, et al. (2006). "Simultaneous determination of isoflavones and lignans at trace levels in natural waters and wastewater sampes using LC-ESI ion-trap MS." Rapid Communications in Mass Spectrometry 20: 2411-2418. Food Analysis and Food Processing Mass transfer is often the rate-limiting step in extraction from foodstuffs. Experience has been built up in this area over nearly twenty years measuring the kinetics and equilibrium behaviour of solvent extraction from foodstuffs such as tea, coffee, citrus fruit and ginger. In addition, my research interest in tea and coffee processing has engendered another interest in extraction and analysis of food components, particularly ones that are bioactive ie have some biological action. At

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present there are two foci to my work: The first area is studying methods of analysis of phytooestrogens in foods and the bioavailability of these important compounds in humans. Soy and linseed products have high phyooestrogens contents, particularly isoflavanols and ligans. These compounds have been implicated in a number of studies to have significant health benefits. The second area is that of chemical and physical changes during the processing of foods. Of particular interest of late have been studies on the effects of air and osmotic dehydration of temperate and tropical fruit. This builds on some developments in techniques previously. Osmotic dehydration is used as a pre-treatment to thermal / air drying to reduce the cost and time for drying and also sometimes to change the flavour and quality characteristics of the fruit. One major focus of the current work is on investigating how the uptake of sugars during the osmotic dehydration treatment modulates the chemical changes that occur during drying. In addition, there is another focus aimed at identifying changes in volatile profile of the food during processing as a method of quality assurance and looking for markers of undesirable changes caused by for example, caramelisation or Maillard reaction. These interests utilises SPME and GC/MS techniques for flavour analysis as well as HPLC analysis of carbohydrates. Selected Publications Larkin, T. A., L. A. Astheimer, et al. (2009). "Dietary combination of soy with a probiotic or prebiotic food significantly reduces total and LDL cholesterol in mildly hypercholesterolaemic subjects " European Journal of Clinical Nutrition 63: 238–245 Larkin, T. A., W. E. Price, et al. (2008). " The key importance of soy isoflavone bioavailability to understanding health benefits." Critical Reviews of Food Science and Nutrition 48: 538-552. Murray, T., J. Kang, et al. (2007). "Tissue Distribution of Lignans in Rats in Response to Diet, Dose – Response and Competition with Isoflavones " Journal of Agricultural & Food Chemistry 55(12): 4907-4912. Nguyen, M. and W. E. Price (2007). "Air-drying of Banana: influence of experimental parameters, slab thickness, banana maturity and harvesting season." Journal of Food Engineering 79(1): 200-207. Electrofunctional Materials In collaboration with Prof. Gordon Wallace and other members of the Intelligent Polymers Research Institute (IPRI) and the ARC Centre of Excellence for Electromaterials Science, I am engaged in research developing novel nanostructured materials for a range of potential applications including artificial muscles, actuators, energy storage and conversion, Selected Publications Akieh, M. M., W. E. Price, et al. (2009). "Ion exchange behaviour and charge compensation mechanism of polypyrrole in electrolytes containing mono-, diand trivalent metal ions." Synthetic Metals 159(23-24): 2590-2598 Ding, J., J. Wu, et al. (2008). "Electrochemical co-deposition of Tin+ phases with gold in ionic liquids." Physical Chemistry Chemical Physics 10(38): 5863-5869. Ding, J., J. Wu, et al. (2008). "Induction of titanium reduction using pyrrole and polypyrrole in the ionic liquid ethyl-methylimidazolium bis(trifluoromethanesulphonyl)amide." Electrochemistry Communications 10: 217-221. El Abedin, S. Z., F. Endres, et al. (2008). "On the electrodeposition of titanium in ionic liquids." Physical Chemistry Chemical Physics 10: 2189-2199.

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Professor Stephen Pyne email: [email protected]

Asymmetric Synthesis of Bioactive Molecules and Natural Products, New Antibacterials, Novel Fullerenes and Natural Products Chemistry. New synthetic strategies are being developed for the asymmetric synthesis of natural products and biologically active molecules. These projects involve modern organic synthetic methods, NMR spectroscopy and computer aided molecular modelling. Other projects involve the development of novel antibiotic agents, amino acid-fullerene derivatives and the isolation, structure elucidation and biological studies on natural products. Particular areas of research interest are: Asymmetric Synthesis of Stemona Alkaloids Extracts of the plants of the Stemonaceae family (Stemona and Croomia species) have been used in traditional Chinese and Japanese medicines to treat respiratory diseases such as bronchitis, pertussis, and tuberculosis and as antihelmintic agents. These plants contain a large number of alkaloids that have novel polycyclic structures. These unique structural features coupled with their interesting biological properties have stimulated the development of new synthetic methodology and synthetic strategies for the synthesis of these alkaloids in my research group and others. Two current target molecules are stemocurtisine 1 and isooxymaistemonine 2. In a cellular assay isooxymaistemonine 2 showed up-regulation of the gene CLA-1 which codes for the human HDL (high-density lipoprotein) receptor.2 High levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk for atherogenesis. Thus isooxymaistemonine 2 and its analogues may have a useful therapeutic value by upregulating HDL levels and providing a protective effect against atherosclerosis.

Asymmetric Synthesis of Polyhydroxylated Pyrrolizidine and Indolizidine Alkaloids and their Analogues Polyhydroxylated pyrrolizidine and indolizidine alkaloids are well known potent glycosidase enzyme inhibitors. For example the pyrrolizidine alkaloids australine 3 and casuarine 4, and related alkaloids, are powerful inhibitors of glycosidase enzymes and thus exhibit antiviral and anti-HIV activity by effectively inhibiting the enzymatic processing of glycoproteins. We are currently developing a common synthetic strategy to these natural products to allow a better understanding of the structural requirements for glycosidase inhibition and to develop more potent, selective and less toxic drugs. We have found from our synthetic projects that the proposed structures of some of these alkaloids are incorrect. Our total synthesis studies have allowed us to correct the structures of these compounds.

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The Development of Novel Cyclic Peptoid Antibiotics (with P. Keller)

The death rate from infectious diseases in the developed world has increased over the last decade. This has been due to a number of factors, including, increasing mobility of people from developed countries to less developed ones, increasing age of the general population, increasing numbers of transplant, cancer and AIDS patients who have lowered immunities to bacterial infections and the increasing numbers of bacterial species that have become multiply resistant to antibacterial drugs. The vancomycin group of antibiotics represents a last line of defence against methicillin-resistant Staphylococcus aureus and other Gram-positive microorganisms. These antibiotics interfere with cell-wall biosynthesis by binding to the DAla-D-Ala terminus of the disaccharyl pentapeptide of the peptidoglycan of the bacterial cell wall, resulting in cell death. Recently vancomycin resistant bacteria have appeared. These bacteria have been identified as having a D-Ala-D-lactate terminus rather than a D-Ala-D-Ala terminus of the peptidoglycan. Vancomycin has a much lower affinity (ca. 1000 fold decrease in affinity) for the D-Ala-D-lactate terminus in vancomycin resistant bacteria and consequently it is much less effective as an antibiotic. Novel cyclic peptide analogues of vancomycin are being designed and synthesised that are much more synthetically accessible than vancomycin itself and have potentially a high affinity for the D-Ala-D-lactate terminus of vancomycin resistant bacteria. One of our compounds (5) has shown very promising in vitro antibacterial activity against a range of Gram-positive pathogens, including organisms resistant to vancomycin, methicillin and linezolid. This compound is readily bactericidal in a concentration dependant manner with an extended post-antibacterial effect. In vivo potency of this compound was also maintained and resistance was very slow to develop in vitro. Compound 5 is being developed for topical indications including wound and catheter-related infections.

Regioselective Functionalization of Fullerenes: New Three Dimensional Templates for Drug Delivery and the Design of New Pharmaceuticals and Catalytic Asymmetric Synthesis (with P. Keller). The fullerene surface potentially offers many possibilities for preparing novel multifunctionalized 3-dimensional surfaces with potential applications in drug delivery, as anti-viral agents, in photodynamic therapy and chemical asymmetric catalysis. We are thus developing chemistry to regioselectively prepare multifunctionalized fullerenes and fulleryl-amino acids and their peptide derivatives. We plan to examine their effects on biological systems. Phytochemical and Synthetic Studies of Stemona Akaloids In collaboration with scientists from the University of Changi Mai in Thailand we are examining the phytochemistry and biological chemistry of the root extracts of Stemona species of plants. Extracts of the roots of these plants have been used as traditional medicines by the Chinese and Japanese to treat respiratory diseases such as bronchitis, pertussis, and tuberculosis and as antihelmintic agents. Recently we discovered three new Stemona alkaloids, with a novel pyrido[1,2a]azepine A,B-ring system, from a root extract of S. curtisii Hook. f., growing in Southern Thailand. We are currently examining the phytochemistry and biological activities of other Stemona plants in Thailand and examining their biological activity profiles. Selected Recent Publications 1.

2. 3.

Novel Binaphthyl-based Dicationic Peptoids with Therapeutic Potential, J. B. Bremner, P. A. Keller, S. G. Pyne, T. P. Boyle, Z. Brkic, D. M. David, J. Morgan, M. Robertson, K. Somphol, M. H. Miller, A. S. Howe, Paul Ambrose, Sujata Bhavnani, T. R. Fritsche, D. J. Biedenbach, R. N. Jones, R. W. Buckheit, Jr, K. M. Watson, D. Baylis, J. A. Coates, J. Deadman, D. Jeevarajah, A. McCracken, and D.I. Rhodes, Angew Chem. Int. Ed. 2010, 49, 537-540. Synthesis of Hyacinthacine B3 and purported Hyacinthacine B7, C. W. G. Au, R. J. Nash and S. G. Pyne, Chem Commun. 2010, 46, 713-715. Total synthesis of uniflorine A, casuarine, australine, 3-epi-australine, and 3,7-diepi-australine from a common precursor, T. Ritthiwigrom, A. C. Willis, and S. G. Pyne, J. Org. Chem. 2010, 75, 815-824.

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A/Professor Stephen Ralph email: [email protected] Interactions of Metal Complexes with Non-Duplex DNA Structures There are a variety of non-standard DNA structures that play significant roles in vivo. For example, bulges in double helical DNA structure can arise when two single stranded oligonucleotides that are not perfectly complementary join together to form a duplex. DNA bulge regions may play an important role in some forms of mutagenesis, highlighting their potential as therapeutic targets. Another non-standard DNA structure that has attracted interest for this reason is quadruplex DNA, which is present in the guanine rich sequences found at the end of chromosomes known as telomeres. These are DNA regions that do not code for specific proteins, but protect the chromosome against damage. The guanine rich DNA sequences form structures in which four co-planar guanines form a tetrad by means of Hoogsteen hydrogen bonds (Figure 1), and the structure is further stabilised by interactions involving monovalent cations such as potassium.

Figure 1. Structure of: (a) an individual guanine-quartet (G-quartet), and (b) a region of quadruplex DNA formed by the sequence d(GGGG)4, containing four G-quartets. Other unusual DNA structures such as triplex DNA, Z-DNA, cruciform’s and Holliday junctions also exist, which may also serve as potential therapeutic targets for small molecules. A range of projects is available for those wishing to study these unusual DNA structures, or their interactions with different compounds. These projects may be centred on the use of spectroscopic techniques (e.g. ion mobility mass spectrometry, circular dichroism spectroscopy) for characterising the DNA structures themselves, or may focus on their interactions with novel metal complexes that target these regions of DNA. Interactions of Gold Complexes with Proteins Several gold(I) complexes are used for the treatment of rheumatoid arthritis. These compounds elicit multiple effects on the body of patients, including producing anti-inflammatory responses, changes in microbial activity, inhibition of enzymes and alterations to the numbers of white blood cells. It is likely that there is therefore no single dominant mechanism of action of these compounds. What is common to all the gold(I) complexes, however, is that after administration the vast majority becomes bound to human serum albumin (HSA), which is the most abundant protein present in blood plasma. HSA is responsible for the transport of the gold complexes throughout the body, including to where it is required for its therapeutic effects. It is likely that uptake of gold into cells is mediated by other proteins, which receive the coordinated gold from HSA. We are currently mass spectrometry to investigate the direct interactions of gold antiarthritic agents, and gold complexes with anticancer activity, with various proteins including haemoglobin, glutathione peroxidase and HSA.

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Molecular Cages for Metal Ions The metal ion chemistry of macrobicyclic hexaamine ligands such as sepulchrate and sarcophagine has been extensively investigated. These ligands act as molecular cages, effectively encapsulating metal ions in an organic coat and shielding them from the external environment. The tremendous stability of metal cage complexes has been exploited for a number of applications including development of novel metallo-radiopharmaceuticals and treatment of heavy metal ion poisoning. We wish to explore the metal ion chemistry of the cage ligands Me5tricosane and Me8tricosane, which are analogues of sepulchrate and sarcophagine featuring slightly larger internal cavities. The latter property has already resulted in some unprecedented chemistry for the metal ion complexes of these ligands. For example, the cobalt(II) complex of Me8tricosane is the only known stable Co(II) hexamine complex, while the Cd(II) and Hg(II) complexes of Me5tricosane are rare examples of hexaamine complexes with exact trigonal prismatic stereochemistry.

Filtration Applications of Carbon Nanotube Membranes A number of papers have recently shown that membranes composed of aligned arrays of carbon nanotubes are extremely permeable towards water and gases, suggesting that these materials may be useful for nanofiltration or ultrafiltration applications. However, aligned carbon nanotube membranes are difficult to prepare on a large scale and require the use of hazardous reagents to open the ends of the tubes to allow solvent and other molecules to enter. We have embarked on a program of study designed to evaluate whether other types of carbon nanotube membranes also exhibit high levels of permeability. Our preliminary work has involved the preparation of network carbon nanotube membranes known as buckypapers, from dispersions of either single-walled or multi-walled nanotubes. The latter dispersions have been prepared using a variety of molecular dispersants, including porphyrins, cyclodextrins, proteins and nucleic acids, with the hope that these molecules would be retained in the final buckypaper and thereby enhance their ability to selectively filter molecules.

Figure 2. SEM images of SWNT buckypapers prepared using different molecular dispersants. Selected Publications 1. 1. J.L. Talib, J.L. Beck and S.F. Ralph, "A Mass Spectrometric Investigation of the Binding of Gold Antiarthritic Agents and the Metabolite [Au(CN)2]- to Human Serum Albumin", Journal of Biological Inorganic Chemistry, 11, 559 (2006). 2. A.M.T. Bygott, R.J. Geue, S.F. Ralph, A.M. Sargeson and A.C. Willis, “Octahedral and Trigonal Prismatic Structure Preferences in a Bicyclic Hexaamine Cage for Zinc(II), Cadmium(II) and Mercury(II) Ions”, Dalton Trans.,4778 (2007). 3. J. Talib, C. Green, K.J. Davis, T. Urathamakul, J.L. Beck, J.R. Aldrich-Wright and S.F. Ralph, “A Comparison of the Binding of Metal Complexes to Duplex and Quadruplex DNA”, Dalton Trans.,1018 (2008). 4. J. Boge, L.J. Sweetman, M. in het Panhuis and S.F. Ralph, "The Effect of Preparation Conditions and Biopolymer Dispersants on the Properties of SWNT Buckypapers”, J. Mat. Chem., 19, 9131 (2009).

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Dr Christopher Richardson

email: [email protected]

Research Interests My groups work is centred in producing useful materials and molecules. The main focus is producing porous solids and hollow supermolecules. Principles of supramolecular chemistry and crystal engineering are used to design in function to these systems. The issues we try to address and understand are events in molecular recognition by creating selfassembling host-guest systems, and how to use molecular interactions and events to craft systems that perform a function well. Synthetic organic and inorganic techniques are used and this is supported with characterisation and analytical techniques such as NMR, IR, UV-Vis and Thermal Gravimetric Analysis (TGA), X-ray diffraction, scanning electron microscopy with electron dispersive X-ray measurements (SEM-EDX). Projects in bionanotechnology are carried out in collaboration with other groups in the School of Chemistry and the School of Biological Sciences/IHMRI.

Metal-Organic Materials Metal-Organic Materials are composed of organic ligands that bind metal ions or clusters of metal ions into a structure or lattice. They can be broadly divided into two sub categories: frameworks, which are the crystalline lattices, and polyhedra, which are discrete supermolecules. The key property to engineer in these materials is permanent porosity. This is the ability to maintain usable space inside a structure or a lattice. It is this space that can be used. With regular pore structures and record high surface areas metal-organic materials are extremely interesting. This combination of properties opens up a range of applications for metal-organics as smart materials in adsorbents, membranes, imaging agents, drug delivery, as energy storage materials, sensors, and catalysts. The current areas that I am interested in are: Reaction Chemistry Bionanotechnology

Reaction Chemistry Porous materials offer unique reaction environments for molecules inside their structures. With this in mind, we want to design systems that enhance or catalyse reactions in these interior spaces. The schematics below depict two avenues of current research effort. One is the functionalisation of the framework - carrying out a reaction in the interior space, but actually on the material itself. The other is represented as the hollow blue ball, where molecules travel inside the structure and react. When the product leaves the pore the reaction cycle can be repeated, leading to a catalytic cycle.

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A schematic of the process of framework functionalisation: organic synthesis of a reactive ligand → formation of a framework → functionalisation of the framework.

A catalytic cycle using a hollow supermolecule.

Bionanotechnology This area of interest is where porous metal-organic materials meet medicinal chemistry. This could be as hosts for medicinal agents and their use as potential theranostics. We want to look at at supermolecules, like the discrete polyhedron shown, that have the characteristics to be usable in a medicinal setting. Another area that we want to develop is the synthetic chemistry of metal-organic nanoparticles that can be dendronised. A supermolecule with a large internal volume and the symmetry of a virus.

Topics of current interest

Producing porous materials for designer catalysis Post-synthetic approaches to specifically functionalised Metal-Organic Frameworks Supermolecule hosts for medicinal agents New metal complexes as potential radiopharmaceuticals and imaging agents

Selected Publications 1. A. D. Burrows, C. G. Frost, M. F. Mahon, P. R. Raithby, C. Richardson, and A. J. Stevenson, “Solid state

interconversion of cages and coordination networks via conformational change of a semi-rigid ligand”, Chemical Communications, 2010, 5064-5066.

2. A D. Burrows, C. G. Frost, M. F. Mahon, P. R. Raithby, C. L. Renouf, C. Richardson, and A. J. Stevenson, “Dipyridyl β-diketonate complexes: versatile polydentate metallologands for metal-organic frameworks and hydrogen-bonded networks”, Chemical Communications, 2010, 5067-5069. 3. A D. Burrows, C. G. Frost, M. F. Mahon, and C. Richardson, “Sulphur-tagged metal-organic frameworks and their post-synthetic oxidation”, Chemical Communications, 2009, 4218-4220. 4. Andrew D. Burrows, C. G. Frost, M. F. Mahon, and C. Richardson, “The post-synthetic modification of tagged

metal-organic frameworks”, Angewandte Chemie Inernational Edition, 2008, 47, 8482–8486. 5. A. D. Burrows, C. G. Frost, M. F. Mahon, M. Winsper, C. Richardson, J. P. Atfield, and J. A. Rogers, “Subtle structural variation in copper metal-organic frameworks: syntheses, structures, magnetic properties and application as catalysts”, Dalton Transactions, 2008, 6788–6895.

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Dr Danielle Skropeta email: [email protected] Bioorganic & Medicinal Chemistry Our research is aimed at the discovery and development of new classes of drugs inspired by Nature. Our main research themes include the isolation and structural elucidation of marine natural products and their biological evaluation as potential new anticancer agents. We are also involved in the synthesis of novel isatin-based anticancer agents, bioactive glycopeptides for radioimaging and biomimetic natural product synthesis. All of our projects are multidisciplinary based and are performed in collaboration with chemists and biologists from within our University, as well as with other research and industry partners both here in Australia and overseas. Isatin-Based Anticancer Agents We have generated a series of over 35 highly potent N-substituted isatinderived cytotoxins, several of which show nanomolar cytotoxicity against a diverse panel of human cancer cell lines. Our current interests are aimed at developing a strategy to conjugate these potent cytotoxins to tumour targeting proteins such as transferrin and the antibody Herceptin, which is selective for the HER2 receptor overexpressed in 20-30% of human breast carcinomas. We are also further exploring and modifying the isatin scaffold itself to create a second generation of even more potent cytotoxic agents, studying their possible mode of action and their potential development as a kinase inhibitors. Biomimetic Synthesis of Bioactive Natural Products Biomimetic syntheses are those where we attempt to mimic in the laboratory the same synthetic route to a natural product as that used by Nature. Conventional syntheses of complex natural products are often marred by an excessive number of steps, complex purification techniques, and low overall yields. On the other hand, by taking cues from Nature, biomimetic syntheses are often characterised by elegant total syntheses that begin with simple starting materials and proceed to the natural product with facility, in only a few steps, and in high overall yield. There is a wealth of elegant biomimetic syntheses of complex natural products that appear in the literature, many of which use the Diels-Alder reaction as the key step in their synthesis. The aim of this project is to use Nature as a source of inspiration, and employ biomimetic pericyclic chemistry in the construction of bioactive natural products such as the potent anticancer agent, panduratin A. The biomimetic synthesis can then be further diversified using different precursors to probe structureactivity relationships.

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Deep-Sea Natural Products Our research aims to harness the pharmaceutical potential of natural products from deep-water marine fauna as prospective new anticancer and antiviral agents. Australia’s deep-sea fauna (>100m depth) are unexplored in terms of their natural products chemistry due to the difficulty in accessing samples. Our lab is a member of SERPENT (Scientific & Environmental ROV Partnership using Existing Industrial Technology), an exciting collaboration with the oil and gas industry providing scientists with access to cutting-edge remotely operated vehicle (ROV) technology for deep-sea research (see www.serpentproject.com for more information). Through an ARC Linkage funded project on drilling effects on deep-sea ecosystems, we have access to a range of deep-sea fauna including sponges, anemones, echinoderms and mollusks. These organisms, along with a variety of shallow-water fauna are currently undergoing assessment for their cytotoxic and antiviral activity. We are also interested in carbohydrate-containing marine natural products and method development for their improved isolation and characterisation. Seaweed-Derived Anticancer Agents Sessile marine organisms rely on chemical defence for their survival by producing toxins that target their prey, predators and competitors. This project aims to exploit the pharmaceutical potential of these natural marine toxins as new anticancer agents. In collaboration with researchers from Biological Sciences, a variety of Australian seaweeds will be screened for their cytotoxic activity and ability to inhibit a range of enzymes (kinases, matrix metalloproteinases, etc) implicated in cancer progression. Promising extracts will be separated using bioassay-guided fractionation, purified by chromatography and their structures identified using various spectroscopic experiments. Identifying novel classes of anticancer agents from Australia’s unique marine fauna is an exciting new challenge in the area of anticancer research. Selected publications 1.

Skropeta, D. (2009) The effect of individual N-glycans on enzyme activity. Bioorg. Med. Chem. 17, 2645-2653.

2.

Vine, K.L., Matesic, L., Locke, J. M., Ranson, M., Skropeta, D. (2009) Cytotoxic and anticancer activities of isatin and its derivatives: a comprehensive review from 2000-2008. Anti-Cancer Agents Med. Chem. 9, 397.

3.

Skropeta, D. (2008) Deep-sea natural products. Nat. Prod. Rep. 25, 1131-1166.

4.

Matesic, L., Locke, J. M., Bremner, J. B., Pyne, S. G., Skropeta, D., Ranson, M., Vine, K.L. (2008) N-Phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents. Bioorg. Med. Chem. 16, 3118-3124.

5.

Skropeta, D. Rickards, R.W. (2007) Domino pericyclic reactions of acyclic conjugated (E,Z,E,E)-tetraenes Tetrahedron Lett. 48: 3281-3284.

6.

Skropeta, D., Settasatian, C., McMahon, M.R., Shearston, K.D., Caiazza, D., McGrath, K.C., Jin, W., Rader, D.J., Barter, P.J., Rye, K.-A. (2007) N-glycosylation regulates endothelial lipase-mediated phospholipid hydrolysis in ApoEand ApoA-I-containing high density lipoproteins. J. Lipid Res. 48: 2047-2057.

7.

Sayyadi, N., Skropeta, D., Jolliffe, K.A. (2005) N,O-Isopropylidenated threonines as tools for peptide cyclization: application to the synthesis of mahafacyclin B. Organic Lett. 7, 5497-5499.

8.

Skropeta, D., Jolliffe, K.A., Turner, P. (2004) Pseudoprolines as removable turn inducers: Tools for the cyclization of small peptides. J. Org. Chem. 69: 8804-8809.

9.

Skropeta, D., Schwörer, R., Haag, T., Schmidt, R.R. (2004) Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues. Glycoconjugate J. 21: 205-219.

10.

Guella, G., Skropeta, D., Mancini, I., Pietra, F. (2003) Calenzanane sesquiterpenes from the red seaweed laurencia microcladia from the Bay of Calenzana, Elba Island: Acid-catalyzed, stereospecific conversion of calenzanol into indene- and guaiazulene-type sesquiterpenes. Chem. Eur. J. 9: 5770-5777.

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Dr Adam Trevitt email: [email protected]

Research Interests: (physical chemistry) Not satisfied with conventional instrumentation, our efforts are directed at developing new experimental techniques to probe chemical reactions. Precision laser spectroscopic techniques and mass spectrometry are a powerful combination that we employ to study reactive molecules. We are interested in radical-reactions that occur in the atmosphere, combustion, extraterrestrial bodies and within our own bodies. Project 1:

Single microdroplet laser spectroscopy

A new experiment is under development in the Trevitt Lab. We are combining microdroplet generation with nanosecond laser beams with the goal of understanding—at the molecular level—how biodiesel fuels burn. Biodiesel-type fuels differ significantly from conventional fuels, as shown in the figure below. Their combustion mechanisms are largely unknown. Fig 1: Molecular species typically comprising petroleum-derived diesel (Left): paraffins (i), isoparaffins (ii), alkybenzenes (iii) and naphthenes (iv) and the methyl ester species that are found in soy-derived biodiesel (Right): methyl palmitate (I), methyl oleate (II) and methyl linolenate.

By studying single microdroplets of fuel we have access to the gas-liquid interface and will use a combination of laser fluorescence and Raman spectroscopy to probe the dynamics of burning. We have collaborations with groups in the USA and together we aim to understanding the oxidation and thermal degradation of these new biodiesel fuels. Fig. 2: (Left) Image of a single microdroplet produced from the droplet generator – reactions occurring at the gas/liquid interface are probed in this proposed study.

Project 2:

Laser-induced synthesis of charge-tagged radicals in an ion trap

In collaboration with A/Prof Blanksby we are investigating novel ways to generate charge-tagged radical species in the gas phase. In this project a Nd:YAG laser will be deployed to selectively break chemical bonds leaving behind radical species. Iodinated radical precursors, containing a “charge-tag”, are introduced into an instrument called an ion trap. By virtue of their charge, these ions can be levitated and confined in an ion trap for an essentially unlimited time-period. Next, a single 10-nanosecond light pulse from a UV laser irradiates these trapped ions. This absorption of energy severs the weakest bond, the carbon-iodine bond, and the I atoms break contact leaving behind a charged radical species. The 266 nm

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UV photon has sufficient energy to break only the carbon-iodine bond. The reactivity of the radical site will subsequently be probed with chemical species like oxygen (O2) and ozone (O3). Computational investigations (using Gaussian) are also incorporated into the investigation. This exciting project, combining ion trap mass spectrometry with laser chemistry, project will pave the way for a whole range of biologically and atmospherically relevant radical chemistry studies. Recent update: This laser-based strategy for preparing radicals in the ion trap has been demonstrated successfully. Dedicated students are now needed to develop the technique – new projects are available.

Project 3:

Laser mediated decomposition of peroxyl radicals

The absorption of a photon can induce intriguing chemistry in an isolated molecule. Photochemistry occurs every day in the Earth’s atmosphere dictating ozone depletion, smog formation and aerosol generation. However, there is much to be understood about how molecules respond subsequent to the absorption of a photon. In this project (in collaboration with A/Prof Blanksby), we are looking at the decomposition of gas-phase peroxyl radicals (ROO•) following irradiation by an infrared (IR) laser source. As outlined in the scheme below, a charge-tagged peroxyl radical can absorb an IR photon (hν) and promoted to an excited electronic state. From here, the excited molecule may decompose by ejecting a hydroxy radical (•OH). In this project, gas-phase charge-tagged peroxyl radicals will be confined in an ion trap. Nanosecond pulses IR photons from a laser will irradiate the trapped species and the formation of decomposition products will be probed using mass spectrometry. If •OH radicals are generated from the IR excitation of peroxyl radicals then this will have profound implications for the generation of •OH radicals in the Earth atmosphere.

Selected Publications 1. S. Soorkia, C. A. Taatjes, D. L. Osborn, T. M. Selby, A. J. Trevitt, K. R. Wilson and S. R. Leone, Direct detection of pyridine formation by the reaction of CH (CD) with pyrrole: a ring expansion reaction, Phys. Chem. Chem. Phys. (accepted) (2010). 2. A. J. Trevitt, F. Goulay, C. A. Taatjes, D. L. Osborn and S. R. Leone, Reactions of the CN Radical with Benzene and Toluene: Product Detection and Low-Temperature Kinetics, J. Phys. Chem. A, 114, 1749, (2010). 3. C. A. Taatjes, D. L. Osborn, T. M. Selby, G. Meloni, A. J. Trevitt, E. Epifanivskii, A. I. Krylov, B. Sirjean, E. Dames and H. Wang, Products of the Benzene + O(3P) Reaction, J. Phys. Chem. A, 114, 3355, (2010). 4. S. Soorkia, A. J. Trevitt, T. M. Selby, D. L. Osborn, C. A. Taatjes, K. R. Wilson and S. R. Leone, Reaction of the C2H radical with 1-butyne (C4H6): Low Temperature Kinetics and Isomer-Specific Product Detection, J. Phys. Chem. A, 114, 3340, (2010). 5. A. J. Trevitt, P. J. Wearne and E. J. Bieske, Coalescence of levitated polystyrene microspheres, J. Aerosol Sci. 40 (5), 431-438 (2009).

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Associate Professor S R Wilson e-mail: [email protected]

Atmospheric Chemistry A number of research areas are being currently pursued:

Ultraviolet/ Visible Solar Radiation The measurement of UV-B radiation is important for the assessment of the impact of stratospheric ozone depletion and climate change, as UV-B radiation drives much of atmospheric chemistry. Work at the Cape Grim Baseline Air Pollution Station, Australia’s background atmospheric monitoring station is studying changes in UV photolysis rates with time to quantify changes in the oxidative capacity of the atmosphere. Such changes have been predicted but it is a significant measurement challenge to measure them. There are also studies of the changes in solar radiation with particular emphasis on the impact of aerosol (dust) on the amount of light reaching the earth’s surface, and how this is changing with time. Elsewhere changes have been observed, primarily due to changes in land use and urban pollution. Changes in the clean atmosphere are not well documented. The measurement techniques are also being used to study biomass burning emissions, combining the molecular information available from remote sensing FTIR methods and the aerosol property information provided by visible radiation measurements. Also this work is being extended to identify molecular components in the atmosphere like formaldehyde and BrO. These compounds are difficult to measure by sampling as they are so reactive, and so remote sensing techniques are needed. Isotopic signatures and emission strengths of Greenhouse gases Quantifying the emissions of greenhouse gases is very important for the long-term management of greenhouse gases in the atmosphere. The emissions are often from a wide range of sources and difficult to quantify. We have been working on the use FTIR spectroscopy to determine both the strength of emissions from various sources, and the isotopic signature of the emitted gases. Selected recent publications: 1. 2. 3.

Paton-Walsh, C., L.K. Emmons, and S.R. Wilson, Estimated total emissions of trace gases from the Canberra Wildfires of 2003: a new method using satellite measurements of aerosol optical depth & the MOZART chemical transport model. Atmos. Chem. Phys., 2010. 10(12): p. 5739-5748. Paton-Walsh, C., et al., Trace gas emissions from savanna fires in northern Australia. Journal of Geophysical Research - Atmospheres, 2010. 115: p. D16314. Denmead, O.T., et al., Linking measured carbon dioxide exchange by sugarcane crops and biomass production. Proceedings of the Australian Society for Sugar Cane Technology, 2010. 32: p. 286-292.

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4. 5. 6. 7. 8.

Stavert, A., S.R. Wilson, and D.F. Jolley, Development and application of a system for the analysis of atmospheric, water and sediment nitrogen and carbon. Journal of Environmental Science and Engineering, 2009. 3(9): p. 35 49. Griffith, D., et al., Absolute calibration of the intramolecular site preference of 15N fractionation in tropospheric N2O by FTIR spectroscopy. Analytical Chemistry, 2009. 81(6): p. 2227-2234. Andrady, A., et al., Environmental effects of ozone depletion and its interactions with climate change: Progress report, 2008. Photochemical & Photobiological Sciences, 2009. 8(1): p. 13-22. Wilson, S.R., Relative performance of Ocean Optics USB4000 and StellarNet EPP2000C-14um spectrometers, R.I. Centre, Editor. 2008, Bureau of Meteorology: Melbourne. pp. 10. Wilson, S.R., Assessment of the EPA Review of Shell benzene monitoring for March and April 2005, Victorian EPA,. 2005: Melbourne. pp. 10.

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Dr Haibo Yu

email: [email protected]

Computer Simulation of Complex (Bio)molecular and Nanoscale Systems My research is at the interface between physics, chemistry and biology. The central theme of my research program can be summarized as developing and applying theoretical and computational tools to understand the structure-dynamics-function relationships in complex (bio)molecular and nanoscale systems. Complementary to experimental investigations, such studies can gain new physical insights into the underlying mechanisms and provide necessary knowledge for manipulation in molecular engineering applications and discovery of novel therapeutics. Importantly, my research benefits from close interactions with other groups within and outside UoW. Although ultimately driven by solving important biological and chemical problems, I have designed my research program to balance state-of-the-art methodological development and mechanistic application studies. Development of new theoretical and computational methods allows us to tackle challenging problems beyond the capability of conventional techniques. Currently, the specific research projects include: (1). Development of multi-scale modeling techniques for complex molecular systems: Due to the complexity of biological and chemical systems in both time and spatial scales, the simulation and modeling protocol needs to be both efficient and accurate. We are interested in developing multi-scale modeling techniques to address these challenges from different aspects in order to gain a coherent picture. The method development will include physically motivated coarse-grained models, polarizable force fields, combined quantum mechanical/molecular mechanical methods and advanced free energy calculation methods. (2). Thermodynamics and kinetics in protein-DNA recognition: Protein-nucleic acid interactions are responsible for the regulation of key biological processes such as transcription, translation, replication and recombination. Understanding the basis for protein-nucleic acid interactions requires the full characterization of the thermodynamics and kinetics of their association and dissociation by exploring the relationship between static structure, solution dynamics and biological functions. We are interested in elucidating the role of dynamics in protein-DNA recognition by establishing a structure and energetics based framework through computational analyses. This will help to illuminate the potential for the exploitation in the context of rational design of new drugs that inhibit protein-DNA interactions that underlie pathological conditions. (3). Computational enzymology and rational molecular design: Understanding how enzymes “work” not only is a fundamentally important problem in biology but also promises routes to new drugs for medical applications and

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novel catalysts for industrial applications. Computational enzymology aims at describing the structural and energetic properties along the catalytic cycle and exploring the physiochemical mechanisms underlying the catalytic efficiency, specificity and promiscuity. A better understanding of the molecular mechanisms of biologically or chemically important enzymes will be helpful for discovery of novel and better inhibitors and may also lead to rational design of enzymes with improved or even altered functions. (4). Multiscale modeling and in silico design of functional polymeric systems: This project will take advantage of the methods I have developed for biomolecular simulations to address the mechanistic issues in functional polymers. It is broadly concerned with the links between microscopic structure and macroscopic properties of functional polymeric systems. Through hierarchical modeling techniques that systematically link simulations at various levels of resolution (from coarse-grained models, non-polarizable and polarizable all atom models, to QM/MM), we would like to achieve a thorough understanding of the properties, the processes and the mechanisms at different spatial and time scales and ultimately to in silico rational design of functional polymeric systems with improved performance. Currently, the specific systems of interest include proton exchange membrane for fuel cell and bioinspired materials. Selected Publications 1. Yu, H.B., Mazzanti, C.L., Whitfield, T.W., Koeppe, R.E., Andersen, O.S. and Roux, B. “A combined experimental and theoretical study on ion solvation in liquid N-methylacetamide” Journal of the American Chemical Society 2010, 132, 10847-10856 2. Yu, H.B., Noskov, S. Y. and Roux B. “Hydration number, topological control and ion selectivity” Journal of Physical Chemistry B 2009, 25, 8725-8730 3. Yu, H.B., Yang, Y., Ma, L. and Cui, Q. “Mechanochemical coupling in molecular motors: insights from molecular simulations of the myosin motor domain” Proteins: Energy, Heat and Signal Flow, Eds. Leinter D.M and Straub J.E., CRC Press, 2009 4. Yang, Y., Yu, H.B. and Cui, Q. “Extensive conformational transitions are required to turn on ATP hydrolysis in myosin” Journal of Molecular Biology 2008, 381, 1407-1420

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MAJOR EQUIPMENT NMR Varian Mercury-VX 300 MHz NMR spectrometer with • 1H/19F/31P/13C + 15N 5mm Autoswitchhabe PFG probe • 1H/19F/31P/13C + 15N 5mm PFG 4NUC DM probe Varian Inova 500 MHZ NMR spectrometer with • Triple axis gradients and triple rf channels • Ultra 40 Channel shims • FTS system temperature controller • Triax 5mm 1H/13C/15N Triple Nucleus PFG probe • gHx Nano magic angle spinning probe • DOTY 8mm-1H/13C/15N/19F/27Al/23Na broadband diffusion probe Varian VNMRS 500 MHZ NMR spectrometer with • Dual rf channels • Z pulse-field gradients • 28 Channel shims • Liquid application module • FTS system temperature controller • Pro-tune dual drive module • 1H 15N-31P 5mm PFG AutoX Indirect Detect probe • 1H-19F/15N-31P 5mm PFG AutoX Indirect Detect probe • 15N – 31P[1H] 4mm Broadband indirect Nano probe

Access to • Bruker DMX-600 MHz NMR spectrometer (at UNSW) • Bruker Avance 800 MHz spectrometer (at ANU)

MS Shimadzu QP 5000 GC/MS: EI, pos CI, DI Shimadzu QP 5050A GC/MS: EI, pos/neg CI, DI VG Autospec-oa-TOF high resolution mass spectrometer with EI, CI, DI and MS/MS Micromass M@LDI - MALDI Mass Spectrometer Micromass Platform LCZ: LC / MS Micromass Quattro micro LCZ: LC-MS/MS Micromass Q-TOF-ULTIMA with capillary LC and nanoelectrospray interfaces and extended mass range Thermo Finnigan LTQ: LC/MSn

HPLC / GC Extensive HPLC facilities (11 units, including preparative capillary and microbore units) with a range of detection options (fluorescence, conductivity, uv-visible, refractive index, electrochemical and evaporative light scattering) Pharmacia 2D Gel electro- phoresis equipment Several gas chromatographs

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Computers Modelling computers: • SGI O2's (IRIX 6.5) • SGI Hydrogen's (IRIX 6.5) • 1 SGI Fuel (IRIX 6.5) • 1 Dell PowerEdge 2800 (Linux 2.6) • Sun Ultra20's (Linux 2.6) These computers provide access to Insight II, Catalyst, Spartan, Autodock and Gaussian '03. Grad/Postgrad computing laboratory (12 Dell Desktops with MS Windows XP)\ 3 Dell Precision Workstations (Linux 2.6) for use on NMR spectrometers

AA Varian Spectra. AA 220 Atomic Absorption Spectrometer GA-76 Vapour generation accessory Instrumentation Lab 451 Atomic absorption spectrometer Varian Sequential ICP-OES

Electrochemical Instruments Extensive electrochemical equipment for cyclic voltammetry, differential pulse, and anodic and cathodic stripping studies An Electrochemical Mapping Facility comprising: i.PAR/UniScan Model SVP100-P Scanning Vibrating Reference Electrode System ii. Solartron/UniScan 1275 Localised Electrochemical Impedance (LEIS) System Raman spectrometry Mapping Facility comprising: Lab Raman Infinity Spectrometer (632.8 & 784.8nm) with Confocal Microscope (Jobin Yvon) and PAR Potentiostat/Galvanostat for electrochemical Raman maping. Electrochemical Quartz Crystal Microbalance Jobin Yvon SPEX Fluorolog FL22 Spectrofluorometer (Double gratings on source and emission) Bruker EMX Electron Spin Resonance Spectrometer with an electrochemical head & cryostat. Shimadzu UV MultiSpec 1501 diode array spectrometer (190-800nm, 10Hz sample rate)

UV / VIS / IR / CD / Fluorescence Jobin Yvon CD6 circular dichroism spectrometer Shimadzu UV1601-PC uv-vis Cary500 UV/VIS/NEAR IR spectrophotometer Hitachi F4500 Fluorimeter

Bruker 125 high resolution FTIR spectrometer Bomem MB 100 FTIR spectrometers (5) Nicolet Avatar 360 FTIR spectrometer (3) Shimadzu uv-160 uv-visible spectrophotometer Shimadzu uv-265 uv-visible spectrophotometer

OTHERS Isco Capillary electrophoresis system Rigaku Thermogravimetric analyser Perkin Elmer 241 polarimeter Biorad Biological Protein Purification System Waters and Shimadzu gel permeation chromatography The School’s extensive range of equipment may be utilised by external institutions, agencies and companies interested in the analysis of environmental, biological and industrial samples. For further information and cost estimates, please contact Dr John Korth (ph 4221 3513), Ms Louisa Willdin or Ms Carol Weall (ph 4221 3509).

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