Mechanistic Studies on Biologically Active Iron Chelators. The need for orally effective drugs as alternatives to invasive treatment regimens such as subcutaneous infusion is an ongoing concern in health care. This is particularly true in people suffering iron overload. In many cases this condition is present at birth and thus the administration of vital iron chelation therapy via the oral route is a much preferred option. We have unearthed a novel series of candidates for iron chelation therapy ....Mechanistic Studies on Biologically Active Iron Chelators. The need for orally effective drugs as alternatives to invasive treatment regimens such as subcutaneous infusion is an ongoing concern in health care. This is particularly true in people suffering iron overload. In many cases this condition is present at birth and thus the administration of vital iron chelation therapy via the oral route is a much preferred option. We have unearthed a novel series of candidates for iron chelation therapy (the pyridine-2-carboxaldehyde isonicotinoyl hydrazone [PCIH] analogues) which show oral activity. These chelators undergo some interesting iron catalysed oxidation chemistry and it is vital that the mechanism of this reaction be elucidated to determine whether it will be of biological significance upon administration of these compounds as iron chelators.Read moreRead less
Gas phase studies of the interactions of electrons with peptide ions: structure assignment and fundamentals. Electron-induced reactions are fundamental to a wide range of processes that underlie many areas of science and technology, ranging from planetary atmospheres, industrial plasmas to living tissues. Since ionizing radiation is believed to be a major cause of damage to living cells, understanding electron interactions with biological molecules is essential to predict the consequences of ex ....Gas phase studies of the interactions of electrons with peptide ions: structure assignment and fundamentals. Electron-induced reactions are fundamental to a wide range of processes that underlie many areas of science and technology, ranging from planetary atmospheres, industrial plasmas to living tissues. Since ionizing radiation is believed to be a major cause of damage to living cells, understanding electron interactions with biological molecules is essential to predict the consequences of exposure. Structure determination of biomolecules is at the heart of identifying, diagnosing and potentially developing treatments for diseases, and thus another important reason for studying these interactions is the potential to develop new mass spectrometry based analytical methods.Read moreRead less
NMR Studies of Second Generation Polynuclear Platinum Compounds. Cancer affects one in four Australians and 50% of cancer patients are treated with cisplatin. BBR3464 is a new type of platinum anticancer drug that has shown promise in clinical trials, including results in cancers that do not respond to cisplatin treatment. Second-generation analogues, now under development, may offer significant advantages. This international collaboration between Prof. Berners-Price and the inventor of these ne ....NMR Studies of Second Generation Polynuclear Platinum Compounds. Cancer affects one in four Australians and 50% of cancer patients are treated with cisplatin. BBR3464 is a new type of platinum anticancer drug that has shown promise in clinical trials, including results in cancers that do not respond to cisplatin treatment. Second-generation analogues, now under development, may offer significant advantages. This international collaboration between Prof. Berners-Price and the inventor of these new drugs puts Australian research at the forefront of the clinical development. There is the potential for the generation of new IP from new strategies in the design of improved anticancer drugs. The project builds strong international links and provides international training for Australian PhD students.Read moreRead less
NMR studies on DNA interactions of polynuclear platinum. BBR3464 is representative of a class of structurally unique platinum anticancer drugs, and is currently undergoing clinical trials. The anticancer activity most likely depends on binding to DNA, but the mechanism is different from that of the widely used drug, cisplatin. This project uses NMR spectroscopy to follow in detail the stepwise formation of DNA adducts. Further extension to reactions of polynuclear platinum complexes with sulfur ....NMR studies on DNA interactions of polynuclear platinum. BBR3464 is representative of a class of structurally unique platinum anticancer drugs, and is currently undergoing clinical trials. The anticancer activity most likely depends on binding to DNA, but the mechanism is different from that of the widely used drug, cisplatin. This project uses NMR spectroscopy to follow in detail the stepwise formation of DNA adducts. Further extension to reactions of polynuclear platinum complexes with sulfur nucleophiles will aid in understanding their metabolism and toxicity. The results of this work will aid in the selection of back-up clinical candidates and the design of drugs that target specific sequences of DNA for use in novel gene-based therapies.Read moreRead less
Development of metal probes for the selective recognition of DNA. Transition metal complexes with large aromatic ligands have recently been shown to bind DNA by intercalation. However, controversy continues over their base sequence and groove selectivity. We will synthesise a range of chiral metal complexes and screen these against combinatorial oligonucleotide libraries to determine their base sequence selectivity. The information obtained will help us design better intercalators that can be us ....Development of metal probes for the selective recognition of DNA. Transition metal complexes with large aromatic ligands have recently been shown to bind DNA by intercalation. However, controversy continues over their base sequence and groove selectivity. We will synthesise a range of chiral metal complexes and screen these against combinatorial oligonucleotide libraries to determine their base sequence selectivity. The information obtained will help us design better intercalators that can be used as sensitive molecular probes and may find application as antitumour drugs. Binding interaction between the complex and DNA will be studied by NMR spectroscopy.Read moreRead less
Simulation of ligand binding-induced conformational changes in biological systems. This project is focused on the development of a methodology that will allow using molecular dynamics simulations to study fundamental biochemical reactions. The benefits to the Australian community are two fold: i) the software developed will be made available to the whole scientific community through peer-reviewed publication. Australian researchers will have the possibility to exploit the software in advance thr ....Simulation of ligand binding-induced conformational changes in biological systems. This project is focused on the development of a methodology that will allow using molecular dynamics simulations to study fundamental biochemical reactions. The benefits to the Australian community are two fold: i) the software developed will be made available to the whole scientific community through peer-reviewed publication. Australian researchers will have the possibility to exploit the software in advance through collaborations with our research group. ii) During this collaboration Australian PhD students will have the opportunity to spend a few months overseas to learn about the most advanced computational techniques and interact with top researchers in the computational chemistry field.Read moreRead less
A reliable physical model of molecular motion in crystals. The scientific benefits would flow, in the first instance, to the large national and international communities of scientists whose research makes use of the results of X-ray diffraction experiments. Applications of the research to amino acids and peptides will benefit investigations into the structure and molecular dynamics of biological systems, including proteins and enzymes. Studies of charge densities in crystals will obtain a standa ....A reliable physical model of molecular motion in crystals. The scientific benefits would flow, in the first instance, to the large national and international communities of scientists whose research makes use of the results of X-ray diffraction experiments. Applications of the research to amino acids and peptides will benefit investigations into the structure and molecular dynamics of biological systems, including proteins and enzymes. Studies of charge densities in crystals will obtain a standard tool for improved modelling of molecular motion, resulting in physically more realistic charge density functions, and hence greater insight into the relationship between properties of crystals and their constituent molecules.Read moreRead less
New Membrane Methods to Extract Lactose From Waste Dairy Streams. Dairy processors throughout the world produce about 145,000,000 t of liquid whey per year. Lactose, the principle component in cheese whey, contributes a significant pollution problem for dairy processors. The aim of this Linkage Award application is to develop membranes that selectively extract the lactose. This requires the preparation of membrane carriers that transport the lactose through the membrane. The development of new a ....New Membrane Methods to Extract Lactose From Waste Dairy Streams. Dairy processors throughout the world produce about 145,000,000 t of liquid whey per year. Lactose, the principle component in cheese whey, contributes a significant pollution problem for dairy processors. The aim of this Linkage Award application is to develop membranes that selectively extract the lactose. This requires the preparation of membrane carriers that transport the lactose through the membrane. The development of new approaches and technologies for the isolation and purification of lactose from feed streams may lead to improved processes for manufacture of purified lactose or new lactose products.Read moreRead less
Electrochemistry of redox-active non-metal compounds. Unsaturated compounds of heavier non-metal elements can exist in multiple stable redox states. The interconversion is best assessed by electrochemical techniques, which can measure the energetics and the mechanism of the redox processes involved in both solution and solid state phases. Compounds to be studied will be prepared in the Canadian laboratories of the partner investigator. The electrochemical and spectroelectrochemical properties ....Electrochemistry of redox-active non-metal compounds. Unsaturated compounds of heavier non-metal elements can exist in multiple stable redox states. The interconversion is best assessed by electrochemical techniques, which can measure the energetics and the mechanism of the redox processes involved in both solution and solid state phases. Compounds to be studied will be prepared in the Canadian laboratories of the partner investigator. The electrochemical and spectroelectrochemical properties will initially be investigated in Australia during the visit of the partner investigator to Monash University with follow up studies in both countries. The mutual skills of synthesis and electrochemistry in the Canadian-Australian laboratories are essential to the project.Read moreRead less
New Synthetic Routes to the Immobilisation of Mixed Valence Transition Metal Complexes on Conducting Metal Oxides. Highly coloured, electrochemically active transition metal dyes may find application electrochromic devices, where they may switch between contrasting coloured forms through a simple redox reaction. A prerequisite is that the dye be immobilised onto a solid conducting support whilst preserving the electrochemical and optical properties of the dye found in solution. This project tack ....New Synthetic Routes to the Immobilisation of Mixed Valence Transition Metal Complexes on Conducting Metal Oxides. Highly coloured, electrochemically active transition metal dyes may find application electrochromic devices, where they may switch between contrasting coloured forms through a simple redox reaction. A prerequisite is that the dye be immobilised onto a solid conducting support whilst preserving the electrochemical and optical properties of the dye found in solution. This project tackles this problem through a combination of organic and inorganic synthesis to develop new electrochromic dyes that may be attached to mesoporous titania.Read moreRead less