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
Dinuclear Ruthenium Complexes as Sequence- and Structure-Selective Binding Agents for DNA. Studies of the interaction of mononuclear metal complexes with DNA have greatly increased our understanding of the ways that small molecules recognise particular sites on DNA. However, in order to design drugs that target specific genes, and hence be potentially capable of controlling gene expression, it is necessary to study the binding of metal complexes that can associate with larger segments of DNA. ....Dinuclear Ruthenium Complexes as Sequence- and Structure-Selective Binding Agents for DNA. Studies of the interaction of mononuclear metal complexes with DNA have greatly increased our understanding of the ways that small molecules recognise particular sites on DNA. However, in order to design drugs that target specific genes, and hence be potentially capable of controlling gene expression, it is necessary to study the binding of metal complexes that can associate with larger segments of DNA. Using the combined expertise of the applicants, it is proposed to stereospecifically synthesise dinuclear complexes and study their DNA binding. This will greatly assist in the development of drugs that can selectively target genes and altered DNA.Read moreRead less
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
Spotlighting biologically active Iron (Fe) chelators within cells. Anti-cancer drugs that act in ways different from traditional chemotherapeutics offer hope in evading acquired drug resistance. Previously we have studied compounds that can enter cancer cells, bind iron and halt cellular proliferation. However, there are many sources of iron in cells and we do not know from where these iron chelators acquire their iron or how these iron complexes kill cancer cells. We will tackle this problem by ....Spotlighting biologically active Iron (Fe) chelators within cells. Anti-cancer drugs that act in ways different from traditional chemotherapeutics offer hope in evading acquired drug resistance. Previously we have studied compounds that can enter cancer cells, bind iron and halt cellular proliferation. However, there are many sources of iron in cells and we do not know from where these iron chelators acquire their iron or how these iron complexes kill cancer cells. We will tackle this problem by attaching light emitting probes to known iron chelators and mapping their location within cells with high resolution fluorescence microscopy. These experiments will spotlight the cellular location of these potential drugs bound to iron for the first time, providing crucial information on their mode of action.Read moreRead less
Intervalence Transfer in Dinuclear and Oligonuclear Polymetallic Assemblies. Mixed-valence compounds (such as the pigment Prussian Blue) have been known for over two centuries, and possess important conductivity, magnetic and spectral properties. Electron transfer between the elements of different valency (intervalence charge transfer, IVCT) gives rise to absorbances in the red or near-infrared region of the spectrum which provide fundamental information on the electron migration. By design of ....Intervalence Transfer in Dinuclear and Oligonuclear Polymetallic Assemblies. Mixed-valence compounds (such as the pigment Prussian Blue) have been known for over two centuries, and possess important conductivity, magnetic and spectral properties. Electron transfer between the elements of different valency (intervalence charge transfer, IVCT) gives rise to absorbances in the red or near-infrared region of the spectrum which provide fundamental information on the electron migration. By design of target di- and higher nuclearity polymetallic species, the project will study IVCT phenomena to understand electron movement, allowing rational development of applicable materials such as catalysts, light-activated devices and non-linear optical materials.Read moreRead less
E-Cadherin Endocytosis In Morphogenesis: Recycling And Growth Factor Induced Uptake.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell ....E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell surface E-cadherin serves to regulate its role in adhesion. More recently, we and others have shown that E-cadherin is endocytosed in response to growth factors, in conjunction with the activated growth factor receptors themselves. E-cadherin can influence the trafficking and signaling of these receptor tyrosine kinases. This joint endocytosis is an elegant mechanism for the simultaneous downregulation of cell adhesion and activation of signaling for cell growth and motility. The growth and differentiation of epithelial cells during tissue patterning or morphogenesis relies critically on these endocytic pathways. Our research is aimed at defining the endosomes and cellular machinery involved in E-cadherin-receptor endocytosis, moreover we will pursue initial findings suggesting that there are different pathways and fates for E-cadherin endocytosed at the behest of different growth factors. We will study endocytosis during the processes of epithelial cyst formation and tubulation of cysts as an in vitro model for mammalian morphogenesis. These studies will provide important and novel information for understanding the roles of E-cadherin in adhesion and in growth factor signaling during epithelial morphogenesis. Ultimately these findings will be of relevance to epithelial development and the prevention of cancer.Read moreRead less
Development of New Materials Based on Multinuclear Ruthenium Complexes. The program aims to design new materials for use in applications such as catalysis and light-activated devices (including light harvesting or solar energy conversion), for the detection and analysis of specific small molecules and anions of particular interest, and to provide an insight to the operation of biological systems such as metal-containing enzymes. The particular molecules will also be investigated for the developm ....Development of New Materials Based on Multinuclear Ruthenium Complexes. The program aims to design new materials for use in applications such as catalysis and light-activated devices (including light harvesting or solar energy conversion), for the detection and analysis of specific small molecules and anions of particular interest, and to provide an insight to the operation of biological systems such as metal-containing enzymes. The particular molecules will also be investigated for the development of a new type of therapeutic agent for the treatment of a range of diseases, with a particular interest in this work on a drug for the treatment of HIV-AIDS. Read moreRead less
Recycling Endosomes Governing Cell Polarity And Cytokine Secretion.
Funder
National Health and Medical Research Council
Funding Amount
$958,412.00
Summary
Cytokines are chemical messengers released by cells to mount inflammatory responses to fight infections. The timing and direction of cytokine release must be tightly regulated. We investigate the cellular compartments and molecules that control cytokine secretion using sophisticated live cell imaging. Uncontrolled cytokine release is the main cause of ongoing inflammation in arthritis and inflammatory bowel disease and our studies aim to identify cellular targets for new drug development.
The fate of copper in atom transfer radical reactions. Copper (Cu) complexes of poly-amine ligands have emerged as extremely active homogeneous catalysts in atom transfer radical reactions, forming organic radicals from alkyl halide precursors, and they are now employed extensively in polymer and organic chemistry. The catalyst cycles between its Cu(I) and Cu(II) oxidation states reversibly yet both forms are susceptible to side reactions, particularly with solvents which can lead to loss of cat ....The fate of copper in atom transfer radical reactions. Copper (Cu) complexes of poly-amine ligands have emerged as extremely active homogeneous catalysts in atom transfer radical reactions, forming organic radicals from alkyl halide precursors, and they are now employed extensively in polymer and organic chemistry. The catalyst cycles between its Cu(I) and Cu(II) oxidation states reversibly yet both forms are susceptible to side reactions, particularly with solvents which can lead to loss of catalytic activity. This project aims to apply a multifaceted approach to interrogate the catalysts in both their Cu(I) and Cu(II) oxidation states and identify for the first time the pathways that lead to undesirable side reactions and provide new ways of optimising catalyst performance.Read moreRead less
Chemical and Biochemical Characterisation of Novel Iron Chelators with Therapeutic Potential. Resistance by cancers to established chemotherapeutics is a growing problem in the community and one that demands the development of new strategies. Chelators that target the essential element iron within cancer cells represent a novel and promising approach to this problem. The Chief Investigators represent a unique combination of expertise in coordination chemistry and the biochemistry of iron chelati ....Chemical and Biochemical Characterisation of Novel Iron Chelators with Therapeutic Potential. Resistance by cancers to established chemotherapeutics is a growing problem in the community and one that demands the development of new strategies. Chelators that target the essential element iron within cancer cells represent a novel and promising approach to this problem. The Chief Investigators represent a unique combination of expertise in coordination chemistry and the biochemistry of iron chelation. They have discovered and characterised new chelators that show marked anticancer activity, and act by a new mechanism that overcomes problems of resistance. In this project they will pursue a course that will lead to a greater understanding of how these compounds work with the outcome that new effective anticancer drugs may emerge.Read moreRead less