Development Of Iron Complexes For The Treatment Of FriedreichÍs Ataxia & The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$616,143.00
Summary
Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal c ....Friedreich's ataxia (FA) is a neuro- & cardio-degenerative disease where there is an accumulation of toxic iron (Fe) in the mitochondrion. Work from our current NHMRC grant showed iron plays a significant role in FA pathology In fact, the CIs dissected the mechanisms of mitochondrial iron-loading & have published 8 papers in high impact journals with 3 papers in PNAS USA in the last 2 yrs Understanding of this process has led to the design of rationalised drugs for FA This work in this Renewal could lead to novel therapies for FARead moreRead less
Examination Of The Molecular Pharmacology Of Anthracyclines Induced Via Their Interaction With Iron
Funder
National Health and Medical Research Council
Funding Amount
$618,401.00
Summary
Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and ....Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.Read moreRead less
Investigating The Cellular Response To Iron-Depletion: The Trilogy Of ASK1, Thioredoxin And Ribonucleotide Reductase
Funder
National Health and Medical Research Council
Funding Amount
$552,572.00
Summary
Iron is crucial for many essential biological processes. Recently, we demonstrated that iron-depletion can affects important signalling pathways (e.g., JNK and p38) that play important roles in growth arrest and apoptosis. This study is designed to investigate the cellular and molecular effects of iron depletion which currently remains unclear. The research is crucial for understanding: (1) the effects of iron deficiency and (2) for understanding the effects of iron chelators that are used for t ....Iron is crucial for many essential biological processes. Recently, we demonstrated that iron-depletion can affects important signalling pathways (e.g., JNK and p38) that play important roles in growth arrest and apoptosis. This study is designed to investigate the cellular and molecular effects of iron depletion which currently remains unclear. The research is crucial for understanding: (1) the effects of iron deficiency and (2) for understanding the effects of iron chelators that are used for treating various diseases.Read moreRead less
Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Asymmetric Synthesis of Chiral Phosphines, Arsines, and Stibines. There are now chiral phosphine-transition metal catalysts that rival enzymes in their efficiency for the asymmetric synthesis of important chiral drugs, fragrants, cosmetics, nutrients, vitamins, and pesticides. This project is aimed at a generalised asymmetric synthesis of the critical components of these enzyme mimics, notably enantiopure chiral phosphines, but also chiral arsines and stibines, by a highly innovative approach t ....Asymmetric Synthesis of Chiral Phosphines, Arsines, and Stibines. There are now chiral phosphine-transition metal catalysts that rival enzymes in their efficiency for the asymmetric synthesis of important chiral drugs, fragrants, cosmetics, nutrients, vitamins, and pesticides. This project is aimed at a generalised asymmetric synthesis of the critical components of these enzyme mimics, notably enantiopure chiral phosphines, but also chiral arsines and stibines, by a highly innovative approach that involves novel six-electron phosphenium, arsenium, and stibinium cations that are themselves stabilised by chiral phosphines so that chemical breeder reactions are possible. The use of chiral auxiliaries from the natural pool and from biotechnology will also be investigated.Read moreRead less
Unlocking the diverse property profile of ultra-lightweight magnesium alloys. This project aims to develop the theory behind why micro alloying contributes to the formation of surface film properties. The exemplar is a prototype Magnesium-Lithium (Mg-Li) base alloy, with high specific-strength and corrosion resistance. This project will lead to the development of a new processable ultra-lightweight, corrosion resistant Mg-Li alloy family that is stronger than the prototype alloy, and with, at le ....Unlocking the diverse property profile of ultra-lightweight magnesium alloys. This project aims to develop the theory behind why micro alloying contributes to the formation of surface film properties. The exemplar is a prototype Magnesium-Lithium (Mg-Li) base alloy, with high specific-strength and corrosion resistance. This project will lead to the development of a new processable ultra-lightweight, corrosion resistant Mg-Li alloy family that is stronger than the prototype alloy, and with, at least, comparable ductility and corrosion resistance. Not only will the outcomes of the work be a fundamental advance to the fields of metallurgy and corrosion science, they will lead to the identification of an optimised compositional window for creating our second generation Mg-Li alloy family capable of being manufactured into ultra-lightweight, corrosion resistant metal products.Read moreRead less
Quantum-chemical design of stereoregular polyphosphines for nanowires. In this project we will be designing and producing stereoregular polyphosphines that can self-assemble gold and silver complexes that mimic the molecular architectures of DNA and certain proteins. The longer gold complexes will behave as insulated nanowires, and are an exciting prospect for the development of nanotechnological devices. The shorter silver and gold complexes are expected to have significant antitumour propertie ....Quantum-chemical design of stereoregular polyphosphines for nanowires. In this project we will be designing and producing stereoregular polyphosphines that can self-assemble gold and silver complexes that mimic the molecular architectures of DNA and certain proteins. The longer gold complexes will behave as insulated nanowires, and are an exciting prospect for the development of nanotechnological devices. The shorter silver and gold complexes are expected to have significant antitumour properties. This project, which will use a unique theoretical-experimental approach to design the stereoregular polyphosphines, will enhance Australia's international scientific reputation, and will contribute to technological advancement in the national priority areas of nanotechnology and biotechnology.Read moreRead less
Towards Nano-circuits: 2 and 3-Dimensional Carbon-Wired Nano-architectures. Whilst Australia has a world-class profile in organotransition metal chemistry, main-group chemistry is under-represented, despite the enormous technological importance of materials based on these elements. In addition to the fundamental breakthrough science to be explored, the project will provide a training vehicle for 5 young scientists in both main group and organometallic chemistry. The target compounds involve an e ....Towards Nano-circuits: 2 and 3-Dimensional Carbon-Wired Nano-architectures. Whilst Australia has a world-class profile in organotransition metal chemistry, main-group chemistry is under-represented, despite the enormous technological importance of materials based on these elements. In addition to the fundamental breakthrough science to be explored, the project will provide a training vehicle for 5 young scientists in both main group and organometallic chemistry. The target compounds involve an essentially unique marriage of the fields of main-group and transition metal chemistry to provide complex nano-architectures based on the modular interconnection of metals and non-metals by carbon wires at the molecular level - nanoscopic counterparts of macroscopic circuit components.Read moreRead less
Understanding and Harnessing the Unique and Curious Metal Boron Bond: Unlocking the Metallaboratrane Cage. Metal-boron bonding holds enormous technological importance due to the emergence of boron-based metal-mediated synthetic transformations that access a diversity of high value-added fine chemicals. Whilst Australia boasts an emergent boron-based fine chemicals industry, no research program into the nature of metal boron bonding exists to provide either fundamental science or advanced trainin ....Understanding and Harnessing the Unique and Curious Metal Boron Bond: Unlocking the Metallaboratrane Cage. Metal-boron bonding holds enormous technological importance due to the emergence of boron-based metal-mediated synthetic transformations that access a diversity of high value-added fine chemicals. Whilst Australia boasts an emergent boron-based fine chemicals industry, no research program into the nature of metal boron bonding exists to provide either fundamental science or advanced training in organometallic boron chemistry. The proposed work offers two distinct national benefits: The maintenance of a discipline in which Australia leads the world (metallaboratranes) and the genesis of one, which whilst intensely studied elsewhere, is notably absent from the Australian science base (low coordinate, unsaturated boron chemistry).Read moreRead less