Chelators for Iron(III) for Therapeutic Uses and Probing Cellular Iron Transport

用于治疗用途和探测细胞铁转运的铁 (III) 螯合剂

• 批准号: 8079471
• 负责人: ARAVAMUDAN S GOPALAN
• 金额: $ 10.86万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079471
• 关键词: Address; Amino Acids; Area; Assimilations; Bacterial Infections; Behavior; Binding; Biochemistry; Biological; Biological Assay; Blood Transfusion; Cations; Cell physiology; Cells; Chelating Agents; Chemistry; Citrates; Citric Acid; Clinical; Collaborations; Coupled; Coupling; Deferoxamine; Development; Development Plans; Diagnostic; Disadvantaged; Disease; Edetic Acid; Generations; Goals; Grant; Growth; Head; Hydrophobicity; Hydroxamic Acids; Investigation; Iron; Iron Chelation; Iron Overload; Knowledge; Lead; Learning; Life; Ligands; Literature; Mediating; Metal Ion Binding; Metals; Methodology; Methods; Molecular; Mycobacterium tuberculosis; Organism; Patients; Phase; Process; Public Health; Reaction; Research; Route; Scientist; Siderophores; Solid; Structure; System; Thalassemia; Therapeutic; Therapeutic Uses; Time; Treatment Efficacy; Universities; Variant; Vertebral column; Virulence; Work; acinetoferrin; base; beta Thalassemia; cancer therapy; chelation; clinical application; combat; design; driving force; drug discovery; experience; flexibility; hydroxamate; improved; in vivo; insight; interest; lipophilicity; microorganism; monomer; novel; professor; programs; uptake

DESCRIPTION (provided by applicant): Patients suffering from ¿-thalassaemia must receive blood transfusions throughout their life and hence have a problem of excess iron in their bodies. In vivo clearance of the excess iron by selective chelation is a must for patient survival and the current treatment regimes with desferrioxamine B have serious limitations. The search must continue to generate a new generation of iron selective chelators that are better suited for clinical use. The use of iron chelators for the treatment of cancer has also sparked a great interest in the molecular mechanisms of iron uptake by the cells. It is very clear that iron depletion can have serious impact in several cellular processes. Also, iron is essential to the growth of all organisms. An understanding of the mechanism governing siderophore mediated iron transport and release in microorganisms (iron transport and iron assimilation) would allow one to manipulate fundamental processes essential to their growth. This in turn will allow the design of a new generation of therapeutics to control the virulence of such important bacterial diseases such as TB (caused by mycobacterium tuberculosis.) The PI and his group have been involved for some time in the development of selective chelators for trivalent cations of biomedical interest (particularly iron) for diagnostic and therapeutic applications. The Aim 1 of this project is to capitalize on our previous results and develop a more efficient and direct/convergent solid phase synthetic route that could rapidly generate chiral tris-hydroxypyridinones (HOPO), tris- hydroxamates and mixed ligands having both HOPO and hydroxamic acid ligands on the backbone. The ligands will be evaluated for their iron selective binding by a number of methods including competitive exchange reactions with EDTA and in collaboration with scientists at Duke University. A perusal of the current literature reveals that the iron complexation abilities (advantages and disadvantages) of mixed ligand systems present in several siderophores has not been widely studied. In Aim 2, we plan to prepare chelating systems that have a variety of ligands including citrate, hydroxamic acid and HOPO in their backbone and to systematically evaluate the effect of structural variation on metal ion binding. We hypothesize this project will allow us to get some new leads for selective iron chelators. Further, our synthetic approach allows us to vary the lipophilicity/hydrophobicity of the chelator, a key factor in biological activity. Useful iron chelators with probes that can provide mechanistic insight on the transport and release of iron in microorganisms will also be a target of our investigation. The driving force for this study is to generate a new generation of therapeutics that can have applications in iron overload diseases, combating bacterial diseases such as TB and give new leads for the treatment of cancer. The proposed work can have a significant positive impact on public health.

描述(申请人提供)：地中海贫血症患者终生必须接受输血，因此存在体内铁过多的问题。在体内，通过选择性螯合清除多余的铁是患者生存所必需的，目前使用去铁胺B的治疗方案有严重的局限性。这项研究必须继续产生更适合临床使用的新一代铁选择性螯合剂。使用铁络合剂治疗癌症也引起了人们对细胞摄取铁的分子机制的极大兴趣。很明显，铁的枯竭会在几个细胞过程中产生严重的影响。此外，铁对所有有机体的生长都是必不可少的。了解铁载体介导的铁在微生物中的运输和释放机制(铁的运输和铁的同化)将使人们能够操纵对微生物生长至关重要的基本过程。这反过来将允许设计新一代疗法来控制诸如结核病(由结核分枝杆菌引起)等重要细菌疾病的毒力。 PI和他的团队已经参与了一段时间的选择性螯合剂的开发，用于生物医学感兴趣的三价阳离子(特别是铁)的诊断和治疗应用。本项目的目标一是利用我们以前的研究成果，开发一条更高效、更直接/更收敛的固相合成路线，可以快速合成手性三羟基吡啶酮(HOPO)、三羟基甲酸酯以及主链上既有HOPO又有异羟肟酸配体的混合配体。这些配体将通过多种方法进行铁选择性结合的评估，包括与EDTA的竞争性交换反应，以及与杜克大学的科学家合作。 对当前文献的研究表明，存在于几个铁载体中的混合配体系统的铁络合能力(优点和缺点)尚未得到广泛的研究。在目标2中，我们计划制备主链上含有柠檬酸、异羟肟酸和HOPO等多种配体的螯合体系，并系统地评价结构变化对金属离子结合的影响。我们假设这个项目将使我们在选择性铁络合剂方面获得一些新的线索。此外，我们的合成方法允许我们改变螯合剂的亲脂性/疏水性，这是生物活性的关键因素。具有探针的有用的铁络合剂也将是我们研究的目标，这些探针可以从机制上洞察铁在微生物中的运输和释放。 这项研究的动力是产生新一代疗法，这些疗法可以应用于铁超载疾病，对抗结核病等细菌疾病，并为癌症的治疗提供新的线索。拟议的工作可以对公共卫生产生重大的积极影响。