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（由应用提供）：患有thalassaemia的患者必须一生都会接受输血，因此身体中铁的过量问题。通过选择性螯合对过量铁的体内清除是患者生存的必要条件，而当前具有desferrioxamine B的治疗方案具有严重的局限性。该搜索必须继续生成新一代的铁选择性螯合剂，这些螯合剂更适合临床使用。铁螯合剂用于治疗癌症也引起了细胞摄取铁摄取的分子机制的极大兴趣。很明显，铁部署在几个细胞过程中可能会严重影响。同样，铁对于所有生物的生长至关重要。了解辅助铁载体介导的铁运输和微生物中释放的机制（铁运输和铁同化）将使人们能够操纵其生长必不可少的基本过程。反过来，这将使新一代治疗剂的设计能够控制这种重要细菌疾病（例如结核分枝杆菌引起的）病毒。 PI和他的小组已经参与了一段时间，用于开发用于生物医学有趣（部分铁）的选择性螯合剂，用于诊断和治疗应用。该项目的目的1是利用我们以前的结果，并开发出更高效，更直接/收敛的固相合成途径，该途径可以快速产生手性的Tris Tris-Hydroxypyridinones（Hopo），Tris-Hydroxamates和混合配体，具有Hopo和Hopo和Hopo和氢糖酸的混合物。通过多种方法，包括与EDTA的竞争交流反应以及与杜克大学的科学家合作的多种方法，对配体的铁选择性结合进行了评估。 对当前文献的细读表明，在几个铁载体中存在的混合配体系统的铁络合能力（优势和灾难）尚未被广泛研究。在AIM 2中，我们计划准备具有多种配体的螯合系统，其中包括柠檬酸盐，羟氨基酸和霍普科的骨架，并系统地评估结构变异对金属离子结合的影响。我们假设这个项目将使我们能够为选择性铁螯合剂获得一些新的潜在客户。此外，我们的合成方法使我们能够改变螯合剂的亲脂性/疏水性，这是生物活性的关键因素。有用的铁螯合剂具有可以为微生物中铁运输和释放提供机械洞察力的问题，这也将是我们研究的目标。 这项研究的推动力是产生新一代的理论，该理论可以在铁超负荷疾病中应用，与TB等细菌疾病作斗争，并为治疗癌症提供新的潜在客户。拟议的工作可能会对公共卫生产生重大积极影响。