Synthesis of new classes of metal ion chelators for therapeutic applications

用于治疗应用的新型金属离子螯合剂的合成

• 批准号: 8475264
• 负责人: ARAVAMUDAN S GOPALAN
• 金额: $ 10.95万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475264
• 关键词: Adamantane; Amaze; Anthrax disease; Area; Bacillus anthracis; Bacteria; Bacterial Infections; Binding; Biochemical; Biological; Biology; Biotin; Breathing; Cancer Center; Catechols; Charge; Chelating Agents; Chemicals; Chemistry; Collaborations; Complex; Disease; Evaluation; Evolution; Fred Hutchinson Cancer Research Center; Goals; Growth; Human; Immune; Immune system; Infection; Ions; Iron; Iron Chelation; Iron Overload; Knowledge; Ligands; Ligation; Malignant Neoplasms; Metals; Modeling; Modification; Mono-S; Mycobacterium tuberculosis; Organic Synthesis; Organism; Pattern; Pharmaceutical Preparations; Play; Positioning Attribute; Proteins; Public Health; Role; Siderophores; Site; Solubility; Staging; Structure; Support System; System; Thalassemia; Therapeutic; Therapeutic Agents; Variant; Viral; Virulence; Work; analog; bacillibactin; base; design; drug development; in vivo; interdisciplinary approach; interest; lipophilicity; meetings; pathogen; pathogenic bacteria; petrobactin; prevent; public health relevance; response; scaffold; therapeutic development; trait

DESCRIPTION (provided by applicant): A common feature in most of the natural siderophores is that they are polydentate ligands, capable of binding iron (III) strongly, to give an octahedral 1:1 complex. Iron chelation has been implicated as an important biochemical factor in many diseases ranging from ¿-thalassemia to bacterial infections and cancer. Given this finding, it is surprising and disappointing that very few therapeutic agents that take their inspiration from the structural motifs of natural siderophores have emerged. It is our goal to show that existing siderophores can offer viable templates for the development of therapeutic drugs for iron overload diseases and also bacterial infections caused by M.tuberculosis (TB) and B.anthracis (anthrax). For this study, petrobactin, PB, a siderophore produced by B. anthracis as the siderophore model has been chosen. This organism relies on two siderophores bacillibactin, BB, and PB, to acquire iron from its human host. The human immune protein siderocalin, Scn, is able to recognize and bind BB but not PB. Hence PB has been called a stealth siderophore. In the first aim, a variety of achiral catechol/hydroxypyridinone analogs of PB will be synthesized with the goal of elucidating the importance of the specific ligand, position of the ligand atoms and substitution patterns in the aromatic/heterocyclic ring in iron binding and Scn interactions. The Scn binding studies will be done in collaboration with Dr. Roland Strong of Fred Hutchinson Cancer Research Center, Seattle, an expert in this area. The second aim of this project is to investigate the role of chirality in iron transport of PB as well as its interacions with Scn. Although PB is achiral, we propose to synthesize structurally related chiral analogs carrying chiral hydroxypyridinone- catechol mixed ligands. Chirality is usually not a consideration in the design of therapeutic agents for clearance of excess iron from the body. However it can play a major role in the transport of iron in bacterial systems and supporting its virulence. During this study, bifunctional catechol and hydroxypyridinone ligands that can be incorporated into the original PB structure will be developed. The use of bifunctional ligand units allows the introduction of desired markers/probes onto the chelator scaffold at the final stage of synthesis. The third aim of this proposal is to develop the use of two different conjugating strategies, the traceless Staudinger ligation and sulfo-click chemistry, to tether probes, ligands and other entities of interest to PB and analogs. These conjugates can be then used as mechanistic probes to study iron transport or even as potential vehicles to deliver desired drugs into the organism.

描述（由适用提供）：在大多数天然辅助载体中，它们的一个共同特征是它们是能够强烈结合铁（III）的多脱牙配体，具有八面体1：1复合物。铁螯合已被暗示为许多疾病的重要生化因素，从thalassymia到细菌感染和癌症。鉴于这一发现，令人惊讶和令人失望的是，很少有从天然铁载体的结构图案中汲取灵感的治疗剂。我们的目的是表明现有的铁载体可以为铁超载疾病的治疗药物提供可行的模板，以及由大麻菌（TB）引起的细菌感染（TB）和hanthracis（炭疽病）。在这项研究中，选择了炭疽芽孢杆菌产生的铁载体petrobactin，pb，作为铁载体模型。这种生物依靠两个铁载体杆菌杆菌，BB和PB从其人类宿主那里获取铁。人类免疫蛋白SIDEROCALIN SCN能够识别和结合BB，但不能结合Pb。因此，PB被称为隐形终极载体。在第一个目的中，将合成各种PB的儿童儿茶酚/羟基吡啶酮类似物，以阐明特定配体的重要性，位置的目标 铁结合和 SCN相互作用。 SCN结合研究将与该领域的专家西雅图的Fred Hutchinson癌症研究中心的Roland Strong博士合作。该项目的第二个目的是研究手性在PB铁运输中的作用及其与SCN的相互作用。尽管Pb是Achiral的，但我们建议合成带有手性羟基苯二酚 - 儿茶酚混合配体的结构相关的手性类似物。在理论剂的设计中，手性通常不是从身体中清除过量铁的设计。但是，它可以在细菌系统中铁的运输中发挥重要作用并支持其病毒。在这项研究中，将开发可掺入原始PB结构的双功能儿茶酚和羟基吡啶酮配体。双功能配体单元的使用 允许在合成的最后阶段将所需的标记/探针引入螯合剂支架上。该提案的第三个目的是开发使用两种不同的共轭策略，即无可及的Staudinger连接和硫酸单击的化学，用于束缚探针，配体和其他感兴趣的PB和类似物实体。然后，这些结合物可以用作研究铁运输的机械问题，甚至可以用作将所需药物输送到生物体中的潜在车辆。