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（由申请人提供）：大多数天然铁载体的共同特征是它们是多齿配体，能够强烈结合铁（III），产生八面体1：1络合物。铁螯合作用被认为是从地中海贫血到细菌感染和癌症等许多疾病的重要生化因素。鉴于这一发现，令人惊讶和失望的是，很少有从天然铁载体的结构基序中获得灵感的治疗剂已经出现。我们的目标是表明现有的铁载体可以为开发用于铁过载疾病以及由结核分枝杆菌（TB）和B.anthracis（炭疽）引起的细菌感染的治疗药物提供可行的模板。对于这项研究，petrobactin，PB，一种由B产生的铁载体。选择炭疽菌作为铁载体模型。这种生物体依赖于两种铁载体bacillibactin，BB和PB，从其人类宿主获得铁。人免疫蛋白铁黄素Scn能够识别和结合BB，但不能识别和结合PB。因此，PB被称为隐形铁载体。 在第一个目标中，将合成PB的各种非手性儿茶酚/羟基吡啶酮类似物，目的是阐明特定配体的重要性，位置 在铁结合中的芳族/杂环中的配体原子和取代模式， Scn相互作用。Scn结合研究将与西雅图弗雷德哈钦森癌症研究中心的罗兰斯特朗博士合作进行，他是该领域的专家。本项目的第二个目的是研究手性在PB铁转运中的作用及其与Scn的相互作用。虽然PB是非手性的，我们建议合成结构相关的手性类似物携带手性羟基吡啶酮-邻苯二酚混合配体。在设计用于从体内清除过量铁的治疗剂时，手性通常不是考虑因素。然而，它可以在细菌系统中运输铁并支持其毒力方面发挥重要作用。在这项研究中，双功能儿茶酚和羟基吡啶酮配体，可以纳入到原来的PB结构将被开发。双官能配体单元的使用 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。该提议的第三个目的是开发两种不同的缀合策略（无痕施陶丁格连接和磺基点击化学）的用途，以将探针、配体和其他感兴趣的实体拴系到PB和类似物。然后，这些缀合物可以用作研究铁转运的机械探针，甚至可以用作将所需药物递送到生物体中的潜在载体。