Synthesis of new classes of metal ion chelators for therapeutic applications

描述(申请人提供)：大多数天然铁载体的一个共同特征是它们是多齿配体，能够与铁(III)强烈结合，形成八面体1：1络合物。从地中海贫血到细菌感染再到癌症，铁的螯合作用被认为是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，很少出现从天然铁载体的结构主题中获得灵感的治疗剂。我们的目标是证明现有的铁载体可以为铁负荷疾病以及结核分枝杆菌(TB)和炭疽杆菌(炭疽)引起的细菌感染的治疗药物的开发提供可行的模板。在本研究中，选择了炭疽杆菌产生的铁载体Petrobactin PB作为铁载体模型。这种生物依靠两种铁载体杆状杆菌，Bb和Pb，从它的人类宿主那里获得铁。人类免疫蛋白铁蛋白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，我们将合成各种PB的非手性邻苯二酚/羟基吡二酮类似物，目的是阐明特定配体位置的重要性。 铁结合中芳香族/杂环环上的配体原子和取代方式 SCN交互作用。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·斯特朗博士合作完成，罗兰·斯特朗是这一领域的专家。本项目的第二个目标是研究手性在PB的铁运输中的作用以及它与SCN的相互作用。虽然PB是非手性的，但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。在设计用于清除体内多余铁的治疗剂时，手性通常不是考虑因素。然而，它可以在细菌系统中铁的运输和支持其毒力方面发挥重要作用。在这项研究中，将开发可并入原始PB结构的双官能性儿茶酚和羟基吡二酮配体。双功能配体单元的应用 允许在合成的最后阶段将所需的标记/探针引入到螯合剂支架上。这项建议的第三个目的是开发两种不同的结合策略的使用，即无迹Staudinger连接和磺基点击化学，以锚定探针、配体和其他PB及其类似物感兴趣的实体。然后，这些偶联物可以作为机械探针来研究铁的运输，甚至可以作为潜在的载体，将所需的药物输送到生物体中。

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.