Synthesis of new classes of metal ion chelators for therapeutic applications

描述（由申请人提供）：大多数天然铁载体的一个共同特征是它们是多齿配体，能够强结合铁（III），形成八面体1:1配合物。从地中海贫血到细菌感染和癌症，铁螯合已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，很少有从天然铁载体的结构基序中获得灵感的治疗剂出现。我们的目标是证明现有的铁载体可以为铁超载疾病以及由结核杆菌和炭疽杆菌引起的细菌感染的治疗药物的开发提供可行的模板。本研究选择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菌杆菌素BB和PB从人类宿主那里获取铁。人免疫蛋白铁蛋白（Scn）能够识别和结合BB，但不能结合PB。因此，PB被称为隐形铁载体。在第一个目标中，将合成各种PB的非手性儿茶酚/羟基吡啶酮类似物，目的是阐明特定配体位置的重要性

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.