Synthesis of new classes of metal ion chelators for therapeutic applications

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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.