Metal Ion Binding Ligands for Biomedical Applications

铁的选择性螯合及其运输是许多生物过程的基础。患者 患有β-地中海贫血症的人一生都必须接受输血，因此他们的体内存在铁过量的问题。通过选择性螯合在体内清除过量的铁是患者生存的必要条件，目前使用去铁胺B的治疗方案具有严重的局限性。此外，铁对所有生物的生长至关重要。了解铁载体介导的铁在微生物中的运输和释放的机制，将使人们能够操纵其生长所必需的基本过程。这反过来又将允许设计新一代的治疗方法来控制它们的毒力。 该计划的主要目标是开发用于铁的特异性结合的螯合剂，以满足各种生物医学应用。在这项工作中，新墨西哥州州立大学团队将得到杜克、科罗拉多和德国合作者的支持。在具体目标1中，我们提出通过优化我们先前研究中已经产生的铅结构来合成用于铁的特异性结合的螯合剂。这项工作还涉及开发新类别的预组织的三异羟肟酸螯合剂，利用氢键和ditopical结合，以提高三价阳离子，如Fe（III）的结合。第二个具体的目标是开发有用的铁载体模型，可以提供运输机制的见解， 铁在微生物中的释放（与杜克大学合作）。该提议的第三个目的是利用组合化学方法来鉴定新型Fe（III）选择性螯合剂，其可以被认为类似于治疗上使用的去铁胺B。我们建议通过高通量平行合成来合成一个包含羟基吡啶酮、异羟肟酸盐和儿茶酚酸盐的六齿配体系统的小型库，并建立我们的方法来鉴定强的和铁特异性的 螯合剂。在具体目标4中，我们建议继续研究N-羟基磺酰胺及其相关配体体系的金属离子络合行为。异羟肟酸的这些结构类似物表现出令人惊讶的不同化学行为。这类化合物有可能用作特定的一氧化氮（NO）生成剂和基质金属蛋白酶抑制剂。

Selective chelation of iron and its transport is fundamental to many biological processes. Patients suffering from beta-thalassaemia must receive blood transfusions throughout their life and hence have a problem of excess iron in their bodies. In vivo clearance of the excess iron by selective chelation is a must for patient survival and the current treatment regimes with desferrioxamine B have serious limitations. Also, iron is essential to the growth of all organisms. An understanding of the mechanism governing siderophore mediated iron transport and release in microorganisms would allow one to manipulate fundamental processes essential to their growth. This in turn will allow the design of a new generation of therapeutics to control their virulence. The primary goal of this program is to develop chelators for the specific binding of iron that can meet a variety of biomedical applications. In this effort, the New Mexico State University team will be supported by collaborators at Duke, Colorado and Germany. In specific aim 1, we propose to synthesize chelators for the specific binding of iron by optimization of lead structures already generated from our previous studies. The work also involves the development of new classes of pre-organized trihydroxamate chelators that exploit hydrogen bonding and ditopical binding to enhance the binding of trivalent cations such as Fe(III). The second specific aim is to develop useful siderophore models that can provide mechanistic insight on the transport and release of iron in microorganisms (a collaboration with Duke University). The third objective of this proposal is to utilize combinatorial chemistry methods for the identification of novel Fe(III) selective chelators that can be considered as analogous to the therapeutically used desferrioxamine B. We propose to synthesize a small library of hexadentate ligand systems incorporating hydroxypyridinones, hydroxamates and catecholates by high throughput parallel synthesis and establish the viability of our approach to identify strong and iron specific chelators. In specific aim 4, we propose to continue our studies on the metal ion complexation behavior of Nhydroxysulfonamides and related ligand systems. These structural analogs to the hydroxamic acid exhibit surprisingly different chemical behavior. There is a possibility that this class of compounds may be useful as specific nitric oxide (NO) generators and matrix metalloproteinase inhibitors.