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。病人 患有β-地中海贫血症的人一生都必须接受输血，因此他们体内存在铁过多的问题。在体内，通过选择性螯合清除多余的铁是患者生存所必需的，目前使用去铁胺B的治疗方案有严重的局限性。此外，铁对所有有机体的生长都是必不可少的。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对微生物生长至关重要的基本过程。这反过来将允许设计新一代疗法来控制它们的毒力。 该计划的主要目标是开发能够满足各种生物医学应用的铁的特定结合的螯合剂。在这项工作中，新墨西哥州立大学的团队将得到杜克大学、科罗拉多州和德国的合作者的支持。在具体目标1中，我们建议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定结合的螯合剂。这项工作还包括开发新类别的预先组织的三羟基甲酸盐络合剂，利用氢键和双键结合来增强三价阳离子(如Fe(III))的结合。第二个具体目标是开发有用的铁载体模型，该模型可以提供对运输和 微生物中铁的释放(与杜克大学合作)。这项建议的第三个目标是利用组合化学方法来鉴定新的铁(III)选择性螯合剂，可以被认为是类似于治疗使用的去铁胺B。我们建议通过高通量并行合成合成一个小的六齿配体系统，包括羟基吡啶酮、羟胺和儿茶酸酯，并建立我们的方法的可行性，以识别强的和铁的特异性 螯合剂。在具体目标4中，我们建议继续研究羟基磺酰胺及其相关配体体系的金属离子络合行为。这些异羟肟酸的结构类似物表现出惊人的不同化学行为。这类化合物有可能被用作特定的一氧化氮(NO)产生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.