Metal Ion Binding Ligands for Biomedical Applications

用于生物医学应用的金属离子结合配体

• 批准号: 6766131
• 负责人: ARAVAMUDAN S GOPALAN
• 金额: $ 13.25万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766131
• 关键词: biological transport; biotechnology; biotherapeutic agent; cations; chelating agents; chelation therapy; chemical models; chemical structure function; chemical synthesis; colorimetry; combinatorial chemistry; deferoxamine; drug design /synthesis /production; high throughput technology; hydroxamate; intermolecular interaction; iron; iron metabolism; ligands; model design /development; nitrous oxide; oxidation reduction reaction; siderophores; sulfonamides

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.

铁及其运输的选择性螯合对许多生物过程至关重要。患者 患有β-丘脑贫血的疾病必须一生都会接受输血，因此他们的身体过多铁。通过选择性螯合对过量铁的体内清除是患者生存的必要条件，而当前具有desferrioxamine B的治疗方案具有严重的局限性。同样，铁对于所有生物的生长至关重要。了解辅助铁载体介导的铁运输和微生物中释放的机制将使人们能够操纵其生长必不可少的基本过程。反过来，这将使新一代治疗剂的设计能够控制其毒力。 该计划的主要目标是开发用于铁的特定结合的螯合剂，以符合各种生物医学应用。在这项工作中，新墨西哥州立大学团队将得到杜克，科罗拉多州和德国的合作者的支持。在特定的目标1中，我们建议通过优化先前研究已经产生的铅结构来合成螯合剂以特异性结合。这项工作还涉及开发新类别的预先组织的三羟氨基螯合剂，这些螯合剂利用氢键和置式结合以增强三价阳离子（例如Fe（III））的结合。第二个具体目的是开发有用的辅助模型，以提供有关运输和运输和的机械洞察力 在微生物中释放铁（与杜克大学的合作）。该建议的第三个目标是利用组合化学方法来识别新型Fe（III）选择性螯合剂，可以被认为与治疗使用的desferrioxamine B类似。我们建议通过通过合成的综合综合综合综合综合综合综合甲酸盐，综合综合的小型库，使其合成一小撮库我们识别特有和铁的方法 螯合剂。在特定的目标4中，我们建议继续研究源自氧磺胺酰胺和相关配体系统的金属离子络合行为。这些对羟酸性酸的结构类似物表现出令人惊讶的不同化学行为。这类化合物有可能作为特定的一氧化氮（NO）发电机和基质金属蛋白酶抑制剂有用。