SELECTIVE CHELATORS FOR TRIVALENT/ TETRAVALENT CATIONS

了解控制选择性金属离子络合的因素是设计和开发新的目标阳离子螯合剂的先决条件，也是欣赏自然界中几种金属结合系统的显着特异性和化学性质的先决条件。配体在生理pH值下形成强大的、动力学惰性的、无毒的蛋白质或水解，在体内解毒、治疗或诊断应用中具有潜在的用途。特别感兴趣的是Fe3+， Gd3+和Pu4+的选择性螯合剂的开发，以满足各种生物医学应用。该项目的第一个具体目标是通过优化早期工作中有前途的/铅多羟基酸盐螯合结构，生成铁、钆和钍的螯合剂。这项工作还包括开发新型的预组织三羟酸盐螯合剂，利用氢键和异位结合来增强三价阳离子（如Fe3+）的结合。首先，我们将开发到目标螯合结构的方便的合成途径，然后评估它们与金属离子（如Fe3+， Gd3+和Th4+）的结合（Pu4+的模型）。这将提供对其络合行为的结构基础的理解，并允许剪裁它们的金属离子选择性。第二个目标是制备新型的去铁胺和DOTA类似物，这些类似物包含迄今未开发的N-羟基磺胺配体系统，并研究它们的金属结合特性。去铁胺是一种众所周知的铁载体，DOTA的钆配合物是磁共振成像的造影剂。本提案的第三个目标是利用化学方法鉴定新型金属离子选择性螯合剂。组合化学为合成和筛选更广泛的螯合结构提供了机会。首先，将生成一个专为铁和/或钍的选择性结合而设计的三羟酸盐和四羟酸盐库。将开发固相合成方法来生成这种配体屏障，以及分析树脂珠以确定有前途的螯合结构的方法。

Understanding of the factors that govern selective metal ion complexation is a prerequisite to design and develop new chelators for target cations and to appreciate the remarkable specificity and chemistry of several metal binding systems in nature. Ligands that form strong and kinetically inert and non-toxic proteins or hydrolysis at physiological pH are potentially useful for in vivo detoxification, therapeutic or diagnostic applications. Of particular interest, is the development of selective chelators for Fe3+, Gd3+ and Pu4+ to meet a variety of biomedical applications. The first specific objective of this project is the generation of chelators for iron, gadolinium and thorium by optimization of promising/lead polyhydroxamate chelating structures from earlier work. The work also involves the development the development of new classes of preorganized trihydroxamate chelators that exploit hydrogen bonding and ditopical binding to enhance the binding of trivalent cations such as Fe3+. Convenient synthetic routes to the target chelating structures will first be developed and then their binding with metal ions such as Fe3+, Gd3+ and Th4+ (a model for Pu4+) will be evaluated. This will provide an understanding of the structural basis of their complexation behavior and allow tailoring of their metal ion selectivities. The second objective is the preparation of novel analogs of desferrioxamine and DOTA that incorporate the hitherto unexplored N- hydroxysulfonamide ligand systems and a study of their metal binding properties. Desferrioxamine is a well known siderophore and the gadolinium complex of DOTA is a contrast agent for magnetic resonance imaging. The third objective of this proposal is to utilize chemistry methods for the identification of novel classes of metal ion selective chelators. Combinatorial chemistry offers the opportunity to synthesize and screen a wider variety of chelating structures. As a start, a library of trihydroxamates and tetrahydroxamates designed for the selective binding of iron and/or thorium will be generated. Both solid phase synthetic methods to generate such ligand barriers as well as methods for analysis of the resin beads to identify the promising chelating structures will be developed.