SELECTIVE CHELATORS FOR TRIVALENT/ TETRAVALENT CATIONS

了解决定选择性金属离子络合作用的因素是设计和开发新的目标阳离子螯合剂以及了解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。形成强的和动力学惰性的和无毒的蛋白质或在生理pH下水解的配体对于体内解毒、治疗或诊断应用是潜在有用的。特别令人感兴趣的是开发用于Fe 3+、Gd 3+和Pu 4+的选择性螯合剂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/铅多异羟肟酸螯合结构来生成铁，钆和钍的螯合剂。这项工作还涉及开发新的预组织三异羟肟酸螯合剂，利用氢键和ditopical结合，以提高三价阳离子，如Fe 3+的结合。首先将开发目标螯合结构的方便合成路线，然后将评估它们与金属离子如Fe 3+、Gd 3+和Th 4+（Pu 4+的模型）的结合。这将提供一个了解其络合行为的结构基础，并允许定制其金属离子的选择性。第二个目的是制备新的类似物的去铁胺和DOTA，纳入迄今未开发的N-羟基磺酰胺配体系统和研究其金属结合性能。去铁胺是众所周知的铁载体，DOTA的钆络合物是用于磁共振成像的造影剂。本提案的第三个目的是利用化学方法鉴定新型金属离子选择性螯合剂。组合化学提供了合成和筛选更广泛的螯合结构的机会。作为一个开始，一个库的三异羟肟酸和四异羟肟酸设计的铁和/或钍的选择性结合将被生成。这两种固相合成方法，以产生这样的配体屏障，以及用于分析的树脂珠，以确定有前途的螯合结构的方法将被开发。

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.