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.
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