The specific aims of this research are the development of efficient syntheses of enterobactin and enantioenterobactin, and the synthesis, complexation, and chemical evaluation of ligands 3-8 and 10-17 which are derivatives or analogs of enterobactin. These compounds are of interest for several reasons: they should be excellent ferric ion binders; they could provide additional insights as to why enterobactin is so exceptional a ligand; and because certain ligands can serve as probes for the elucidation of some of the details of the biological processes which recognize and transport enterobactin-bound iron into the bacterial cell ,and subsequently release the iron and make it available for cellular biochemistry. Some are derivatives of enterobactin in that they all contain the 12- membered trilactone platform. These compounds represent the first generation of synthetic ligands which incorporate the serine trilactone nucleus. Another is a derivative where L-threonine rather than L-serine is used in the trilactone ring. Some ligands incorporate binding units other than catecholate (such as dihydroxyterephthalamide, dihydroxynaphthoyl, hydroxypyridinone, hydroxamate) The proposed ligands include exocyclic and macrobicyclic structures. Enterobactin structural components are of interest for the design of other, derivative, ligands which may offer some therapeutic advantage over current detoxification agents. Also, because of the close similarity between ferric ion and the actinides (in charge to radius), compounds which bind ferric ion may also find utility in actinide detoxification. The ligands we propose to synthesize will allow us to explore the role of the triserine backbone in the efficacy of ferric binding by enterobactin, and to ask the following questions which are of both chemical and biological Interest. * What is the structure of enterobactin in aqueous medium? * Is there a role for alkali or alkali earth cations in the preorganization of free enterobactin? * Can we make ligands which are better than enterobactin? * How selective is the active transport mechanism for the trilactone backbone of enterobactin? * How specific is the cytoplasmic esterase?
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