The overall goal of this research is to synthesize and study hydroxamic acid based microbial iron chelators and analogues, The key to this research is the development of syntheses of the basis hydroxylamine and hydroxamic acid constituents of the natural ferric chelators (siderophores). Recent developments in this laboratory have provided efficient routes to these constituents, and a number of related versatile, but unnatural, building blocks. The utility of these approaches have been demonstrated by our synthesis of six natural siderophores and over a dozen novel analogues. This proposal will further test the generality and power of our synthetic methods by incorporating them into the synthesis of other citrate, diketopiperazine, isocyanuric acid and spermidine based siderophores and analogues. Further extensions to the synthesis of the antibiotic albomycins, and analogues of the ferrichromes and pseudobactins will illustrate the compatability of the methods with more complex molecular systems. These synthetic studies, in combination with studies of partition (transport) phenomena, biological activity, conformational effects of chelation (by NMR) and iron release mechanisms, are anticipated to facilitate a better understanding of iron metabolism in general. In addition, the hydroxamate based siderophore analogues are potential therapeutic agents for the treatment of iron overload. Others may also provide unique molecular drug delivery systems. The design of such systems (covalent siderophore, antibiotic combinations) is described.
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