Selective chelation of iron and its transport is fundamental to many biological processes. Patients suffering from beta-thalassaemia must receive blood transfusions throughout their life and hence have a problem of excess iron in their bodies. In vivo clearance of the excess iron by selective chelation is a must for patient survival and the current treatment regimes with desferrioxamine B have serious limitations. Also, iron is essential to the growth of all organisms. An understanding of the mechanism governing siderophore mediated iron transport and release in microorganisms would allow one to manipulate fundamental processes essential to their growth. This in turn will allow the design of a new generation of therapeutics to control their virulence. The primary goal of this program is to develop chelators for the specific binding of iron that can meet a variety of biomedical applications. In this effort, the New Mexico State University team will be supported by collaborators at Duke, Colorado and Germany.
In specific aim 1, we propose to synthesize chelators for the specific binding of iron by optimization of lead structures already generated from our previous studies. The work also involves the development of new classes of pre-organized trihydroxamate chelators that exploit hydrogen bonding and ditopical binding to enhance the binding of trivalent cations such as Fe(III). The second specific aim is to develop useful siderophore models that can provide mechanistic insight on the transport and release of iron in microorganisms (a collaboration with Duke University). The third objective of this proposal is to utilize combinatorial chemistry methods for the identification of novel Fe(III) selective chelators that can be considered as analogous to the therapeutically used desferrioxamine B. We propose to synthesize a small library of hexadentate ligand systems incorporating hydroxypyridinones, hydroxamates and catecholates by high throughput parallel synthesis and establish the viability of our approach to identify strong and iron specific chelators.
In specific aim 4, we propose to continue our studies on the metal ion complexation behavior of Nhydroxysulfonamides and related ligand systems. These structural analogs to the hydroxamic acid exhibit surprisingly different chemical behavior. There is a possibility that this class of compounds may be useful as specific nitric oxide (NO) generators and matrix metalloproteinase inhibitors.
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