Patients suffering from ?-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. The search must continue to generate a new generation of iron selective chelators that are better suited for clinical use. The use of iron chelators for the treatment of cancer has also sparked a great interest in the molecular mechanisms of iron uptake by the cells. It is very clear that iron depletion can have serious impact in several cellular processes. Also, iron is essential to the growth of all organisms. An understanding of the mechanism governing siderophore mediated iron transport and release in microorganisms (iron transport and iron assimilation) 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 the virulence of such important bacterial diseases such as TB (caused by mycobacterium tuberculosis.) The PI and his group have been involved for some time in the development of selective chelators for trivalent cations of biomedical interest (particularly iron) for diagnostic and therapeutic applications.
The Aim 1 of this project is to capitalize on our previous results and develop a more efficient and direct/convergent solid phase synthetic route that could rapidly generate chiral tris-hydroxypyridinones (HOPO), tris- hydroxamates and mixed ligands having both HOPO and hydroxamic acid ligands on the backbone. The ligands will be evaluated for their iron selective binding by a number of methods including competitive exchange reactions with EDTA and in collaboration with scientists at Duke University. A perusal of the current literature reveals that the iron complexation abilities (advantages and disadvantages) of mixed ligand systems present in several siderophores has not been widely studied.
In Aim 2, we plan to prepare chelating systems that have a variety of ligands including citrate, hydroxamic acid and HOPO in their backbone and to systematically evaluate the effect of structural variation on metal ion binding. We hypothesize this project will allow us to get some new leads for selective iron chelators. Further, our synthetic approach allows us to vary the lipophilicity/hydrophobicity of the chelator, a key factor in biological activity. Useful iron chelators with probes that can provide mechanistic insight on the transport and release of iron in microorganisms will also be a target of our investigation. The driving force for this study is to generate a new generation of therapeutics that can have applications in iron overload diseases, combating bacterial diseases such as TB and give new leads for the treatment of cancer. The proposed work can have a significant positive impact on public health.
|Gibson, Sarah; Fernando, Rasika; Jacobs, Hollie K et al. (2015) Preparation of 3-benzyloxy-2-pyridinone functional linkers: Tools for the synthesis of 3,2-hydroxypyridinone (HOPO) and HOPO/hydroxamic acid chelators. Tetrahedron 71:9271-9281|
|Martinez, Gloria; Arumugam, Jayanthi; Jacobs, Hollie K et al. (2013) 3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: Aza-Michael addition reactions and the preparation of poly-HOPO chelators. Tetrahedron Lett 54:630-634|
|Fernando, Rasika; Shirley, Jonathan M; Torres, Emilio et al. (2012) Preparation of bifunctional isocyanate hydroxamate linkers: Synthesis of carbamate and urea tethered polyhydroxamic acid chelators. Tetrahedron Lett 53:6367-6371|
|Young, Jennifer A; Karmakar, Sukhen; Jacobs, Hollie K et al. (2012) Synthetic approaches to mixed ligand chelators on t-butylphenol-formaldehyde oligomer (PFO) platforms. Tetrahedron 68:10030-10039|
|Arumugam, Jayanthi; Brown, Hayley A; Jacobs, Hollie K et al. (2011) New Synthetic Approach for the Incorporation of 3,2-Hydroxypyridinone (HOPO) Ligands: Synthesis of Structurally Diverse Poly HOPO Chelators. Synthesis (Stuttg) 2011:57-64|
|Gibson, Sarah; Jacobs, Hollie K; Gopalan, Aravamudan S (2011) Chiral oxazolidinones as electrophiles: Intramolecular cyclization reactions with carbanions and preparation of functionalized lactams. Tetrahedron Lett 52:887-890|
|Liu, Yuan; Jacobs, Hollie K; Gopalan, Aravamudan S (2011) A new approach to fused furan ring systems and benzofurans: Intramolecular cyclization reactions of unsaturated acyloxy sulfone derivatives. Tetrahedron Lett 52:2935-2939|
|Liu, Yuan; Jacobs, Hollie K; Gopalan, Aravamudan S (2011) A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles. Tetrahedron 67:2206-2214|
|Gibson, Sarah; Romero, Dickie; Jacobs, Hollie K et al. (2010) Concurrent esterification and N-acetylation of amino acids with orthoesters: A useful reaction with interesting mechanistic implications. Tetrahedron Lett 51:6737-6740|
|Harrington, James M; Chittamuru, Sumathi; Dhungana, Suraj et al. (2010) Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics. Inorg Chem 49:8208-21|
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