Synthesis of iron chelators used by oil-degrading bacteria (Artwork credit: Abi Bell)

Figure 1

Figure 2

Iron is essential for life. However, the human body does not have any formal mechanisms for the excretion of iron. Once an individual absorbs or acquires too much iron, it lodges in tissues, which are not equipped for its storage, and damages the surrounding tissue. Chelation therapy is, in some cases, the only option in treating these individuals. Iron binding drugs clear the iron from the tissues and allow for iron excretion in a water-soluble form. To address this need for iron clearance, we are developing the chemistry of benzoyloxyamines (R-NHOCOPh). These unique substrates allow synthetic access to both iron binding drugs (used in the treatment of iron poisoning) and zinc binding drugs (arthritis). We are currently working on new synthetic methods to convert these intermediates into polyhydroxamic acids (RCON(OH)R') built upon peptide architectures. Ref: "Synthesis of N-Hydroxy)amide and N-(Hydroxy)thioamide-Containing Peptides," Phanstiel et al, J. Org. Chem. 2000, 65, 1442-1447.

Another offshoot of this technology is the synthesis and biological evaluation of new iron chelators as potential antimicrobial agents. Our group has synthesized new ligands (like Figure 2), which can cross feed Mycobacterium paratuberculosis nearly five more efficiently than the native Mycobactin J chelator. These new ligands provide important mechanistic probes for the investigation of iron transport in mycobacteria. Mycobacterium paratuberculosis provides a non-virulent model to study its cousin, Mycobacterium tuberculosis, the bacteria responsible for tuberculosis in humans.

Our group is also developing new siderophore structures that can target the iron transport system of virulent bacteria and provide a pathway for the selective delivery of antibiotic agents. Siderophores are naturally-occurring iron binding agents biosynthesized by bacteria to acquire iron from their environment. These iron atoms are essential micronutrients, which support bacterial growth. As such, bacteria have transport systems which allow for internalization of these unique metal complexes.

Ref: "Synthesis and Biological Evaluation of New Citrate-Based Siderophores as Potential Probes for the Mechanism of Iron Uptake in Mycobacteria" Phanstiel et al, J. Med. Chem. 2002, 45, 2056-2063.

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     Otto Phanstiel
     Department of Chemistry, CH 117
     University of Central Florida
     Orlando, FL 32816