The proposed research project will focus on the design, synthesis, evaluation, and development of targeted desferrithiocin analogues for the treatment of iron overload. Physicians have a pressing clinical need for new, more effective iron-chelating agents which selectively remove iron from the liver, heart, and pancreas, the organs at greatest risk of iron-induced injury in patients with thalassemia major, sickle cell disease, hereditary hemochromatosis and other forms of iron overload. Desferrithiocin (DFT), a natural product iron chelator (siderophore) isolated from Streptomyces antibioticus, is one of the most orally effective iron chelating agents yet identified but renal toxicity precludes its clinical use. Our systematic structure-activity studies have allowed the design and synthesis of analogues and derivatives, which retain the exceptional iron-chelating activity of DFT without adverse effects on the kidneys or other organs. Our lead compound, the orally active DFT analogue (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT (28)], which is nearly three times as effective as sc DFO in the C. apella primate model, has been licensed to a commercial sponsor and currently is in Phase I/II clinical trials. We now hypothesize that the DFT platform can be structurally programmed to target delivery to organs at greatest risk of iron induced injury and to further enhance iron clearance. To test these hypotheses, our research plan has three specific aims:
Aim 1 : to design and synthesize partition-variant desferrithiocin analogues with enhanced access to organs vulnerable to iron-induced injury (eg, liver, heart, pancreas) and/or increased iron clearing efficiency;
Aim 2 : to design and synthesize polyamine-vectored desferrithiocin analogues that use the polyamine transport apparatus to gain entry into cells;
and Aim 3 : to assess these new desferrithiocin analogues in physiochemical, cellular and animal models to identify safe and effective compounds for GLP preclinical evaluation in preparation for human studies. The development of safe, effective, and well-tolerated iron-chelating agents based on DFT would be a major advance in the treatment of iron overload that would greatly enhance both the quality and length of life of affected patients in the United States and worldwide.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-ELB (01))
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Bishop, Terry Rogers
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University of Florida
Schools of Pharmacy
United States
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Bergeron, Raymond J; Bharti, Neelam; McManis, James S et al. (2015) Metabolically programmed iron chelators. Bioorg Med Chem 23:5954-71
Bergeron, Raymond J; Wiegand, Jan; McManis, James S et al. (2014) Desferrithiocin: a search for clinically effective iron chelators. J Med Chem 57:9259-91
Sammet, Christina L; Swaminathan, Srirama V; Tang, Haiying et al. (2013) Measurement and correction of stimulated echo contamination in T2-based iron quantification. Magn Reson Imaging 31:664-8
Bergeron, Raymond J; Wiegand, Jan; Bharti, Neelam et al. (2012) Substituent effects on desferrithiocin and desferrithiocin analogue iron-clearing and toxicity profiles. J Med Chem 55:7090-103
Kim, Daniel; Jensen, Jens H; Wu, Ed X et al. (2011) Rapid monitoring of iron-chelating therapy in thalassemia major by a new cardiovascular MR measure: the reduced transverse relaxation rate. NMR Biomed 24:771-7
Bergeron, Raymond J; Singh, Shailendra; Bharti, Neelam (2011) Synthesis of Heterobactins A and B and Nocardia Heterobactin. Tetrahedron 67:3163-3169
Cheung, Jerry S; Au, Wing-Yan; Ha, Shau-Yin et al. (2011) Reduced transverse relaxation rate (RR2) for improved sensitivity in monitoring myocardial iron in thalassemia. J Magn Reson Imaging 33:1510-6
Bergeron, Raymond J; Wiegand, Jan; Bharti, Neelam et al. (2011) Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity. Biometals 24:239-58
Brittenham, Gary M (2011) Iron-chelating therapy for transfusional iron overload. N Engl J Med 364:146-56
Bergeron, Raymond J; Singh, Shailendra; Bharti, Neelam et al. (2010) Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators. Synthesis (Stuttg) 2010:3631-3636

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