The research project encompasses the systematic design, synthesis and evaluation of the safety and effectiveness of heterocyclic derivatives as orally active iron-chelating agents for the treatment of iron overload. Animal studies of a siderophore isolated from S. antibioticus, have shown the parent compound to be a very efficient iron chelator but also nephrotoxic. Dr. Bergeron and his co-workers have identified specific components of the compound that are responsible for the three major properties of interest: (1) chelation of iron, (2) nephrotoxicity, and (3) gastrointestinal absorption. This has been accomplished by designing, synthesizing and evaluating in animals a series of derivatives. At least one of the derivatives seems to be orally active and less toxic than the parent compound. Other compound may have the advantage of combining different ligands, which would act as a carrier molecular across the gastrointestinal tract. In the proposed studies, the investigators will extend their efforts to design and synthesis heterocyclic derivatives and analogues to improve the understanding of structure and activity relationships, to identify candidate compounds for further evaluation, and to define, for such compounds, their safety, efficiency, specificity, pharmacokinetics and metabolism, and effect on disposition of tissue iron in animals. The development of a safe and orally effective iron chelator would be a major advance in the treatment of iron overload.
| Tang, Haiying; Jensen, Jens H; Sammet, Christina L et al. (2014) MR characterization of hepatic storage iron in transfusional iron overload. J Magn Reson Imaging 39:307-16 |
| 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 |
| 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 |
| Wu, Ed X; Kim, Daniel; Tosti, Christina L et al. (2010) Magnetic resonance assessment of iron overload by separate measurement of tissue ferritin and hemosiderin iron. Ann N Y Acad Sci 1202:115-22 |
| Bergeron, Raymond J; Singh, Shailendra; Bharti, Neelam et al. (2010) Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators. Synthesis (Stuttg) 2010:3631-3636 |
| Jensen, Jens H; Tang, Haiying; Tosti, Christina L et al. (2010) Separate MRI quantification of dispersed (ferritin-like) and aggregated (hemosiderin-like) storage iron. Magn Reson Med 63:1201-9 |
| Kim, Daniel; Jensen, Jens H; Wu, Ed X et al. (2009) Breathhold multiecho fast spin-echo pulse sequence for accurate R2 measurement in the heart and liver. Magn Reson Med 62:300-6 |
| Guo, Hua; Au, Wing-Yan; Cheung, Jerry S et al. (2009) Myocardial T2 quantitation in patients with iron overload at 3 Tesla. J Magn Reson Imaging 30:394-400 |
| Bergeron, Raymond J; Bharti, Neelam; Wiegand, Jan et al. (2005) Polyamine-vectored iron chelators: the role of charge. J Med Chem 48:4120-37 |
| Bergeron, Raymond J; Wiegand, Jan; McManis, James S et al. (2005) Partition-variant desferrithiocin analogues: organ targeting and increased iron clearance. J Med Chem 48:821-31 |
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