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Desferrithiocin: a search for clinically effective iron chelators
Raymond J Bergeron1, Jan Wiegand, James S McManis
1Department of Medicinal Chemistry, University of Florida , Box 100485 JHMHC, Gainesville, Florida 32610-0485, United States.
Journal of Medicinal Chemistry
|September 11, 2014
Summary
This study reviews the development of orally active iron chelators for treating iron overload diseases like thalassemia. It highlights the reengineering of a natural product to create effective and safe treatments, with three new ligands entering clinical trials.
Area of Science:
- Biochemistry
- Pharmacology
- Medicine
Background:
- Iron is essential for biological redox reactions but toxic when dysregulated.
- Iron overload diseases, such as thalassemia, result from disrupted iron homeostasis.
- Uncontrolled iron can lead to cellular damage via Fenton chemistry.
Purpose of the Study:
- To overview the development of orally active iron chelators.
- To discuss the challenges and strategies in designing effective iron chelating agents.
- To present desferrithiocin as a platform for developing novel iron chelators.
Main Methods:
- Review of iron's biological role and homeostasis mechanisms.
- Analysis of iron overload pathophysiology and damage mechanisms.
- Structure-activity relationship studies of desferrithiocin for drug design.
Main Results:
- Identification of design principles for iron-chelating ligands.
- Overcoming toxicological issues associated with iron chelators.
- Development of three novel ligands evaluated in human clinical trials.
Conclusions:
- Systematic reengineering of natural product pharmacophores can yield effective therapeutics.
- Orally active iron chelators offer a promising treatment for transfusional iron overload.
- The developed ligands demonstrate potential for improved iron chelation therapy.
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