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Published on: June 21, 2015
Desferrithiocin analogue uranium decorporation agents
Raymond J Bergeron1, Jan Wiegand, Shailendra Singh
1Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, USA. rayb@ufl.edu
International Journal of Radiation Biology
|April 29, 2009
Summary
New desferrithiocin (DFT)-related analogues show promise for uranium decorporation. Two compounds significantly reduced kidney uranium levels, primarily promoting excretion via bile.
Area of Science:
- Medicinal Chemistry
- Toxicology
- Pharmacology
Background:
- Systematic structure-activity studies of desferrithiocin (DFT) led to analogues with retained iron-chelating activity and reduced toxicity.
- This study explored adapting DFT-related compounds for effective uranium decorporation.
Purpose of the Study:
- To identify and evaluate DFT-related analogues for their efficacy in decorporating uranium.
- To assess the impact of dosing regimens on the decorporation activity of these analogues.
Main Methods:
- Nine DFT-related analogues were tested in a bile duct-cannulated rat model.
- Diethylenetriaminepentaacetic acid (DTPA) was used as a positive control.
- Uranium excretion (urine, bile) and tissue levels were quantified using ICP-MS.
Main Results:
- Two analogues, (S)-4'-(HO)-DADFT-PE (9) and (S)-3'-(HO)-DADFT-PE (10), demonstrated significant uranium reduction in kidneys (57% and 62% respectively) upon oral administration.
- The primary route of uranium excretion induced by these analogues was biliary, reducing renal actinide burden.
- Delayed subcutaneous dosing of analogue 9 reduced its efficacy.
Conclusions:
- DFT-related analogues show potential as uranium decorporation agents.
- Oral administration of analogues 9 and 10 is effective, with excretion favoring bile.
- Modifications, such as esterification of analogue 9, may improve efficacy with delayed administration.
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