Journal
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY
Volume 85, Issue 4, Pages 348-361Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/09553000902781089
Keywords
Uranium; decorporation; desferrithiocin analogues; inductively coupled plasma mass spectroscopy (ICP-MS)
Funding
- National Institute of Allergy And Infectious Diseases [R01AI074068]
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Purpose: Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and methods: The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results: The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions: While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue.
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