Desferrithiocin analogue uranium decorporation agents.

Abstract:

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 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue.

journal_name

Int J Radiat Biol

authors

Bergeron RJ,Wiegand J,Singh S

doi

10.1080/09553000902781089

subject

Has Abstract

pub_date

2009-04-01 00:00:00

pages

348-61

issue

4

eissn

0955-3002

issn

1362-3095

pii

910751539

journal_volume

85

pub_type

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