Desferrithiocin analogue uranium decorporation agents.
OBJECTIVE
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.


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.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, USA. rayb@ufl.edu
Wiegand
Jan
J
Singh
Shailendra
S
D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D004369:Pentetic Acid / Q000494:pharmacology; D051381:Rats; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014501:Uranium / Q000737:chemistry* / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000633:toxicity
D002614:Chelating Agents; D004095:Dihydropyridines; D008024:Ligands; D013844:Thiazoles; D014501:Uranium; D004369:Pentetic Acid; C050223:desferrithiocin