Desferrithiocin analogue uranium decorporation agents

Int J Radiat Biol. 2009 Apr;85(4):348-61. doi: 10.1080/09553000902781089.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bile Ducts / drug effects
  • Bile Ducts / metabolism
  • Chelating Agents / chemistry*
  • Chelating Agents / pharmacology*
  • Dihydropyridines / chemistry*
  • Dihydropyridines / pharmacology*
  • Dose-Response Relationship, Drug
  • Femur / drug effects
  • Femur / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Ligands
  • Liver / drug effects
  • Liver / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Pentetic Acid / pharmacology
  • Rats
  • Spleen / drug effects
  • Spleen / metabolism
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*
  • Uranium / chemistry*
  • Uranium / isolation & purification*
  • Uranium / pharmacokinetics
  • Uranium / toxicity

Substances

  • Chelating Agents
  • Dihydropyridines
  • Ligands
  • Thiazoles
  • Uranium
  • Pentetic Acid
  • desferrithiocin