Related Experiment Videos
Desferrithiocin analogue based hexacoordinate iron(III) chelators
Raymond J Bergeron1, Guangfei Huang, William R Weimar
1Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. bergeron@mc.cop.ufl.edu
Journal of Medicinal Chemistry
|December 28, 2002
Summary
Hexacoordinate iron chelators show improved radical scavenging but no overall advantage over tricoordinate analogues for preventing Fenton chemistry. In vivo studies revealed varied efficacy based on administration route and species.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Toxicology
Background:
- Hexacoordinate Fe(III) ligands were traditionally thought superior for preventing reactive oxygen species (ROS) and Fenton chemistry.
- The tricoordinate ligand (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid [4'-(HO)-DADMDFT] is well-characterized.
Purpose of the Study:
- To synthesize and evaluate a hexacoordinate analogue of 4'-(HO)-DADMDFT.
- To determine if hexacoordination offers advantages in preventing Fenton chemistry, radical trapping, and iron clearance.
Main Methods:
- Molecular modeling for ligand design.
- In vitro and in vivo evaluations in rodents and primates.
- Assessment of iron-mediated oxidation of ascorbate and iron clearance efficiency.
Main Results:
- The hexacoordinate analogue showed superior prevention of ascorbate oxidation at low ligand/metal ratios and acted as an effective radical scavenger.
- In rodents, oral administration of the tricoordinate ligand was 3-fold more effective than the hexacoordinate derivative, while subcutaneous administration showed the reverse.
- Primate studies did not replicate rodent findings; the hexacoordinate ligand was less efficient than the tricoordinate parent via subcutaneous administration.
Conclusions:
- Coupling two 4'-(HO)-DADMDFT molecules to create a hexacoordinate derivative does not offer an overall advantage for iron chelation and Fenton chemistry prevention.
- Efficacy of iron chelators is highly dependent on denticity, administration route, and species.