Multidentate Terephthalamidate and Hydroxypyridonate Ligands: Towards New Orally Active Chelators

Abstract

The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using ⁵⁹Fe, ²³⁸Pu, and ²⁴¹Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

• Iron overload
• Actinide contamination
• Hydroxypyridonate ligands
• Terephthalamidate ligands
• Chelating agents
• Chelation therapy