Metabolically programmed iron chelators

Abstract

Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogues being evaluated clinically for the treatment of iron overload diseases, e.g., thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, log Papp, could have a profound effect on the drug’s iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of “metabolically programmed” iron chelators, i.e., highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.

Iron chelators or therapeutic modulators of iron overload: Are we anywhere near ideal one?

“…Iron chelator has also been used to reduce daunorubicin toxicity on the heart using a heart directed iron chelator dexrazoxane32. However, one of the interesting ways to reduce toxicity and develop efficiency of the iron chelator is by developing metabolically programmable iron chelators33 where the compound is designed in such a way that after reaching the tissue and chelating iron, the compound is metabolically transformed into more polar compound hence quickly excreted from the body.…”