Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators

The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-Delta(2)-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-Delta(2)-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-Delta(2)-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-Delta(2)-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the bent-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these bent-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.