Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators.
The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-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 benz-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 benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, 32610, USA.
Wiegand
J
J
Wollenweber
M
M
McManis
J S
JS
Algee
S E
SE
Ratliff-Thompson
K
K
D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron; C050223:desferrithiocin