Evaluation of desferrithiocin and its synthetic analogues as orally effective iron chelators.
Desferrithiocin, a novel microbial siderophore isolated from cultures of Streptomyces antibioticus DSM 1865, and a number of its derivatives and analogues are evaluated for their ability to promote iron clearance. The compounds have been designed with the objective of identifying the structural features of desferrithiocin which render this ligand an orally effective iron chelator. The desferrithiocin aromatic hydroxyl and the thiazoline ring carboxyl group are shown to be central to desferrithiocin's activity. The ligand's methyl and the aromatic nitrogen play little role in the compound's efficacy. The animal model chosen for this study, the bile duct cannulated rat, provides information regarding both the chelator-induced total iron output and the kinetics of both biliary and urinary iron excretion.
Bergeron
R J
RJ
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville 32610.
Wiegand
J
J
Dionis
J B
JB
Egli-Karmakka
M
M
Frei
J
J
Huxley-Tencer
A
A
Peter
H H
HH
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000032:analysis / Q000652:urine; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron; C050223:desferrithiocin