Evaluation of desferrithiocin and its synthetic analogs 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 feat...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-07, Vol.34 (7), p.2072-2078
Main Authors: Bergeron, Raymond J, Wiegand, Jan, Dionis, John B, Egli-Karmakka, Majia, Frei, Joerg, Huxley-Tencer, Alica, Peter, Heinrich H
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Bile - chemistry
Bile - drug effects
Biological and medical sciences
chelating agents
Chemical Phenomena
Chemistry
desferrithiocin
Dihydropyridines - administration & dosage
Dihydropyridines - pharmacology
Drug Evaluation, Preclinical
General and cellular metabolism. Vitamins
iron
Iron - analysis
Iron - urine
Iron Chelating Agents - administration & dosage
Iron Chelating Agents - chemical synthesis
Iron Chelating Agents - pharmacology
Male
Medical sciences
Pharmacology. Drug treatments
Rats
Rats, Inbred Strains
Structure-Activity Relationship
Thiazoles - administration & dosage
Thiazoles - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00111a023