title: Structure-activity relationships among desazadesferrithiocin analogues.
abstract: Desferrithiocin, a natural product iron chelator (siderophore), offers an excellent platform from which to construct orally active iron chelators which have a good therapeutic window. A systematic structure-activity study on desferrithiocin identified the structural fragments necessary for the compound's oral iron-clearing activity. There are strict requirements regarding the distance between the ligating centers; they cannot be altered without loss of efficacy. The thiazoline ring must remain intact. Benz-fusions, which were designed to improve the ligands' tissue residence time and possibly iron-clearing efficiency, are ineffective. The maintenance of an (S)-configured C-4 carbon is optimal in the design of desferrithiocin-based iron chelators. With this information in hand, alteration of the redox potential of the aromatic ring was initiated. Introduction of a hydroxy in the 4'-position of at least three different desazadesferrithiocin analogues resulted in moderate to small changes in iron clearing efficacy yet dramatic reductions in the toxicity of the compounds were observed. Although the toxicity studies of these desferrithiocin analogues are continuing, it is clear that it is possible to alter a siderophore in such a way as to ameliorate its toxicity profile while maintaining its iron-clearing properties.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: Jan
authors.initials: J
authors.lastname: Wiegand
authors.forename: James S
authors.initials: JS
authors.lastname: McManis
authors.forename: William R
authors.initials: WR
authors.lastname: Weimar
authors.forename: Guangfei
authors.initials: G
authors.lastname: Huang
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy / Q000378:metabolism; D008024:Ligands; D017262:Siderophores / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004095:Dihydropyridines; D007502:Iron Chelating Agents; D008024:Ligands; D017262:Siderophores; D013844:Thiazoles; D007501:Iron; C050223:desferrithiocin