Methoxylation of desazadesferrithiocin analogues: enhanced iron clearing efficiency.
The impact of altering the octanol-water partition properties (log P) of analogues of desazadesferrithiocin, (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid, on the ligands' iron clearing properties is described. Increasing chelator lipophilicity can both substantially augment iron clearing efficiency in Cebus apella primates as well as alter the mode of iron excretion, favoring fecal over urinary output. The complications of iron overload are often associated with the metal's interaction with hydrogen peroxide, generating hydroxyl radicals (Fenton chemistry) and, ultimately, other related deleterious species. In fact, some iron chelators actually promote this chemistry. All of the compounds synthesized and tested in the current study are shown to be both inhibitors of the iron-mediated oxidation of ascorbate, thus removing the metal from the Fenton cycle, and effective radical scavengers.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610-0485, USA. bergeron@mc.cop.ufl.edu
Wiegand
Jan
J
McManis
James S
JS
Bussenius
Jörg
J
Smith
Richard E
RE
Weimar
William R
WR
D020003:1-Octanol; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D002428:Cebus; D005243:Feces / Q000737:chemistry; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019190:Iron Overload / Q000378:metabolism; D008024:Ligands; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D012997:Solvents; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014556:Urine / Q000737:chemistry; D014867:Water
D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D008024:Ligands; D011725:Pyridines; D012997:Solvents; D013844:Thiazoles; D014867:Water; D007501:Iron; D020003:1-Octanol; D001205:Ascorbic Acid