Iron chelation promoted by desazadesferrithiocin analogs: An enantioselective barrier.
For patients who require lifelong blood transfusions, there is no efficient means, unless chelation therapy is employed, for elimination of excess iron. Alternatives to desferrioxamine, the currently accepted treatment for transfusional iron overload, are being investigated. The current article focuses on an enantiomeric pair of analogs of desferrithiocin, (+)-(S)- and (-)-(R)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (4'-hydroxydesazadesferrithiocin). The crystal structure corroborated the absolute configuration of the two compounds, (+) and (-) for the (S)- and (R)-enantiomers, respectively. Job's plots established the tridentate nature of both analogs and circular dichroism spectra confirmed the ligands' antipodal relationship. (+)-(S)-4'-Hydroxydesazadesferrithiocin is a more efficient deferration agent than is the (-)-(R)-enantiomer in a Cebus apella model of iron overload. Pharmacokinetic analyses and IC(50) measurements in L1210 murine leukemia cells were undertaken in an effort to account for the contrast in efficacy between the two enantiomers. Some differences exist in the plasma pharmacokinetic parameters between the two analogs. However, a more plausible explanation may be the apparent differences in transport across the cell membrane; the IC(50) value in L1210 cells of the (+)-(S)-enantiomer was at least 5-fold lower than that of the (-)-(R)-compound.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida.
Wiegand
Jan
J
Weimar
William R
WR
McManis
James S
JS
Smith
Richard E
RE
Abboud
Khalil A
KA
D000818:Animals; D002428:Cebus; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000652:urine; D005243:Feces / Q000737:chemistry; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry*; D051379:Mice; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000652:urine
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; C477594:desazadesferrithiocin