Desferrithiocin analogue based hexacoordinate iron(III) chelators.
Traditional thinking has been that hexacoordinate Fe(III) ligands are more effective at preventing iron's interactions with reactive oxygen species, most particularly the Fe(II)-mediated reduction of hydrogen peroxide to the hydroxyl radical (i.e., Fenton chemistry), than are ligands of lower denticity. Thus, a hexacoordinate derivative of the well-characterized tricoordinate ligand (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid [4'-(HO)-DADMDFT], (S,S)-1,11-bis[5-(4-carboxy-4,5-dihydrothiazol-2-yl)-2,4-dihydroxyphenyl]-4,8-dioxaundecane, was designed with the aid of a molecular modeling program and synthesized. Evaluations both in vitro and in vivo were carried out to determine whether there is any advantage, at the level of prevention of Fenton chemistry, radical trapping, or iron clearance, to constructing a desferrithiocin-based hexacoordinate analogue. The hexacoordinate analogue was more effective at preventing the iron-mediated oxidation of ascorbate at low ligand/metal ratios than was its tricoordinate parent and can function as an excellent radical scavenger. At equivalent iron binding doses in the bile duct cannulated rodent, oral administration of the tricoordinate ligand was 3-fold more effective than was po administration of the hexacoordinate derivative. However, sc administration of the hexacoordinate derivative resulted in an efficiency that was 3 times greater than that of the tricoordinate chelator. Unfortunately, the rodent findings were not substantiated in the primates. The hexacoordinate ligand was only about one-half as efficient as its tricoordinate parent when administered sc. Owing to these results, po dosing was not attempted. Thus, there appears to be no overall advantage to coupling two molecules of 4'-(HO)-DADMDFT to afford a hexacoordinate derivative.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. bergeron@mc.cop.ufl.edu
Huang
Guangfei
G
Weimar
William R
WR
Smith
Richard E
RE
Wiegand
Jan
J
McManis
James S
JS
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D001646:Bile / Q000737:chemistry; D002428:Cebus; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry*; D005243:Feces / Q000737:chemistry; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry; D007501:Iron / Q000378:metabolism / Q000652:urine; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D010084:Oxidation-Reduction; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C470651:1,11-bis(5-(4-carboxy-4,5-dihydrothiazol-2-yl)-2,4-dihydroxyphenyl)-4,8-dioxaundecane; C470650:2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid; D004095:Dihydropyridines; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D008024:Ligands; D012118:Resorcinols; D013844:Thiazoles; D007501:Iron; D001205:Ascorbic Acid; C050223:desferrithiocin