The desferrithiocin pharmacophore.
The (S)-desferrithiocin (DFT) skeleton is shown to be a useful pharmacophore on which to design orally effective iron chelators. While the study clearly indicates that formal reduction of the desazadesmethyldesferrithiocin thiazoline to a thiazolidine (6), expansion of the desmethyldesferrithiocin thiazoline to a thiazine (7), or substitution of the thiazoline sulfur of of desazedes-methyldesferrithiocin by an oxygen (8 and 9) lead to a substantial loss of activity, conversion of (S)-desmethyldesferrithiocin (1) to an N-methylhydroxamate (4) or to the hexacoordinate dihydroxamate ligand (5) results in active compounds. This investigation thus demonstrates which structural components of the siderophore are required for iron clearance after oral administration and suggests the use of the desferrithiocin platform as a vector for other chelators.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610.
Liu
C Z
CZ
McManis
J S
JS
Xia
M X
MX
Algee
S E
SE
Wiegand
J
J
D000818:Animals; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron; C050223:desferrithiocin