Synthesis and biological evaluation of hydroxamate-based iron chelators.
A new and versatile route to desferrioxamine B (DFO, 1) is described. Hydroxamate reagent 4 was elaborated in a series of high yield steps to the tert-butoxycarbonyl nitrile 11, which provided DFO in three transformations. The intermediate 11 could also be utilized in the preparation of DFO analogues which contain terminal N-acyl groups other than acetyl. The methodology was further employed in the syntheses of the DFO polyether analogues 2 and 3, beginning with the 3,6,9-trioxadecylation of N-(tert-butoxycarbonyl)-O-benzylhydroxylamine. Polyethers 2 and 3 are neutral molecules, which are somewhat more lipophilic than the parent DFO. Polyether hydroxamate 2 was shown to be nearly 3 times as effective as desferrioxamine at clearing iron in rats.
Bergeron
R J
RJ
Department of Medicinal Chemistry, J. Hillis Miller Health Center, University of Florida, Gainesville 32610.
Wiegand
J
J
McManis
J S
JS
Perumal
P T
PT
D000818:Animals; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D003676:Deferoxamine