Hydroxamate-based iron chelators: combinatorial syntheses of desferrioxamine B analogues and evaluation of binding affinities.
This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.
MetaPhore Pharmaceuticals, Inc., 1910 Innerbelt Business Center Drive, Saint Louis, MO 63114, USA.
Amruta R
AR
Poreddy
Otto F
OF
Schall
Todd A
TA
Osiek
James R
JR
Wheatley
Denise D
DD
Beusen
Garland R
GR
Marshall
Urszula
U
Slomczynska
D000478:Alkylation; D002851:Chromatography, High Pressure Liquid; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000737:chemistry*; D005290:Ferric Compounds / Q000737:chemistry; D006877:Hydroxamic Acids / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000138:chemical synthesis*; D008956:Models, Chemical; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000737:chemistry
D005290:Ferric Compounds; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D015125:Oxyquinoline; C013053:8-hydroxyquinoline-5-sulfonic acid; D003676:Deferoxamine