title: Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation.
abstract: Attachment of various iron chelating moieties to hydrophobic steroids greatly enhanced their abilities to inhibit iron-dependent lipid peroxidation. Using whole rat brain homogenates, lipid peroxidation initiated by the addition of 200 microM Fe2+ was assessed by the formation of thiobarbituric acid reactive products (TBAR). Under these conditions, 50% inhibitory concentrations of Fe3+ chelators such as desferrioxamine or N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound II) were around 170 and 50 microM respectively. Coupling desferrioxamine or compound II to a steroid at the D ring increased their potency in lipid peroxidation assays by 5- to 10-fold. Evidence that inhibition of lipid peroxidation by the steroid-chelator adducts was due to iron chelation was suggested by the fact that methylation of the catechol oxygens of compound II, which are essential for chelation, completely eliminated activity of the steroid adduct. A series of 21-aminosteroids which complex Fe2+ iron and potently inhibit iron-dependent lipid peroxidation has also been synthesized. Coupling Fe2+ chelators to hydrophobic steroids increased their inhibitory potencies by as much as 10- to 100-fold. Some steroid-based Fe2+ chelators stimulated lipid peroxidation at low concentrations in the presence of Fe3+. The degree of stimulation was related to the affinity of a compound for Fe2+ with the stronger chelators causing greater stimulation. The most potent inhibitors of lipid peroxidation in the 21-aminosteroid series were found to be those compounds forming the weakest Fe2+ complexes. The findings suggest that it is iron at or near the membrane that is responsible for the catalysis of lipid peroxidation. The compounds described should provide useful tools for studies of the involvement of iron in the lipid peroxidation process.
authors.affiliation: Central Nervous Systems Diseases Research Unit, Upjohn Company, Kalamazoo, MI 49001.
authors.forename: J M
authors.initials: JM
authors.lastname: Braughler
authors.forename: P S
authors.initials: PS
authors.lastname: Burton
authors.forename: R L
authors.initials: RL
authors.lastname: Chase
authors.forename: J F
authors.initials: JF
authors.lastname: Pregenzer
authors.forename: E J
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: F J
authors.initials: FJ
authors.lastname: VanDoornik
authors.forename: J M
authors.initials: JM
authors.lastname: Tustin
authors.forename: D E
authors.initials: DE
authors.lastname: Ayer
authors.forename: G L
authors.initials: GL
authors.lastname: Bundy
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D010084:Oxidation-Reduction; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D013256:Steroids / Q000494:pharmacology
chemical_list: D007502:Iron Chelating Agents; D011281:Pregnatrienes; D013256:Steroids; C053356:U 74500A; D003676:Deferoxamine