title: Reduction of the active-site iron by potent inhibitors of lipoxygenases.
abstract: Lipoxygenases are non-heme iron dioxygenases that catalyze the oxygenation of polyunsaturated fatty acids. Using soybean lipoxygenase-1 as a model, we have shown that two classes of lipoxygenase inhibitors currently in development as potential antiinflammatory agents obtain a significant amount of their potency by reducing the lipoxygenase active-site iron from the active ferric state to the inactive ferrous state. It is not surprising that the members of the first of these classes, the 2-benzyl-1-naphthols, are reducing agents. The members of the second class, the N-alkyl-hydroxamic acids, were not anticipated to be sufficiently strong reducing agents to be oxidized by the lipoxygenase ferric center; that they are provides additional evidence for that iron having a high reduction potential. This brings to (at least) five the number of classes of lipoxygenase inhibitors that are capable of reducing the active-site ferric ion and suggests the generality of this approach in the rational design of lipoxygenase inhibitors.
authors.affiliation: Central Research and Development Department and Medical Products Department, E. I. du Pont de Nemours & Co., Wilmington, Delaware 19880-0328.
authors.forename: M J
authors.initials: MJ
authors.lastname: Nelson
authors.forename: D G
authors.initials: DG
authors.lastname: Batt
authors.forename: J S
authors.initials: JS
authors.lastname: Thompson
authors.forename: S W
authors.initials: SW
authors.lastname: Wright
mesh_terms: D001665:Binding Sites; D004578:Electron Spin Resonance Spectroscopy; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D009284:Naphthols / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013025:Glycine max / Q000201:enzymology
chemical_list: D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D007501:Iron