Reduction of the active-site iron by potent inhibitors of lipoxygenases.
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.
Nelson
M J
MJ
Central Research and Development Department and Medical Products Department, E. I. du Pont de Nemours & Co., Wilmington, Delaware 19880-0328.
Batt
D G
DG
Thompson
J S
JS
Wright
S W
SW
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
D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D007501:Iron