| Abstract: | Based on the substrate specificity for 5-lipoxygenase and the known stereochemical course of the reaction, a hypothetical model of the enzyme active site was developed and used to design 2 types of selective inhibitors of 5-lipoxygenase. Both inhibitor types used aromatic rings in place of ( Z )-olefins of the substrate and were designed to mimic the nonpolar end of arachidonic acid. One inhibitor type used a carboxylic-acid interaction with the O-binding centre of the enzyme in analogy with known cyclooxygenase inhibitors, whereas a second type employed a hydroxylamine function to interact with a presumed tyrosine or cysteinyl radical predicted to be in the enzyme active site. Selective 5-lipoxygenase inhibitors were 7-(hexyloxy) naphthalene-2-acetic acid ( 1 ) and N -methyl;- N (7-propoxynaphthalene-2-ethyl)hydroxylamine ( 2 ). Structure-activity relationships for both types of inhibitors are discussed. |
