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Design and Synthesis of 5‐Lipoxygenase Inhibitors
Author(s) -
Strasser Michael,
Cooper Philip,
Dewald Beatrice,
Payne Trevor
Publication year - 1988
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19880710528
Subject(s) - chemistry , hydroxylamine , lipoxygenase , stereochemistry , substrate (aquarium) , active site , enzyme , arachidonic acid , enzyme inhibitor , naphthalene , biochemistry , organic chemistry , oceanography , geology
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.