ChemInform Abstract: Design and Synthesis of 5-Lipoxygenase Inhibitors.
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 is developed and used to design 2 types of selective inhibitors of 5-lipoxygenase.
ChemInform 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 is developed and used to design 2 types of selective inhibitors of 5-lipoxygenase. One inhibitor type represented by, e.g., the compounds (IV)-(VI) uses a carboxylic acid interaction with the O-binding center of the enzyme in analogy with known cyclooxygenase inhibitors. The second type represented by, e.g., the compounds (XII)-(XVI) employs a hydroxylamine function to interact with a presumed tyrosine or cysteinyl radical predicted to be in the enzyme active site. The compounds (Va) and (XIVc) are found to be the most effective inhibitors. Structure-activity relationships for both types of inhibitors are discussed. The syntheses of the various compounds, examples of which are given in the scheme (→ (IV), → (XII)), are described.
