Files in this item



application/pdf9210777.pdf (4MB)Restricted to U of Illinois
(no description provided)PDF


Title:The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors
Author(s):Dai, Wei
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Biochemistry
Abstract:Human neutrophil elastase (HNE) has been found to be responsible for the destruction of lung tissue in emphysema. Based on the primary substrate selectivity of HNE, a series of valine mimic protio and bromo enol lactones were designed as HNE inhibitors. General methods were developed for the preparation of $\alpha$- and $\beta$-alkyl-substituted 5-alkynoic acids by the bromoform reaction of the corresponding alkynoic methyl ketone, prepared by the Eschenmoser-Tanabe fragmentation. $\beta$-Methyl- and $\beta,\beta$-dimethyl-5-hexynoic acids were synthesized from commercially available isophorone and 3,5-dimethyl-2-cyclohexen-2-one, respectively. $\alpha$-Substituted 5-hexynoic acids were prepared from 3-ethoxy-2-cyclohexen-1-one, using a novel ZnCl$\sb2$-mediated alkylation of 3-ethoxy-2-cyclohexen-1-one. The most efficient method for preparation of $\alpha$-substituted-5-hexynoic acids involved a four reaction sequence--alkylation of the corresponding $\alpha$-substituted ester with 1,4-dibromobutane, elimination, bromination and bis-dehydrobromination--with an overall yield of 40%. Protio enol lactonizations were performed with mercury(II) catalysis in CH$\sb2$Cl$\sb2$ or CH$\sb2$Cl$\sb2$-H$\sb2$O. Stereoselective Z-bromo enol lactonization was carried out by Br$\sp+$-induced lactonization in the presence of Ag$\sp+$. E-Bromo enol lactones were stereoselectively prepared by an improved method with NBS in CH$\sb2$Cl$\sb2$-H$\sb2$O.
The inhibition of HNE by valine mimic enol lactones was studied in terms of inhibitory potency, efficiency, and nature of the inhibition. The enzyme-inhibitor binding constant and first-order and second-order acylation rate constants were determined for HNE and porcine pancreatic elastase (PPE). The structure-activity relationships show that $\alpha$-substituted enol lactones are more effective inhibitors than $\beta$-substituted ones for HNE. The protio enol lactones with longer $\alpha$-substituted carbon chains (3 carbons) are better inhibitors than those with shorter carbon chains (2 carbons). The $\alpha$-isopropyl bromo enol lactone with a 6-methyl substituent is a less effective k$\sb{\rm cat}$ inhibitor than the 6-unsubstituted one. The enantiomeric selectivity of $\alpha$-iPr6Br may be small due to its low turnover number. No olefinic geometry stereoselectivity, i.e., $\alpha$-iPr6(Z)Br vs $\alpha$-iPr6(E)Br is evident in the inhibition.
Issue Date:1991
Rights Information:Copyright 1991 Dai, Wei
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9210777
OCLC Identifier:(UMI)AAI9210777

This item appears in the following Collection(s)

Item Statistics