The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors
Dai, Wei
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Permalink
https://hdl.handle.net/2142/19894
Description
Title
The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors
Author(s)
Dai, Wei
Issue Date
1991
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Biochemistry
Language
eng
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.
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