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Dai, Wei 2011-05-07T12:22:05Z 2011-05-07T12:22:05Z 10000-01-01 1991 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. Made available in DSpace on 2011-05-07T12:22:05Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9210777.pdf: 4313973 bytes, checksum: 8f1fef2cc6cf0eb5f2c6e162d01f5c6c (MD5) Previous issue date: 1991 Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:40:09Z Item is restricted indefinitely. Restriction data tranferred 2014-07-01T11:17:08-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission ETDs are only available to UIUC Users without author permission U of I Only AAI9210777 (UMI)AAI9210777 http://hdl.handle.net/2142/19894 eng Copyright 1991 Dai, Wei Chemistry, Biochemistry The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.