{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/19894"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/19894","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors","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.","abstract_html":"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 <span class=\"etd-inline-math\">&alpha;</span>- and <span class=\"etd-inline-math\">&beta;</span>-alkyl-substituted 5-alkynoic acids by the bromoform reaction of the corresponding alkynoic methyl ketone, prepared by the Eschenmoser-Tanabe fragmentation. <span class=\"etd-inline-math\">&beta;</span>-Methyl- and <span class=\"etd-inline-math\">&beta;,&beta;</span>-dimethyl-5-hexynoic acids were synthesized from commercially available isophorone and 3,5-dimethyl-2-cyclohexen-2-one, respectively. <span class=\"etd-inline-math\">&alpha;</span>-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 <span class=\"etd-inline-math\">&alpha;</span>-substituted-5-hexynoic acids involved a four reaction sequence--alkylation of the corresponding <span class=\"etd-inline-math\">&alpha;</span>-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.","abstract_has_math":true,"creators":["Dai, Wei"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-05-07T12:22:05Z","date_published":"2011-05-07T12:22:05Z","updated_at":"2026-07-22T22:25:14Z","subjects":["Chemistry, Biochemistry"],"languages":["eng"],"rights":["Copyright 1991 Dai, Wei"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9210777","(UMI)AAI9210777"],"render_values":[{"text":"AAI9210777","href":null,"code":true},{"text":"(UMI)AAI9210777","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/19894","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Dai, Wei"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-05-07T12:22:05Z","10000-01-01","1991"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Biochemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 1991 Dai, Wei"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9210777","(UMI)AAI9210777","http://hdl.handle.net/2142/19894"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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"]},{"key":"dc:title","label":"Title","values":["The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors"]}]}],"canonical_facts":{"dc:creator":["Dai, Wei"],"dc:date":["2011-05-07T12:22:05Z","10000-01-01","1991"],"dc:description":["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"],"dc:identifier":["AAI9210777","(UMI)AAI9210777","http://hdl.handle.net/2142/19894"],"dc:language":["eng"],"dc:rights":["Copyright 1991 Dai, Wei"],"dc:subject":["Chemistry, Biochemistry"],"dc:title":["The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors"],"dc:type":["text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:14Z"}