{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/22319"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/22319","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases","abstract":"Two classes of valero enol lactones were synthesized and examined as potential inhibitors of trypsin-like serine proteases. The first class of protio and iodo enol lactones had either a 4-guanidino phenyl substituent (3-(4-guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (1) and 3-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (2)) or a 4-guanidinomethyl phenyl substituent (3-(4-guanidinomethylphenyl)-6-methylidene tetrahydro-2-pyranone (3) and 3-(4-guanidinomethylphenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (4)) at the $\\alpha$-position. The $\\beta$-aryl substituted system included the 4-guanidino phenyl substituted protio and iodo enol lactones 4-(4-guanidinophenyl)-6-(methylidene) tetrahydro-2-pyranone (5) and 4-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (6), as well as the corresponding $\\alpha$-benzamido substituted analogs (3R*,4R*) 3-benzamido-4-(guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (7) and (3R*,4R*) 3-benzamido-4-(4-guanidinophenyl)-6(E)-iodomethylidene tetrahydro-2-pyranone (8).","abstract_html":"Two classes of valero enol lactones were synthesized and examined as potential inhibitors of trypsin-like serine proteases. The first class of protio and iodo enol lactones had either a 4-guanidino phenyl substituent (3-(4-guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (1) and 3-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (2)) or a 4-guanidinomethyl phenyl substituent (3-(4-guanidinomethylphenyl)-6-methylidene tetrahydro-2-pyranone (3) and 3-(4-guanidinomethylphenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (4)) at the <span class=\"etd-inline-math\">&alpha;</span>-position. The <span class=\"etd-inline-math\">&beta;</span>-aryl substituted system included the 4-guanidino phenyl substituted protio and iodo enol lactones 4-(4-guanidinophenyl)-6-(methylidene) tetrahydro-2-pyranone (5) and 4-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (6), as well as the corresponding <span class=\"etd-inline-math\">&alpha;</span>-benzamido substituted analogs (3R*,4R*) 3-benzamido-4-(guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (7) and (3R*,4R*) 3-benzamido-4-(4-guanidinophenyl)-6(E)-iodomethylidene tetrahydro-2-pyranone (8).","abstract_has_math":true,"creators":["Rai, Roopa"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Katzenellenbogen, John A."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-05-07T13:36:05Z","date_published":"2011-05-07T13:36:05Z","updated_at":"2026-07-22T22:25:19Z","subjects":["Chemistry, Organic"],"languages":["eng"],"rights":["Copyright 1992 Rai, Roopa"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9236573","(UMI)AAI9236573"],"render_values":[{"text":"AAI9236573","href":null,"code":true},{"text":"(UMI)AAI9236573","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/22319","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Katzenellenbogen, John A."]},{"key":"dc:creator","label":"Author","values":["Rai, Roopa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-05-07T13:36:05Z","10000-01-01","1992"]},{"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, Organic"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 1992 Rai, Roopa"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["AAI9236573","(UMI)AAI9236573","http://hdl.handle.net/2142/22319"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Two classes of valero enol lactones were synthesized and examined as potential inhibitors of trypsin-like serine proteases. The first class of protio and iodo enol lactones had either a 4-guanidino phenyl substituent (3-(4-guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (1) and 3-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (2)) or a 4-guanidinomethyl phenyl substituent (3-(4-guanidinomethylphenyl)-6-methylidene tetrahydro-2-pyranone (3) and 3-(4-guanidinomethylphenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (4)) at the $\\alpha$-position. The $\\beta$-aryl substituted system included the 4-guanidino phenyl substituted protio and iodo enol lactones 4-(4-guanidinophenyl)-6-(methylidene) tetrahydro-2-pyranone (5) and 4-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (6), as well as the corresponding $\\alpha$-benzamido substituted analogs (3R*,4R*) 3-benzamido-4-(guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (7) and (3R*,4R*) 3-benzamido-4-(4-guanidinophenyl)-6(E)-iodomethylidene tetrahydro-2-pyranone (8).","The lactones were tested for inhibitory activity against some trypsin-like enzymes, namely tyypsin, urokinase, tissue plasminogen activator (t-PA), plasmin and thrombin, as well as $\\alpha$-chymotyypsin and human neutrophil elastase (HNE). The $\\alpha$-(guanidino phenyl) substituted iodo lactone 2 was a suicide substrate of urokinase, plasmin, t-PA, thrombin and $\\alpha$-chymotrypsin, with an exceptionally high specificity for the former two enzymes. The guanidinomethyl phenyl substituted iodo lactone 4 was a suicide substrate of all the trypsin-like enzymes tested, exhibiting exceptionally high specificity in its inhibition of trypsin and urokinase. The corresponding protio lactone 3 was an alternate substrate inhibitor of urokinase and thrombin, its potency being attributed to moderately stable acyl enzyme intermediates. Among the $\\beta$-aryl substituted lactones, no new suicide substrates for trypsin-like enzymes were found. The lactones 5 and 6 were alternate substrate inhibitors, selective for the trypsin-like enzymes. The iodo lactone 8 was a potent transient inactivator of trypsin and urokinase; in addition, it was a very selective and effective suicide substrate of $\\alpha$-chymotrypsin.","In general, the guanidino-aryl substituted enol lactones showed selectivity and superior specificities for trypsin-like enzymes, over $\\alpha$-chymotrypsin and HNE. In addition, there was some selectivity within the class of trypsin-like enzymes. The $\\alpha$-aryl substituted iodo lactones were suicide substrates and the $\\beta$-aryl substituted systems were potent alternate substrate inhibitors of some of the trypsin-like enzymes.","Made available in DSpace on 2011-05-07T13:36:05Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9236573.pdf: 3308353 bytes, checksum: f6ab6c20a66f57ae49d3c0c41536dad1 (MD5) Previous issue date: 1992","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:56:48Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:26:35-05:00 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":["Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases"]}]}],"canonical_facts":{"dc:contributor":["Katzenellenbogen, John A."],"dc:creator":["Rai, Roopa"],"dc:date":["2011-05-07T13:36:05Z","10000-01-01","1992"],"dc:description":["Two classes of valero enol lactones were synthesized and examined as potential inhibitors of trypsin-like serine proteases. The first class of protio and iodo enol lactones had either a 4-guanidino phenyl substituent (3-(4-guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (1) and 3-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (2)) or a 4-guanidinomethyl phenyl substituent (3-(4-guanidinomethylphenyl)-6-methylidene tetrahydro-2-pyranone (3) and 3-(4-guanidinomethylphenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (4)) at the $\\alpha$-position. The $\\beta$-aryl substituted system included the 4-guanidino phenyl substituted protio and iodo enol lactones 4-(4-guanidinophenyl)-6-(methylidene) tetrahydro-2-pyranone (5) and 4-(4-guanidinophenyl)-6-(E)-iodomethylidene tetrahydro-2-pyranone (6), as well as the corresponding $\\alpha$-benzamido substituted analogs (3R*,4R*) 3-benzamido-4-(guanidinophenyl)-6-methylidene tetrahydro-2-pyranone (7) and (3R*,4R*) 3-benzamido-4-(4-guanidinophenyl)-6(E)-iodomethylidene tetrahydro-2-pyranone (8).","The lactones were tested for inhibitory activity against some trypsin-like enzymes, namely tyypsin, urokinase, tissue plasminogen activator (t-PA), plasmin and thrombin, as well as $\\alpha$-chymotyypsin and human neutrophil elastase (HNE). The $\\alpha$-(guanidino phenyl) substituted iodo lactone 2 was a suicide substrate of urokinase, plasmin, t-PA, thrombin and $\\alpha$-chymotrypsin, with an exceptionally high specificity for the former two enzymes. The guanidinomethyl phenyl substituted iodo lactone 4 was a suicide substrate of all the trypsin-like enzymes tested, exhibiting exceptionally high specificity in its inhibition of trypsin and urokinase. The corresponding protio lactone 3 was an alternate substrate inhibitor of urokinase and thrombin, its potency being attributed to moderately stable acyl enzyme intermediates. Among the $\\beta$-aryl substituted lactones, no new suicide substrates for trypsin-like enzymes were found. The lactones 5 and 6 were alternate substrate inhibitors, selective for the trypsin-like enzymes. The iodo lactone 8 was a potent transient inactivator of trypsin and urokinase; in addition, it was a very selective and effective suicide substrate of $\\alpha$-chymotrypsin.","In general, the guanidino-aryl substituted enol lactones showed selectivity and superior specificities for trypsin-like enzymes, over $\\alpha$-chymotrypsin and HNE. In addition, there was some selectivity within the class of trypsin-like enzymes. The $\\alpha$-aryl substituted iodo lactones were suicide substrates and the $\\beta$-aryl substituted systems were potent alternate substrate inhibitors of some of the trypsin-like enzymes.","Made available in DSpace on 2011-05-07T13:36:05Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9236573.pdf: 3308353 bytes, checksum: f6ab6c20a66f57ae49d3c0c41536dad1 (MD5) Previous issue date: 1992","Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:56:48Z Item is restricted indefinitely.","Restriction data tranferred 2014-07-01T11:26:35-05:00 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":["AAI9236573","(UMI)AAI9236573","http://hdl.handle.net/2142/22319"],"dc:language":["eng"],"dc:rights":["Copyright 1992 Rai, Roopa"],"dc:subject":["Chemistry, Organic"],"dc:title":["Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases"],"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":"2026-07-22T22:25:19Z"}