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oai:www.ideals.illinois.edu:2142/22319 2023-07-10 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

Katzenellenbogen, John A. Rai, Roopa 2011-05-07T13:36:05Z 2011-05-07T13:36:05Z 10000-01-01 1992 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 AAI9236573 (UMI)AAI9236573 http://hdl.handle.net/2142/22319 eng Copyright 1992 Rai, Roopa Chemistry, Organic Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.