Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases
Rai, Roopa
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Permalink
https://hdl.handle.net/2142/22319
Description
Title
Guanidino-aryl substituted enol lactones: Selective and potent mechanism-based inhibitors of trypsin-like serine proteases
Author(s)
Rai, Roopa
Issue Date
1992
Doctoral Committee Chair(s)
Katzenellenbogen, John A.
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, Organic
Language
eng
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).
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.
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