Guanidinophenyl-substituted enol lactones as selective, mechanism-based inhibitors of trypsin-like serine proteases.
We have synthesized four guanidinophenyl-substituted protio enol and iodo enol lactones (3-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (1), 3-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (2), 4-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone+ ++ (3), and 4-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (4)) and tested them for inhibitory activity against some trypsin-like enzymes, namely trypsin, urokinase, tissue plasminogen activator (t-PA), plasmin, and thrombin, as well as alpha-chymotrypsin and human neutrophil elastase (HNE). The beta-aryl-substituted protio lactone 3 was a potent alternate substrate inhibitor of trypsin and urokinase. The alpha-aryl-substituted iodo lactone 2 was a permanent inactivator of urokinase, plasmin, t-PA, thrombin, and alpha-chymotrypsin, exhibiting a relatively high specificity for the former two enzymes. In general, these compounds showed a preference for inactivating trypsin-like enzymes over alpha-chymotrypsin and HNE. Also, within the class of trypsin-like enzymes, there was generally good selectivity of inhibition.
Rai
R
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Department of Chemistry, University of Illinois, Urbana 61801.
Katzenellenbogen
J A
JA
D000595:Amino Acid Sequence; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006146:Guanidines; D007783:Lactones; D015842:Serine Proteinase Inhibitors