143774-31-6Relevant articles and documents
Effect of Conformational Mobility and Hydrogen-Bonding Interactions on the Selectivity of Some Guanidinoaryl-Substituted Mechanism-Based Inhibitors of Trypsin-like Serine Proteases
Rai, Roopa,Katzenellenbogen, John A.
, p. 4297 - 4305 (2007/10/02)
Previously, we had reported that some guanidino-substituted α- and β-aryl enol lactones I and II behaved as selective, mechanism-based inhibitors of some trypsin-like proteases (Rai, R.; Katzenellenbogen.J.A.J.Med.Chem., submitted).In this study, we describe the synthesis and kinetic evaluation of some related, guanidino-substituted enol lactones having greater conformational mobility and affording additional hydrogen-bonding sites at the active site.The α-aryl-substituted lactones 1 and 2, which have greater conformational mobility in the guanidinoaryl linkage than I, selectively inhibited the trypsin-like enzymes, and they were relatively poor inactivators of α-chymotrypsin and human neutrophil elastase (HNE).The iodo enol lactone 2 permanently inactivated trypsin, urokinase, tissue plasminogen activator, and plasmin, showing exceptionally high specificity in its interaction with trypsin and urokinase.The selectivity pattern exhibited by the closely related, conformationally less mobile α-aryl-substituted iodo lactone Ib, which was previously shown to be a selective suicide substrate of urokinase and plasmin, provides an interesting comparison.The α-benzamido-substituted lactones 3 and 4, which afford an additional site for active-site hydrogen bonding, were found to be very potent alternate substrate inhibitors of trypsin and urokinase.In addition, the iodo lactone 4 permanently inactivated α-chymotropsin.The importance of secondary interactions in increasing the specificities in the case of α-chymotrypsin is discussed.
