N-(SULFONYLOXY)PHTHALIMIDES AND ANALOGS ARE POTENT INACTIVATORS OF SERINE PROTEASES

A series of 2-(sulfonyloxy) and 2-(acyloxy)-1H-isoindole-1,3(2H)-dione s and analogous 1H-benz[de]isoquinoline-1,3(2H)-diones was prepared, a nd their potential to inactivate chymotrypsin was investigated. The N- (sulfonyloxy) and N-(acyloxy)phthalimides were found to be potent inac tivators of chymotrypsin and related serine proteinases. For the most active compounds, N-(dansyloxy)phthalimide and N-(tosyloxy)phthalimide , the second-order rate constant of chymotrypsin inactivation was in t he range of 250,000 M(-1) s(-1). N-(Mesyloxy)phthalimide was the most active compound for inactivation of leukocyte elastase. It was shown t hat these compounds act as true suicide substrates. Enzyme-catalyzed o pening of the heterocyclic ring results in the formation of an acyl-en zyme with attached O-acyl or O-sulfonylhydroxamic acid moiety. Subsequ ent Lossen rearrangement leads to the formation of a highly reactive i socyanate, which irreversibly modifies the target protease.