U. Neumann et M. Gutschow, N-(SULFONYLOXY)PHTHALIMIDES AND ANALOGS ARE POTENT INACTIVATORS OF SERINE PROTEASES, The Journal of biological chemistry, 269(34), 1994, pp. 21561-21567
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.