N-(sulfonyloxy)phthalimides and analogues are potent inactivators of serine proteases.
A series of 2-(sulfonyloxy) and 2-(acyloxy)-1H-isoindole-1,3(2H)-diones and analogous 1H-benz[de]isoquinoline-1,3(2H)-diones was prepared, and their potential to inactivate chymotrypsin was investigated. The N-(sulfonyloxy) and N-(acyloxy)phthalimides were found to be potent inactivators 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 the range of 250,000 m-1 s-1. N-(Mesyloxy)-phthalimide was the most active compound for inactivation of leukocyte elastase. It was shown that these compounds act as true suicide substrates. Enzyme-catalyzed opening of the heterocyclic ring results in the formation of an acyl-enzyme with attached O-acyl or O-sulfonylhydroxamic acid moiety. Subsequent Lossen rearrangement leads to the formation of a highly reactive isocyanate, which irreversibly modifies the target protease.
Neumann
U
U
Friedrich Miescher-Institut, Basel, Switzerland.
Gütschow
M
M
D000215:Acylation; D000595:Amino Acid Sequence; D002918:Chymotrypsin / Q000187:drug effects*; D004549:Elastin / Q000187:drug effects*; D004793:Enzyme Reactivators; D007962:Leukocytes / Q000201:enzymology; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence
D004793:Enzyme Reactivators; D010797:Phthalimides; D015842:Serine Proteinase Inhibitors; D004549:Elastin; D002918:Chymotrypsin