3-(Alkylthio)-N-hydroxysuccinimide derivatives: potent inhibitors of human leukocyte elastase
Groutas, William C.
Brubaker, Michael J.
Epp, Jeffrey B.
Chong, Lee S.
Stanga, Michael A.
McClenahan, Jerald J.
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Biochimica et biophysica acta. 1993 Aug 7; 1164(3): 283-8.
A series of 3-(alkylthio)-N-hydroxysuccinimide derivatives was synthesized and their inhibitory activity towards human leukocyte elastase (HLE) was investigated. The interaction of the compounds having a 3-alkylthioether side chain (compounds 1 and 2) with HLE was found to involve rapid acylation of the enzyme, followed by total regain of enzymatic activity within 3 h. Interestingly, compounds 3-8, having an oxidized thioether side chain, were found to be highly effective, time-dependent, irreversible inhibitors of the enzyme. The k(obs)/I values for compounds 3-8 ranged between 890 and 24,000 M-1 s-1. These findings demonstrate that, unlike the physiological inhibitor of HLE (alpha-1-proteinase inhibitor), which is inactivated upon oxidation, low-molecular-weight compounds retain and/or show enhanced inhibitory activity towards HLE upon oxidation of the thioether side chain and lay the groundwork for the development of compounds that embody proteinase inhibitory and antioxidant activity.
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