3-(Alkylthio)-N-hydroxysuccinimide derivatives: potent inhibitors of human leukocyte elastase.
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.
Groutas
W C
WC
Department of Chemistry, Wichita State University, KS 67208.
Venkataraman
R
R
Brubaker
M J
MJ
Epp
J B
JB
Chong
L S
LS
Stanga
M A
MA
McClenahan
J J
JJ
Tagusagawa
F
F
D000215:Acylation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013388:Succinimides; D013440:Sulfides; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase