Inhibition of human leucocyte elastase by fatty acyl-benzisothiazolinone, 1,1-dioxide conjugates (fatty acyl-saccharins).
Derivatives of benzisothiazolinone 1,1-dioxide (saccharin) N-acetylated with aliphatic and aromatic substituted aliphatic acyl groups were prepared. The inhibitory activity of the compounds was assayed against human leucocyte elastase (EC 3.4.21.37) and several other proteases. The IC50 values for inhibition of the human leucocyte elastase decreased with increasing length of the acyl residue, and reached a minimum value at C16 (2 microM). This phenomenon and the decrease of the inhibition by surfactants or by saturation of the enzyme with palmitic acid, indicates that in addition to acylation, hydrophobic interactions are also involved in the inhibition of this proteinase by compounds substituted with acyl groups containing at least 12 carbon atoms. The inhibitory activity of N-palmitoyl-benzisothiazolinone 1,1-dioxide (palmitoyl-saccharin) is about 14 times higher toward human leucocyte elastase than for thrombin (EC 3.4.21.5), and several hundred times, compared to porcine pancreatic elastase (EC 3.4.21.36) and to plasmin (EC 3.4.21.7). Fatty acylated saccharin derivatives were seen to bind in a saturable fashion to insoluble elastin, and decreased the susceptibility of this protein to hydrolysis by human leucocyte elastase.
Laboratoire de Biologie du Tissu Conjonctif, URA CNRS 1460, Faculté de Médecine, Université Paris XII, Créteil, France.
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Kerneur
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Hornebeck
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Robert
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Moczar
D000595:Amino Acid Sequence; D004549:Elastin / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D012439:Saccharin / Q000031:analogs & derivatives*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D005227:Fatty Acids; D015842:Serine Proteinase Inhibitors; D004549:Elastin; D010196:Pancreatic Elastase; D012439:Saccharin