INHIBITION OF HUMAN-LEUKOCYTE ELASTASE BY FATTY ACYL-BENZISOTHIASOLINONE, 1,1-DIOXIDE CONJUGATES (FATTY ACYL-SACCHARINS)

Derivatives of benzisothiazolinone 1,1-dioxide (saccharin) N-acetylate d with aliphatic and aromatic substituted aliphatic acyl groups were p repared. The inhibitory activity of the compounds was assayed against human leucocyte elastase (EC 3.4.21.37) and several other proteases. T he IC50 values for inhibition of the human leucocyte elastase decrease d with increasing length of the acyl residue, and reached a minimum va lue at C-16 (2 muM). This phenomenon and the decrease of the inhibitio n by surfactants or by saturation of the enzyme with palmitic acid, in dicates that in addition to acylation, hydrophobic interactions are al so involved in the inhibition of this proteinase by compounds substitu ted with acyl groups containing at least 12 carbon atoms. The inhibito ry activity of N-palmitoyl-benzisothiazolinone 1,1-dioxide (palmitoyl- saccharin) is about 14 times higher toward human leucocyte elastase th an 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 saturab le fashion to insoluble elastin, and decreased the susceptibility of t his protein to hydrolysis by human leucocyte elastase.