Michael A. Stanga

Isoxazoline derivatives as potential inhibitors of the proteolytic enzymes human leukocyte elastase, cathepsin G and proteinase 3: a structure-activity relationship study.

Abstract A series of isoxazoline derivatives were synthesized and investigated for their in vitro inhibitory activity towards human leukocyte elastase, cathepsin G and proteinase 3.

Inhibitors of human neutrophil cathepsin G : structural and biochemical studies

The interaction of a series of sulfonate and phosphate esters derived from N-hydroxysuccinimide with human leukocyte cathepsin G was investigated. The synthesized compounds were found to be time-dependent inhibitors of the enzyme. The composite interplay of steric and electronic effects leads to the formation of acyl enzymes of variable stability, ultimately resulting in partial or full recovery of enzymatic activity. Compounds acting via phosphorylation of the active site serine inactivated the enzyme rapidly and irreversibly.

Sulfonate salts of amino acids: Novel inhibitors of the serine proteinases

A series of amino acid-derived sulfonate salts have been synthesized. They were found to inactivate efficiently and selectively human leukocyte elastase. The sulfonate salts of the methyl esters of L-norleucine, L-norvaline and L-valine were the most potent. The enzyme is inactivated irreversibly with concomitant release of bisulfite ion. The results demonstrate for the first time that ionic compounds can indeed function as novel inhibitors for the serine proteinases.

Hydantoin Derivatives. A New Class of Inhibitors of Human Leukocyte Elastase

Derivatives of hydantoin have been found to inactivate human leukocyte elastase irreversibly. Chymotrypsin and cathepsin G are also inhibited by these compounds.

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.

Enantioselective inhibition of human leukocyte elastase

(RS)-Diethyl-2-benzyl-succinate was resolved using alpha-chymotrypsin. The two enantiomers were then elaborated to yield (S)-(+) and (R)-(-)-3-benzyl-N-[(methyl-sulfonyl)oxy]succinimide and the inhibitory activity of the two enantiomers toward human leukocyte elastase was subsequently determined. The k2/KI values for the R and S isomers were found to be 330 and 1500 M-1 s-1, respectively.

Inhibition of human leukocyte elastase and cathepsin G by isoxazoline derivatives

Abstract The interaction of a series of derivatives of cis-N-hydroxy-3-phenyl-2-isoxazoline-4,5-dicarboximide toward human leukocyte elastase and cathepsin G was investigated. Both enzymes were rapidly acylated and the corresponding acyl enzymes exhibited variable stability.

Heterocyclic inhibitors of human leukocyte elastase: 3-Hydroxypyridazopyrimidine, 3-hydroxypyridopyrimidine and 3-hydroxyquinazoline-2,4-1H,3H0dione derivatives

Abstract Several heterocyclic compounds derived from 3-hydroxypyridazopyrimidine-(I), 3-hydroxypyridopyrimidine-(II) and 3-hydroxyquinazoline-2,4(1H,3H)diones-(III) have been found to be time-dependent irreversible inhibitors of human leukocyte elastase.