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Titolo:
Synthesis and in-vitro evaluation of novel low molecular weight thiocarbamates as inhibitors of human leukocyte elastase
Autore:
Rodis, NP; Digenis, GA;
Indirizzi:
Univ Kentucky, Coll Pharm, Div Med Chem & Pharmaceut, Lexington, KY 40536 USA Univ Kentucky Lexington KY USA 40536 Pharmaceut, Lexington, KY 40536 USA
Titolo Testata:
JOURNAL OF ENZYME INHIBITION
fascicolo: 2, volume: 16, anno: 2001,
pagine: 95 - 105
SICI:
8755-5093(2001)16:2<95:SAIEON>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
PORCINE PANCREATIC ELASTASE; HUMAN NEUTROPHIL ELASTASE; CATHEPSIN-G; SERINE PROTEASES; REACTIVE SITE; SUBSTRATE; COMPLEX; STATES; PURIFICATION; PROTEINASES;
Keywords:
human leukocyte elastase; thiocarbamates; irreversible inhibition; HLE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Digenis, GA Univ Kentucky, Coll Pharm, Div Med Chem & Pharmaceut, Rose St,Lexington, KY 40536 USA Univ Kentucky Rose St Lexington KY USA 40536 ton, KY 40536 USA
Citazione:
N.P. Rodis e G.A. Digenis, "Synthesis and in-vitro evaluation of novel low molecular weight thiocarbamates as inhibitors of human leukocyte elastase", J ENZ INHIB, 16(2), 2001, pp. 95-105

Abstract

A series of novel low molecular weight thiocarbamate esters (1e-6e) were synthesized and evaluated as inhibitors of human leukocyte elastase (HLE). The thiocarbamate esters studied consist of a substituted primary or secondary aliphatic or aromatic amine and a 1-phenyl-1H-tetrazole-5-thiol (Table 1). The HLE catalyzed hydrolysis of N-methoxysuccinyl- L-Ala-LAla-L-Pro-L-Val-p-nitroanilide substrate was utilized as the measure of inhibition. N-n-butyl, 1-phenyl-1H-tetrazole- 5-thiocarbamate (1e) exhibited the highest inhibitory activity (k(obs)/[1] = 2.1 x 10(5) M-1 min(-1)) and N-allyl, 1-phenyl-2H-tetrazole-5-thiocarbamate (2e) (K-obs/[I]] = 6.1 x 10(4) M-2 . min(-1)) exhibited the second highest inhibitory activity of all the thiocarbamates. The aromatic N-phenyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (4e) showed the lowest inhibitory activity (K-obs/[I] = 1.9 x 10(2) M-1 (.) min(-1)) among the N-monosubstituted derivatives, similar to that of N-ethyl-N-n-butyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (5e) (K-obs/[I] = 1.8 x 10(2) M-1(.) min(-1)). The N-isopropyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (3e) (K-obs/[I] = 3.3 x 10(3) M (1) (.) min(-1)) was about 10 fold more active than (4e) and N, N-diisopropyl, 1-phenyl-1H-tetrazole- Ei-thiocarbamate (6e)showed no inhibitory activity against HLE. In the present work less than 3% of HLE specific activity was regained after 24 hours incubation with eachof the tested N-monosubstituted thiocarbamates (1e-4e). The time-dependentinhibition of HLE by the thiocarbamate compounds (1e-5e) seems to involve the interaction and possible chemical modification of one enzyme residue. Straight chain nonpolar aliphatic substituents on the nitrogen of the thiocarbamate functionality may be essential for high inhibitory activity. As thedegree of substitution (branching) on the nitrogen of the thiocarbamate functionality increases the inhibitory activity of the compounds decreases. The time-dependent inhibition of HLE and the slow deacylation rates by the N-monosubstituted thiocarbamates are consistent with irreversible inhibition.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/06/20 alle ore 14:04:22