Synthesis, hydrolysis, biochemical and theoretical evaluation of 1,4-bis(alkoxycarbonyl)azetidin-2-ones as potential elastase inhibitors
(2002) Tetrahedron — Vol. 58, n° 12, p. 2423-2433 (2002)
Files
pdfdocument.pdf
Restricted Access - Adobe PDF
- 560.83 KB
Details
- Authors
- Abstract
- A series of 1,4-bis(alkoxycarbonyl)azetidin-2-ones, designed as potential suicide-inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). The most active compound (K(i)similar to10 muM; reversible inhibitor) was equipped with phenethyloxycarbonyl and benzyloxycarbonyl side-chains at positions N1 and C4, respectively, with the (S)-configuration. H-1 NMR spectroscopic analysis of the reaction mixtures showed that the ester function is preferentially hydrolyzed, in both chemical and enzyme-catalyzed reactions, with regard to the azetidinone and urethane functions. Considering the three potentially sensitive carbonyl functions and the two stereoisomers, ab initio calculations were performed to determine the energetic barriers required to reach the transition state structures of hydrolysis in a model of the enzyme pocket. (C) 2002 Elsevier Science Ltd. All rights reserved.
- Affiliations
Citations
Gérard, S., Dive, G., Clamot, B., Touillaux, R., & Marchand-Brynaert, J. (2002). Synthesis, hydrolysis, biochemical and theoretical evaluation of 1,4-bis(alkoxycarbonyl)azetidin-2-ones as potential elastase inhibitors. Tetrahedron, 58(12), 2423-2433. https://doi.org/10.1016/S0040-4020(02)00112-6 (Original work published 2002)