Issue 1, 2003
From the journal:

Organic & Biomolecular Chemistry

Structure–reactivity relationships in the inactivation of elastase by β-sultams

Paul S. Hinchliffe,a   J. Matthew Wood,a   Andrew M. Davis,b   Rupert P. Austin,b   R. Paul Beckettc  and  Michael I. Page*a  

* Corresponding authors

a Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, UK

b AstraZeneca R&D, Charnwood, Bakewell Road, Loughborough, UK

c British Biotech Pharmaceuticals Limited, Wellington Road, Oxford, UK

Abstract

N-Acyl-β-sultams are time dependent irreversible active site directed inhibitors of elastase. The rate of inactivation is first order with respect to β-sultam concentration and the second order rate constants show a similar dependence on pH to that for the hydrolysis of a peptide substrate. Inactivation is due to the formation of a stable l ∶ l enzyme inhibitor complex as a result of the active site serine being sulfonylated by the β-sultam. Ring opening of the β-sultam occurs by S–N fission in contrast to the C–N fission observed in the acylation of elastase by N-acylsulfonamides. Structure–activity effects are compared between sulfonylation of the enzyme and alkaline hydrolysis. Variation in 4-alkyl and N-substituted β-sultams causes differences in the rates of inactivation by 4 orders of magnitude.

Graphical abstract: Structure–reactivity relationships in the inactivation of elastase by β-sultams

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Article information

DOI
https://doi.org/10.1039/B208079F
Article type
Paper
Submitted
20 Aug 2002
Accepted
30 Sep 2002
First published
27 Nov 2002

Org. Biomol. Chem., 2003,1, 67-80

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Structure–reactivity relationships in the inactivation of elastase by β-sultams

P. S. Hinchliffe, J. M. Wood, A. M. Davis, R. P. Austin, R. P. Beckett and M. I. Page, Org. Biomol. Chem., 2003, 1, 67 DOI: 10.1039/B208079F

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