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Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted ?-lactams as novel inhibitors of human leukocyte elastase

Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted ?-lactams as novel inhibitors of human leukocyte elastase
Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted ?-lactams as novel inhibitors of human leukocyte elastase
Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.
neutrophil elastase, chemical-reactivity, 1.84-a resolution, drug design, esters, antibiotics, complex, acid
0022-2623
4861-4870
Moreira, Rui
d7a6f33d-f4d9-493e-a5b7-c9fa467e98d4
Santana, Ana Bela
ce35f046-d209-4118-8d53-974b9da6ffd2
Iley, Jim
1b8a12ce-eac3-405c-ac57-c3929a895236
Neres, João
209a809f-7e8e-40c8-b206-4266a890d6cc
Douglas, Kenneth T.
b6e45088-305d-46b3-b70b-cb79a5d6756c
Horton, Peter N.
48f162d1-d6ce-43c1-aeef-d58b3ec702b8
Hursthouse, Michael B.
57a2ddf9-b1b3-4f38-bfe9-ef2f526388da
Moreira, Rui
d7a6f33d-f4d9-493e-a5b7-c9fa467e98d4
Santana, Ana Bela
ce35f046-d209-4118-8d53-974b9da6ffd2
Iley, Jim
1b8a12ce-eac3-405c-ac57-c3929a895236
Neres, João
209a809f-7e8e-40c8-b206-4266a890d6cc
Douglas, Kenneth T.
b6e45088-305d-46b3-b70b-cb79a5d6756c
Horton, Peter N.
48f162d1-d6ce-43c1-aeef-d58b3ec702b8
Hursthouse, Michael B.
57a2ddf9-b1b3-4f38-bfe9-ef2f526388da

Moreira, Rui, Santana, Ana Bela, Iley, Jim, Neres, João, Douglas, Kenneth T., Horton, Peter N. and Hursthouse, Michael B. (2005) Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted ?-lactams as novel inhibitors of human leukocyte elastase. Journal of Medicinal Chemistry, 48 (15), 4861-4870. (doi:10.1021/jm0501331).

Record type: Article

Abstract

Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.

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More information

Published date: 28 July 2005
Keywords: neutrophil elastase, chemical-reactivity, 1.84-a resolution, drug design, esters, antibiotics, complex, acid

Identifiers

Local EPrints ID: 20870
URI: http://eprints.soton.ac.uk/id/eprint/20870
ISSN: 0022-2623
PURE UUID: 51486b29-4528-4487-b0a9-a204ca3d6a7f

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Date deposited: 02 Mar 2006
Last modified: 15 Mar 2024 06:26

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Contributors

Author: Rui Moreira
Author: Ana Bela Santana
Author: Jim Iley
Author: João Neres
Author: Kenneth T. Douglas
Author: Peter N. Horton

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