Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21515
Título: Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted beta-lactams as novel inhibitors of human leukocyte elastase
Autor: Moreira, R
Santana, AB
Iley, J
Neres, J
Douglas, KT
Horton, PN
Hursthouse, MB
Palavras-chave: Chemistry, Medicinal
Data: 2005
Citação: JOURNAL OF MEDICINAL CHEMISTRY. - Vol. 48, n. 15 (2005), p. 4861-4870
Resumo: 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.
URI: http://hdl.handle.net/10451/21515
ISSN: 0022-2623
Aparece nas colecções:FF - Produção Científica 2000-2009

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