Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21668
Título: Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitors
Autor: Mulchande, Jalmira
Guedes, Rita C.
Tsang, Wing-Yin
Page, Michael I.
Moreira, Rui
Iley, Jim
Palavras-chave: Chemistry, Medicinal
Data: 2008
Editora: AMER CHEMICAL SOC
Citação: JOURNAL OF MEDICINAL CHEMISTRY. - Vol. 51, n. 6 (2008), p. 1783-1790
Resumo: A new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett p-value of 0.65. Compared with a p-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of similar to 5 x 10(5) M-1 s(-1).
URI: http://hdl.handle.net/10451/21668
DOI: http://dx.doi.org/10.1021/jm701257h
ISSN: 0022-2623
Aparece nas colecções:FF - Produção Científica 2000-2009

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