功能化的N-芳基氮杂环丁酮作为新型的基于机制的中性粒细胞弹性蛋白酶抑制剂。

Functionalized N-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase.

作者信息

Wakselman M, Joyeau R, Kobaiter R, Boggetto N, Vergely I, Maillard J, Okochi V, Montagne J J, Reboud-Ravaux M

机构信息

Centre National de la Recherche Scientifique, Centre d'Etudes et de Recherches de Chimie Organique Appliquée, Laboratoire de Chimie Organique Biologique, Thiais, France.

出版信息

FEBS Lett. 1991 May 6;282(2):377-81. doi: 10.1016/0014-5793(91)80517-7.

DOI:10.1016/0014-5793(91)80517-7

PMID:2037052

Abstract

A functionalized N-aryl azetidinone has been shown to inactivate human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) by an enzyme-mediated process. The inactivation is characterized by the following kinetic constants at pH 8.0 and 37 degrees C: kinact = 0.035 s-1, KI = 1.2 x 10(-4) M for HLE, 0.08 s-1 and 2.7 x 10(-4) M for PPE, respectively. Two parent molecules devoid of the latent leaving group failed to inactivate HLE and PPE and behaved as substrates of these enzymes. A suicide mechanism is postulated involving the formation of an acyl-enzyme and the simultaneous unmasking of a latent quinonimmonium methide ion which irreversibly reacts with an active site nucleophile. Moreover, the inhibitor is still effective at inhibiting elastase preabsorbed onto elastin.

摘要

一种功能化的N-芳基氮杂环丁酮已被证明可通过酶介导的过程使人类白细胞弹性蛋白酶（HLE）和猪胰弹性蛋白酶（PPE）失活。在pH 8.0和37摄氏度下，这种失活的特征由以下动力学常数表示：对于HLE，kinact = 0.035 s-1，KI = 1.2×10（-4）M；对于PPE，分别为0.08 s-1和2.7×10（-4）M。两种没有潜在离去基团的母体分子无法使HLE和PPE失活，而是表现为这些酶的底物。推测存在一种自杀机制，涉及酰基酶的形成以及潜在的醌亚甲基离子的同时暴露，该离子与活性位点亲核试剂发生不可逆反应。此外，该抑制剂对抑制预吸附在弹性蛋白上的弹性蛋白酶仍然有效。