Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases:: Synthesis, biological evaluation, and mechanism studies

被引：10

作者：

Park, SK

Han, SB

Lee, K

Lee, HJ

Kho, YH

Chun, H

Choi, Y

Yang, JY

Yoon, YD

Lee, CW

Kim, HM

Choi, HM

Tae, HS

Lee, HY

Nam, KY

Han, G

机构：

[1] KRIBB, Taejon 305333, South Korea

[2] Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea

[3] Yonsei Engn Res Complex, Res Inst Bioinformat & Mol Design, BMD, Seoul 120740, South Korea

[4] Yonsei Univ, Dept Biotechnol, Seoul 120740, South Korea

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2006年 / 341卷 / 02期

关键词：

tumor necrosis factor alpha; inhibitors; TNF alpha converting enzyme; alpha-secretase;

D O I：

10.1016/j.bbrc.2005.12.219

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by I step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-alpha production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-alpha inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and alpha-secretase was examined Using cellular alpha-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode For the further analogue design. (c) 2006 Elsevier Inc. All rights reserved.

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收藏

页码：627 / 634

页数：8

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