Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

被引：16

作者：

Kim, Young Seub ^{[1
,2
]}

Jung, Sun Hwa ^{[1
,3
]}

Park, Beoung-Geon ^{[1
,4
]}

Ko, Min Kyung ^{[1
]}

Jang, Hyun-Seo ^{[1
]}

Choi, Kihang ^{[3
]}

Baik, Ja-Hyun ^{[4
]}

Lee, Jiyoun ^{[5
]}

Lee, Jae Kyun ^{[1
]}

Pae, Ae Nim ^{[1
,2
]}

Cho, Yong Seo ^{[1
,2
]}

Min, Sun-Joon ^{[1
,2
]}

机构：

[1] Korea Inst Sci & Technol, Brain Sci Inst, Ctr Neuromed, Seoul 136791, South Korea

[2] Univ Sci & Technol, Taejon 305333, South Korea

[3] Korea Univ, Dept Chem, Seoul 136701, South Korea

[4] Korea Univ, Sch Life Sci & Biotechnol, Seoul 136701, South Korea

[5] Sungshin Womens Univ, Dept Global Med Sci, Seoul 142732, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 62卷

基金：

新加坡国家研究基金会;

关键词：

Alzheimer's disease; Mitochondrial permeability transition pore (mPTP); Oxime derivatives; Amyloid beta; Pharmacokinetics; PERMEABILITY TRANSITION; ALZHEIMERS-DISEASE; DIMEBON; TRANSPORT; ENHANCER;

D O I：

10.1016/j.ejmech.2012.12.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics. (C) 2012 Elsevier Masson SAS. All rights reserved.

引用

页码：71 / 83

页数：13

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