Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation

被引：45

作者：

Chen, Hui-Ling ^{[2
]}

Chang, Chun-Yi ^{[1
]}

Lee, Hsun-Tzu ^{[1
]}

Lin, Hua-Hsuan ^{[1
]}

Lu, Pei-Jung ^{[2
]}

Yang, Chia-Ning ^{[3
]}

Shiau, Chung-Wai ^{[4
]}

Shaw, Arthur Y. ^{[1
]}

机构：

[1] Tamkang Univ, Dept Chem, Tamsui 251, Taiwan

[2] Natl Cheng Kung Univ, Inst Clin Med, Tainan 701, Taiwan

[3] Natl Univ Kaohsiung, Inst Biotechnol, Kaohsiung 700, Taiwan

[4] Natl Yang Ming Univ, Inst Biopharmaceut Sci, Taipei 112, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 20期

关键词：

Clioquinol; Mannich-type reaction; Metal-binding property; Reactive oxygen species (ROS); MAPK pathway activation; ALZHEIMERS-DISEASE; MECHANISM; DEATH; CELLS;

D O I：

10.1016/j.bmc.2009.08.054

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

In the present study, we carried out Mannich-type reaction to synthesize clioquinol-derived 7-methylarylsulfonylpiperazine analogs with improved growth-inhibitory effects. 11 bearing 5-nitro group on the quinoline ring exhibited 26-fold more potent than that of clioquinol against HeLa cells with a GI(50) value of 0.71 mu M. In addition, 11 revealed synergistic effects on the growth inhibition of HeLa cells with GI(50) values of 0.65, 0.25, and 0.06 mu M in the presence of 1, 10, and 50 mu M copper, respectively. Consistent to the clioquinol-mediated apoptosis, mechanistic study indicates that 9- and 11-induced growth inhibition is attributed to caspase-dependent pathway. Detection of reactive oxygen species in response to clioquinol, 9 and 11 confirmed that ROS was dramatically stimulated in the presence of copper and partially abolished upon treatment of 1 mM tempol. Further study indicated that 9- and 11-mediated induction of oxidative stress by ROS generation resulted in the activation MAPK pathway. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：7239 / 7247

页数：9

共 13 条

[1]

AMINO- AND CHLOROMETHYLATION OF 8-QUINOLINOL - MECHANISM OF PREPONDERANT ORTHO SUBSTITUTION IN PHENOLS UNDER MANNICH CONDITIONS [J].