Benzodiazepinone derivatives protect against endoplasmic reticulum stress-mediated cell death in human neuronal cell lines.
Benzodiazepinone derivatives protect against endoplasmic reticulum stress-mediated cell death in human neuronal cell lines.
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DOI：
10.1021/cn500297v
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发表时间：
2015-03-18
影响因子：
5
通讯作者：
Cosford, Nicholas D. P.
中科院分区：
文献类型：
--
作者：
Zou, Haixia;Limpert, Allison S.;Zou, Jiwen;Dembo, Anna;Lee, Pooi-San;Grant, Daniel;Ardecky, Robert;Pinkerton, Anthony B.;Magnuson, Gavin K.;Goldman, Mark E.;Rong, Juan;Teriete, Peter;Sheffler, Douglas J.;Reed, John C.;Cosford, Nicholas D. P.
内质网（ER）应激导致神经元功能障碍，随后细胞死亡，被认为是许多神经退行性疾病的特征。使用表型筛选，我们最近确定了苯二氮卓酮衍生物，减少ER应激介导的大鼠神经元祖细胞系（CSM 14.1）的凋亡。在本文中，我们描述了围绕这些筛选命中的结构-活性关系（SAR）研究如何导致在SH-SY 5 Y和H4人神经元细胞系中对毒胡萝卜素诱导的ER应激显示出稳健的细胞保护活性的化合物。我们证明了这些衍生物中最有效的化合物4 hh抑制p38 MAP激酶（p38）和c-Jun N-末端激酶（JNK）的活化，这些蛋白激酶是未折叠蛋白反应（UPR）的下游信号效应物。化合物4 hh特异性地保护免于毒胡萝卜素诱导的细胞死亡，并且不显示保护免于已知诱导细胞应激或激活p38的其他损伤。然而，化合物4 hh提供对由破坏钙稳态的化合物刺激的p38活性的适度抑制。我们的数据表明，探针化合物4 hh是一种有价值的小分子工具，可用于研究ER应激对人类神经元的影响。这种方法可能为未来开发治疗神经退行性疾病的疗法提供基础。
Endoplasmic reticulum (ER) stress causes neuronal dysfunction followed by cell death and is recognized as a feature of many neurodegenerative diseases. Using a phenotypic screen, we recently identified benzodiazepinone derivatives that reduce ER stress-mediated apoptosis in a rat neuronal progenitor cell line (CSM14.1). Herein we describe how structure–activity relationship (SAR) studies around these screening hits led to compounds that display robust cytoprotective activity against thapsigargin-induced ER stress in SH-SY5Y and H4 human neuronal cell lines. We demonstrate that the most potent of these derivatives, compound 4hh, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal kinase (JNK), protein kinases that are downstream signal effectors of the unfolded protein response (UPR). Compound 4hh specifically protects against thapsigargin-induced cell death and displays no protection against other insults known to induce cellular stress or activate p38. However, compound 4hh provides moderate inhibition of p38 activity stimulated by compounds that disrupt calcium homeostasis. Our data indicate that probe compound 4hh is a valuable small molecule tool that can be used to investigate the effects of ER stress on human neurons. This approach may provide the basis for the future development of therapeutics for the treatment of neurodegenerative diseases.
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DOI：
10.1016/j.bbrc.2012.11.137
发表时间：
2013-01-25
影响因子：
3.1
作者：
Shimizu, Sachie;Kadowaki, Mitsutoshi;Yoshioka, Hiroki;Kambe, Atsushi;Watanabe, Takashi;Kinyamu, H. Karimi;Eling, Thomas E.
通讯作者：
Eling, Thomas E.
影响因子：
10.5
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
通讯作者：
Ichijo, H
影响因子：
2.7
作者：
Limpert AS;Mattmann ME;Cosford ND
通讯作者：
Cosford ND
影响因子：
3.3
作者：
DuRose, Jenny B.;Tam, Arvin B.;Niwa, Maho
通讯作者：
Niwa, Maho
影响因子：
10.5
作者：
Nishitoh, Hideki;Kadowaki, Hisae;Ichijo, Hidenori
通讯作者：
Ichijo, Hidenori