Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties.
Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties.
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DOI：
10.1016/j.ejmech.2016.07.010
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发表时间：
2016-10-21
影响因子：
6.7
通讯作者：
Dekker, Frank J.
中科院分区：
文献类型：
--
作者：
Eleftheriadis, Nikolaos;Poelman, Hessel;Leus, Niek G. J.;Honrath, Birgit;Neochoritis, Constantinos G.;Dolga, Amalia;Domling, Alexander;Dekker, Frank J.
关键词：
酶15-脂氧合酶-1（15-LOX-1）在具有炎症组分的疾病中起双重作用。一方面，15-LOX-1在促炎基因表达中起作用，另一方面，已显示其通过其在缺氧条件下介导氧化应激和线粒体膜损伤的能力而参与中枢神经系统（CNS）病症。为了进一步探索在中枢神经系统中的应用，需要开发具有良好理化性质的新型15-LOX-1抑制剂。在这里，我们提出了取代导向片段筛选（SOS）结合多组分化学（MCR）作为一种有效的策略，以确定一个二氮杂取代的小杂环抑制剂15-LOX-1，表示ThioLox，与以前确定的抑制剂的物理化学性质上级。在精密切割肺切片（PCLS）的体外生物学评价显示，抑制促炎基因的表达和神经元HT-22细胞的体外研究显示，对谷氨酸毒性的这种15-LOX-1抑制剂的强有力的保护。这提供了一种新的方法，以确定新的小的具有有利的物理化学性质的探索15-LOX-1作为药物靶点在炎症性疾病和神经退行性疾病。
The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented fragment Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.
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影响因子：
3.5
作者：
Fairfax BP;Vannberg FO;Radhakrishnan J;Hakonarson H;Keating BJ;Hill AV;Knight JC
通讯作者：
Knight JC
影响因子：
15
作者：
Chernyak, Natalia;Buchwald, Stephen L.
通讯作者：
Buchwald, Stephen L.
DOI：
10.1016/j.bbalip.2014.12.017
发表时间：
2015-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Ibrahim AS;Tawfik AM;Hussein KA;Elshafey S;Markand S;Rizk N;Duh EJ;Smith SB;Al-Shabrawey M
通讯作者：
Al-Shabrawey M
影响因子：
6.1
作者：
Chu, H. W.;Balzar, S.;Wenzel, S. E.
通讯作者：
Wenzel, S. E.
影响因子：
11
作者：
Chu, J.;Li, J-G;Pratico, D.
通讯作者：
Pratico, D.