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Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.
ChemPlusChem ( IF 3.0 ) Pub Date : 2018-03-08 , DOI: 10.1002/cplu.201700539 Shirin Kahremany 1 , Ilana Babaev 1 , Pinhas Hasin 1 , Tigist Y Tamir 2 , Tali Ben-Zur 3 , Guy Cohen 4 , Zhengyu Jiang 5 , Sagiv Weintraub 1 , Daniel Offen 3 , Shai Rahimipour 1 , M Ben Major 2 , Hanoch Senderowitz 1 , Arie Gruzman 1
ChemPlusChem ( IF 3.0 ) Pub Date : 2018-03-08 , DOI: 10.1002/cplu.201700539 Shirin Kahremany 1 , Ilana Babaev 1 , Pinhas Hasin 1 , Tigist Y Tamir 2 , Tali Ben-Zur 3 , Guy Cohen 4 , Zhengyu Jiang 5 , Sagiv Weintraub 1 , Daniel Offen 3 , Shai Rahimipour 1 , M Ben Major 2 , Hanoch Senderowitz 1 , Arie Gruzman 1
Affiliation
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The design and synthesis of a novel nuclear factor erythroid 2-related factor 2 (Nrf2) enhancer is reported. Using a structure-based virtual screening approach, several commercially available compounds were identified as having high probability to interact with the Nrf2-binding pocket in the Kelch-like ECH-associated protein 1 (Keap1). Keap1 is an adaptor protein that recruits Nrf2 to a cullin-3-dependent ubiquitin ligase complex. The identified compounds were tested against rat pheochromocytoma PC-12 cells for their cytoprotective activity, and one compound (SKT359126) demonstrated an Nrf2-mediated cell-protective effect. Based on the structure of SKT359126, 23 novel derivatives were synthesized and evaluated. Of the screened derivatives, 1-{4-[(3,4-dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic acid demonstrated better activity than the parent molecules in activating the Nrf2 transduction pathway in a dose- and time-dependent manner. This compound represents a promising starting point for the development of therapeutics for the treatment of oxidative-stress-related diseases.
中文翻译：
作为Nrf2增强剂的1- {4-[（3,4-二羟基亚苄基）氨基]苯基} -5-氧吡咯烷-3-羧酸的计算机辅助设计和合成。
报道了新型核因子红系2相关因子2（Nrf2）增强剂的设计与合成。使用基于结构的虚拟筛选方法，几种可商购的化合物被鉴定为与Kelch样ECH相关蛋白1（Keap1）中的Nrf2结合口袋相互作用的可能性很高。Keap1是一种衔接蛋白，可将Nrf2募集到cullin-3依赖性泛素连接酶复合体上。测试了鉴定出的化合物对大鼠嗜铬细胞瘤PC-12细胞的细胞保护活性，其中一种化合物（SKT359126）表现出Nrf2介导的细胞保护作用。根据SKT359126的结构，合成并评估了23种新型衍生物。在筛选的导数中，1- {4-[（3，在活化Nrf2转导途径中，4-二羟基亚苄基）氨基]苯基} -5-氧吡咯烷-3-羧酸表现出比母体分子更好的活性，且呈剂量和时间依赖性。该化合物代表了开发用于治疗与氧化应激相关疾病的疗法的有希望的起点。
更新日期：2018-03-08
中文翻译：
作为Nrf2增强剂的1- {4-[（3,4-二羟基亚苄基）氨基]苯基} -5-氧吡咯烷-3-羧酸的计算机辅助设计和合成。
报道了新型核因子红系2相关因子2（Nrf2）增强剂的设计与合成。使用基于结构的虚拟筛选方法，几种可商购的化合物被鉴定为与Kelch样ECH相关蛋白1（Keap1）中的Nrf2结合口袋相互作用的可能性很高。Keap1是一种衔接蛋白，可将Nrf2募集到cullin-3依赖性泛素连接酶复合体上。测试了鉴定出的化合物对大鼠嗜铬细胞瘤PC-12细胞的细胞保护活性，其中一种化合物（SKT359126）表现出Nrf2介导的细胞保护作用。根据SKT359126的结构，合成并评估了23种新型衍生物。在筛选的导数中，1- {4-[（3，在活化Nrf2转导途径中，4-二羟基亚苄基）氨基]苯基} -5-氧吡咯烷-3-羧酸表现出比母体分子更好的活性，且呈剂量和时间依赖性。该化合物代表了开发用于治疗与氧化应激相关疾病的疗法的有希望的起点。
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