Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators
Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators
复制标题
DOI：
10.1016/j.freeradbiomed.2016.03.026
复制
发表时间：
2016-06-01
影响因子：
7.4
通讯作者：
Sang, Shengmin
中科院分区：
文献类型：
--
作者：
Zhu, Yingdong;Wang, Pei;Sang, Shengmin
氧化应激是许多慢性疾病的核心组成部分。Kelch样ECH相关蛋白1（Keap 1）核因子红细胞2 p45相关因子2（Nrf 2）系统是细胞保护基因对抗氧化和亲电应激的主要调控途径。Nrf 2通路的激活在各种诱导剂的化学预防作用中起着至关重要的作用。在这项研究中，我们开发了一类新的有效的Nrf 2激活剂，从生姜化合物，[6]-姜烯酚（6S），使用Tg[谷胱甘肽S-转移酶pi 1（gstp 1）：绿色荧光蛋白（GFP）]转基因斑马鱼模型。6S衍生物的构效关系的研究表明，在一个化合物中的α，β-不饱和羰基实体和儿茶酚部分的组合增强了斑马鱼胚胎中的Tg（gstp 1：GFP）荧光信号。四种最有效的6S衍生物的化学反应和体内代谢研究表明，α，β-不饱和羰基实体和儿茶酚部分作为与半胱氨酸残基的巯基缀合的主要活性基团。此外，我们进一步证明了6S衍生物以剂量和时间依赖性方式增加Nrf 2下游靶标血红素加氧酶-1的表达。这些结果表明，α，β-不饱和羰基实体和6S衍生物的儿茶酚部分可能与Keap 1的半胱氨酸残基反应，破坏Keap 1 Nrf 2复合物，从而释放和激活Nrf 2。我们对天然产物衍生的Nrf 2激活剂的研究结果为进一步优化强效Nrf 2激活剂提供了设计选择。(C)2016 Elsevier Inc. All rights reserved.
Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1) nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers. In this study, we developed a novel class of potent Nrf2 activators derived from ginger compound, [6]-shogaol (6S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure activity relationships of 6S derivatives indicates that the combination of an alpha,beta-unsaturated carbonyl entity and a catechol moiety in one compound enhances the Tg(gstp1:GFP) fluorescence signal in zebrafish embryos. Chemical reaction and in vivo metabolism studies of the four most potent 6S derivatives showed that both alpha,beta-unsaturated carbonyl entity and catechol moiety act as major active groups for conjugation with the sulfhydryl groups of the cysteine residues. In addition, we further demonstrated that 6S derivatives increased the expression of Nrf2 downstream target, heme oxygenase-1, in both a dose- and time-dependent manner. These results suggest that alpha,beta-unsaturated carbonyl entity and catechol moiety of 6S derivatives may react with the cysteine residues of Keap1, disrupting the Keap1 Nrf2 complex, thereby liberating and activating Nrf2. Our findings of natural product-derived Nrf2 activators lead to design options of potent Nrf2 activators for further optimization. (C) 2016 Elsevier Inc. All rights reserved.