Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives
Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives
复制标题
神经源性龙胆苷衍生物的合成及SAR研究
DOI：
10.1248/cpb.c15-00795
复制
发表时间：
2016-02-01
影响因子：
1.7
通讯作者：
Qi, Jianhua
中科院分区：
文献类型：
--
作者：
Wang, Guangfa;Bian, Linglin;Qi, Jianhua
基于龙胆皂苷的构效关系，设计合成了治疗阿尔茨海默病的先导化合物2，3-二羟基苯甲酸十四烷基酯（ABG-001）。本文对ABG-001的烷基链和酯键进行了改性。因此，几个系列的新型龙胆苷衍生物的设计和合成，并在PC 12细胞中评估其神经突生成活性。在所有测试的化合物中，S-十二烷基2，3-二羟基硫代苯甲酸酯（15天，命名为ABG-199）是最有效的;该化合物在0.1 μ m时诱导显著的神经突生长，这与最佳浓度40 ng/mL的神经生长因子和1 μ m的ABG-001相当。对ABG-199作用机制的简要研究表明，细胞外信号调节激酶磷酸化参与了ABG-199诱导的PC 12细胞神经突生长。
Tetradecyl 2,3-dihydroxybenzoate (ABG-001) has been designed and synthesised as a lead compound to treat Alzheimer's disease, based on structure activity relationships of gentisides. In this paper, the alkyl chain and ester linkage group of ABG-001 were modified. Consequently, several series of novel gentiside derivatives were designed and synthesised, and their neuritogenic activity was evaluated in PC12 cells. Among all the tested compounds, S-dodecyl 2,3-dihydroxybenzothioate (15d, named as ABG-199) was the most potent; the compound induced significant neurite outgrowth at 0.1 mu m, which was comparable to that of nerve growth factor at the optimal concentration of 40 ng/mL and ABG-001 at 1 mu m. A brief study on the mechanism of action of ABG-199 revealed that extracellular signal-regulated kinase phosphorylation was involved in ABG-199-induced neurite outgrowth in PC12 cells.