Structure-activity relationships of talaumidin derivatives: Their neurite-outgrowth promotion in vitro and optic nerve regeneration in vivo.
Structure-activity relationships of talaumidin derivatives: Their neurite-outgrowth promotion in vitro and optic nerve regeneration in vivo.
复制标题
talaumidin 衍生物的结构-活性关系：体外促进神经突生长和体内视神经再生。
DOI：
10.1016/j.ejmech.2018.02.014
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Y. Fukuyama.
中科院分区：
文献类型：
--
作者：
K. Harada;K. Zaha;R. Bando;R. Irimaziri;M. Kubo;Y. Koriyama;Y. Fukuyama.
(-)-Talaumidin(1)是一种2，5-联芳基-3，4-二甲基四氢呋喃木脂素，具有促进神经突起生长和神经保护等强大的神经营养活性。以前，我们发现(-)-(1S，2R，3S，4R)-立体异构体2比天然产物talaumidin(1)显示出更显著的活性。然而，光学活性(-)-2的制备需要复杂的合成路线。为了探索可以大规模获得的新的神经营养化合物，我们建立了塔拉米丁衍生物的短步骤合成路线，并基于(-)-2的结构合成了14个类似物。首先，我们合成了外消旋化合物(-)-2(2a)，并对其神经营养活性进行了评价。我们发现消旋体2aA的神经营养活性与(-)-2相似。使用相同的合成方法，合成了几个塔拉米丁衍生物，以优化芳环上的氧官能团。结果表明，双(亚甲二氧基苯)衍生物2b具有最高的神经营养活性。此外，对化合物2的构效关系研究表明，2，5-二苯基-四氢呋喃结构是必需结构，四氢呋喃环上的两个甲基可增强神经营养活性。此外，还发现化合物2a和2b在体内可诱导小鼠视神经再生。
(–)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan, shows potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection. Previously, we found that (–)-(1S,2R,3S,4R)-stereoisomer2exhibited more significant activity than did the natural product talaumidin (1). However, the preparation of optically active (–)-2requires a complicated synthetic route. To explore new neurotrophic compounds that can be obtained on a large scale, we established a short step synthetic route for talaumidin derivatives and synthesized fourteen analogues based on the structure of (–)-2. First, we synthesized a racemic compound of (–)-2(2a) and assessed its neurotrophic activity. We found that the neurotrophic property of racemic2ais similar in activity to that of (–)-2. Using the same synthetic methodology, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. As a result, bis(methylenedioxybenzene) derivative2bpossessed the highest neurotrophic activity. Furthermore, examination of the structure-activity relationships of2brevealed that the 2,5-diphenyl-tetrahydrofuran structure was an essential structure and that two methyl groups on THF ring could enhance neurotrophic activity. In addition, compounds2aand2bwere found to induce mouse optic nerve regenerationin vivo.