Harada Kenichi, Kubo Miwa, Fukuyama Yoshiyasu
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Front Chem. 2020 Apr 23;8:301. doi: 10.3389/fchem.2020.00301. eCollection 2020.
(-)-Talaumidin (), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, exhibits significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells. The first enantioselective total synthesis of was achieved by a flexible and reliable synthetic pathway involving an Evans asymmetric aldol reaction, as well as a stereocontrolled hydroboration and Friedel-Crafts arylation, to construct the four contiguous chiral centers on the tetrahydrofuran (THF) ring of . In order to investigate the stereochemistry-activity relationship of , a systematic synthesis of all diastereomers of was accomplished by applying the synthetic strategy used for natural product . The evaluation of neurite-outgrowth promotion by all of the synthesized diastereomers indicated that the (-)-(1,2,3,4)-isomer was significantly more active than naturally occurring . Additionally, we established a synthetic methodology for talaumidin derivatives that could be used to prepare a variety of analogs in a few steps and on a large scale. The synthesized racemic analog - () exhibited neurite-outgrowth promoting activity in NGF-differentiated PC12 cells to the same degree as the optically active (-)-, revealing that a relative configuration bearing all-- substituents is important for potent neurotrophic activity, whilst the absolute configuration does not affect activity. Fourteen analogs based on (±)- were prepared via the same synthetic methodology. Among them, with a methylenedioxy group on both benzene rings was found to exhibit the most significant neurite outgrowth promotion. In addition, and induced regeneration of the mouse optic nerve , and their activity was higher than that of talaumidin, as well as their measured activity. Furthermore, the structure-activity relationship of indicated that the two benzene rings were essential structures, and that the methyl groups on the THF ring could enhance the neurotrophic activity. This result suggests that the two benzene rings of the talaumidin derivatives are essential structures for neurotrophic activity, while the two methyl groups on the THF ring can enhance neurite-outgrowth activity. Finally, it was observed that 1 and derivatives and exhibited potent regenerative activity in the injured mouse optic nerve .
（-）-塔劳米丁（）是从马兜铃科植物马兜铃中分离得到的一种2,5-二芳基-3,4-二甲基四氢呋喃木脂素，在原代培养的大鼠皮质神经元和经神经生长因子（NGF）分化的PC12细胞中表现出显著的促神经突生长和神经保护作用。通过一条灵活可靠的合成路线首次实现了的对映选择性全合成，该路线涉及埃文斯不对称羟醛反应以及立体控制的硼氢化反应和傅克芳基化反应，以构建上四氢呋喃（THF）环上的四个相邻手性中心。为了研究的立体化学-活性关系，通过应用用于天然产物的合成策略完成了的所有非对映异构体的系统合成。对所有合成的非对映异构体的促神经突生长评估表明，（-）-（1,2,3,4）-异构体的活性明显高于天然存在的。此外，我们建立了一种塔劳米丁衍生物的合成方法，该方法可用于在几步内大规模制备各种类似物。合成的外消旋类似物 - （）在经NGF分化的PC12细胞中表现出与光学活性的（-）-相同程度的促神经突生长活性，表明具有所有 - 取代基的相对构型对于有效的神经营养活性很重要，而绝对构型不影响活性。通过相同的合成方法制备了基于（±）-的14种类似物。其中，两个苯环上均带有亚甲二氧基的被发现表现出最显著的促神经突生长作用。此外，和诱导了小鼠视神经的再生，并且它们的活性高于塔劳米丁，以及它们测定的活性。此外，的构效关系表明两个苯环是必需结构，并且THF环上的甲基可以增强神经营养活性。该结果表明塔劳米丁衍生物的两个苯环是神经营养活性的必需结构，而THF环上的两个甲基可以增强神经突生长活性。最后，观察到1以及衍生物和在受伤的小鼠视神经中表现出强大的再生活性。
