Plants produce a high diversity of metabolites that can act as regulators of cholinergic dysfunction. Among plants, the potential of species of the genus Tabernaemontana to treat neurological disorders has been linked to iboga-type alkaloids that are biosynthesized by those species. In this context, precursor-directed biosynthesis approaches were carried out using T. catharinensis plantlets to achieve new-to-nature molecules as promising agents against Alzheimer's disease. Aerial parts of T. catharinensis, cultured in vitro, produced 7 unnatural alkaloids (5-fluoro-ibogamine, 5-fluoro-voachalotine, 5-fluoro-12-methoxy-Nb-methyl-voachalotine, 5-fluoro-isovoacangine, 5-fluoro-catharanthine, 5-fluoro-19-(S)-hydroxy-ibogamine, and 5-fluoro-coronaridine), while root extracts showed the presence of the same unnatural iboga-type alkaloids and 2 additional ones: 5-fluoro-voafinine and 5-fluoro-affinisine. Moreover, molecular docking approaches were carried out to evaluate the potential inhibition activity of T. catharinensis' natural and unnatural alkaloids against AChE and BChE enzymes. Fluorinated iboga alkaloids (5-fluoro-catharanthine, 5-fluoro-voachalotine, 5-fluoro-affinisine, 5-fluoro-isovoacangine, 5-fluoro-corinaridine) were more active than natural ones and controls against AchE, while 5-fluoro-19-(S)-hydroxy-ibogamine, 5-fluoro-catharanthine, 5-fluoro-isovoacangine, and 5-fluoro-corinaridine showed better activity than natural ones and controls against BChE. Our findings showed that precursor-directed biosynthesis strategies generated "new-to-nature" alkaloids that are promising Alzheimer's disease drug candidates. Furthermore, the isotopic experiments also allowed us to elucidate the initial steps of the biosynthetic pathway for iboga-type alkaloids, which are derived from the MEP and shikimate pathways.

中文翻译：

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Tabernaemontana catharinensis 中前体导向的生物合成作为阿尔茨海默氏病调节剂的新途径

植物产生高度多样性的代谢物，可作为胆碱能功能障碍的调节剂。在植物中，Tabernaemontana 属物种治疗神经系统疾病的潜力与这些物种生物合成的伊博加型生物碱有关。在这种情况下，使用 T. catharinensis 植株进行了前体导向的生物合成方法，以实现新的自然分子作为对抗阿尔茨海默病的有希望的药物。T. catharinensis 的地上部分，在体外培养，产生了 7 种非天然生物碱（5-氟-伊波胺、5-氟-伏查洛汀、5-氟-12-甲氧基-Nb-甲基-伏查洛汀、5-氟-异伏阿查碱、5-氟-长春花碱、5-氟-19-(S)-羟基-伊波胺和 5-氟-冠花碱)，而根提取物显示存在相同的非天然伊博加型生物碱和另外 2 种生物碱：5-氟-voafinine 和 5-fluoro-affinisine。此外，还进行了分子对接方法以评估长春花的天然和非天然生物碱对 AChE 和 BChE 酶的潜在抑制活性。氟化伊博加生物碱（5-氟-长春花碱、5-氟-伏查洛汀、5-氟-亲和素、5-氟-异伏阿姜碱、5-氟-corinaridine）比天然生物碱更有效，并能对抗 AchE，而 5-氟- 19-(S)-羟基-伊波胺、5-氟-长春花碱、5-氟-异瓦姜碱和 5-氟-corinaridine 显示出比天然化合物和对照品更好的抗 BChE 活性。我们的研究结果表明，前体导向的生物合成策略产生了“新自然” 生物碱有望成为阿尔茨海默病的候选药物。此外，同位素实验还使我们能够阐明来自 MEP 和莽草酸途径的伊博加型生物碱生物合成途径的初始步骤。