Simplified immunosuppressive and neuroprotective agents based on gracilin A
Simplified immunosuppressive and neuroprotective agents based on gracilin A
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DOI：
10.1038/s41557-019-0230-0
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发表时间：
2019-04-01
期刊：
影响因子：
21.8
通讯作者：
Romo, Daniel
中科院分区：
文献类型：
--
作者：
Abbasov, Mikail E.;Alvarino, Rebeca;Romo, Daniel
天然产物的结构和生物活性经常作为探索生物相关化学空间的出发点。全合成之后的衍生物合成在历史上使人们能够更深入地理解结构-活性关系。然而，天然产物的合成策略并不总是由关于生物活性所需的结构特征的假设指导。在这里，我们报告了一种天然产物全合成的方法，我们称之为“药效团定向逆合成”。一个假设的，天然产物的药效团被选为早期的合成目标，这决定了逆合成分析。在理想的应用中，这种最小结构的结构复杂性的连续增加使得能够在整个合成过程中开发结构-活性关系曲线。这种方法能够识别更简单的同源物保留生物活性在一个更早的阶段的合成努力，这里证明的海绵二萜类，gracilin A，导致简化的衍生物具有强大的神经保护和免疫抑制活性。
The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.