Natural Product Synthesis through the Lens of Informatics.
Natural Product Synthesis through the Lens of Informatics.
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通过信息学的视角进行天然产物合成。
DOI：
10.1021/acs.accounts.0c00791
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发表时间：
2021
影响因子：
18.3
通讯作者：
Shenvi,RyanA
中科院分区：
文献类型：
--
作者：
Woo,Stone;Shenvi,RyanA
概述逆综合分析出现于 20 世纪 60 年代，作为一种具有深远影响的教学工具。通过浏览 50 多年后的全合成手稿，可以了解其教育价值，其中大部分在第一页包含逆合成。它的愿景扩展到了计算机语言——这是 20 世纪的开创性想法，至今仍在不断拓展前沿。指导学生评估、扩展和完善一系列键剖分的相同原理可以进行编程，以便计算机辅助可以以更快的速度执行相同的任务。然而，复杂结构合成中缓慢的步骤很少是路线设计。将分子信息压缩到紧密接近的程度 (Cm/Å3) 需要探索和经验主义，即理论与实验之间的紧密联系。在这里，逆合成分析指导实验的选择，以便优先考虑最简单但通常最不可靠的断开：高风险、高回报的策略。与 20 世纪 60 年代相比，21 世纪的逆合成分析发现自己置身于具有难以想象的能力的计算机和日益分子化的生物学之中。总而言之，逆合成的逻辑、结构生物学的洞察力和计算的预测激发了我们想象三者的整合。合成目标被视为动态的（相关结构的星座），以便找到具有最接近亲和力但合成路线最短的最近同源物。这种方法将合成设计与结构设计相结合，以实现改善功能的可及性。在这篇文章中，我们详细介绍了我们的程序从传统天然产物（NP）全合成的开始到目前通过化学信息学的表达方式的演变：将NP视为定义化学空间中单个点的分子参数的聚合体。早期关于表观金属池结合剂和非选择性共价亲电子试剂（天青生物碱、异氰萜烯、Nuphardimers）的合成和生物学注释的工作让位于具有明确蛋白质靶标的纳米颗粒。植物代谢物 Salvinorin A (SalA) 有效且选择性地激动 κ-阿片受体 (KOR)，快速渗透大脑，是下一代镇痛药和止痒药的重要先导药物。为了综合和多样化这一领先优势，我们采用了现在所谓的动态方法。删除中心甲基可以稳定 SalA 支架，打开快速合成通道，并保留高效力和选择性。然后针对另一种神经活性类别测试了这个想法的普遍性。作为 TrkB 通道的另一种假设，我们提出所谓的“神经营养性”八角萜可能与 γ-氨基丁酸 (GABA) 门控离子通道结合，引起微弱的慢性兴奋。 (−)-jiadifenolide、3,6-二脱氧-10-羟基假茴香碱、(−)-11-O-去苯甲酰塔代宁、(−)-bilobalide 和 (−)-picrotoxinin (PXN) 的合成使这一假设得到了更广泛的探讨。来自蛋白质结构和合成勘察的反馈导致了 PXN 的动态逆合成和 5MePXN 的鉴定，5MePXN 是一种中度 GABAAR 拮抗剂，具有更高的水稳定性，可通过八个步骤从二甲基香芹酮中获得。我们期望这种动态的合成目标分析方法在未来几年变得更加可行，并希望下一代科学家发现这种方法有助于解决化学和生物学前沿的问题。
ConspectusRetrosynthetic analysis emerged in the 1960s as a teaching tool with profound implications. Its educational value can be appreciated by a glance at total synthesis manuscripts over 50 years later, most of which contain a retrosynthesis on page one. Its vision extended to computer language—a pioneering idea in the 20th century that continues to expand the frontiers today. The same principles that guide a student to evaluate, expand, and refine a series of bond dissections can be programmed, so that computer assistance can perform the same tasks but at faster speeds.The slow step in the synthesis of complex structures, however, is seldom route design. Compression of molecular information into close proximity (Cm/Å3) requires exploration and empiricism, a close connection between theory and experiment. Here, retrosynthetic analysis guides the choice of experiment, so that the most simplifying—but often least assured—disconnection is prioritized: a high-risk, high reward strategy. The reimagining of total synthesis in a future era of retrosynthetic software may involve, counterintuitively, target design, as discussed here.Compared to the 1960s, retrosynthetic analysis in the 21st century finds itself among computers of unimaginable power and a biology that is increasingly molecular. Put together, the logic of retrosynthesis, the insight of structural biology, and the predictions of computation have inspired us to imagine an integration of the three. The synthetic target is treated as dynamic—a constellation of related structures—in order to find the nearest congener with the closest affinity but the shortest synthetic route. Such an approach merges synthetic design with structural design toward the goal of improved access for improved function.In this Account, we detail the evolution of our program from its inception in traditional natural product (NP) total synthesis to its current expression through the lens of chemical informatics: a view of NPs as aggregates of molecular parameters that define single points in a chemical space. Early work on synthesis and biological annotation of apparent metal pool binders and nonselective covalent electrophiles (asmarine alkaloids, isocyanoterpenes,Nuphardimers) gave way to NPs with well-defined protein targets. The plant metabolite salvinorin A (SalA) potently and selectively agonizes the κ-opioid receptor (KOR), rapidly penetrates the brain, and represents an important lead for next-generation analgesics and antipruritics. To synthesize and diversify this lead, we adopted what we now call a dynamic approach. Deletion of a central methyl group stabilized the SalA scaffold, opened quick synthetic access, and retained high potency and selectivity. The generality of this idea was then tested against another neuroactive class. As an alternative hypothesis to TrkB channels, we proposed that the so-called “neurotrophic”Illiciumterpenes may bind to γ-aminobutyric acid (GABA)-gated ion channels to cause weak, chronic excitation. Syntheses of (−)-jiadifenolide, 3,6-dideoxy-10-hydroxypseudoanisatin, (−)-11-O-debenzoyltashironin, (−)-bilobalide, and (−)-picrotoxinin (PXN) allowed this hypothesis to be probed more broadly. Feedback from protein structure and synthetic reconnaissance led to a dynamic retrosynthesis of PXN and the identification of 5MePXN, a moderate GABAAR antagonist with greater aqueous stability available in eight steps from dimethylcarvone. We expect this dynamic approach to synthetic target analysis to become more feasible in the coming years and hope the next generation of scientists finds this approach helpful to address problems at the frontier of chemistry and biology.