Pharmacophore-Directed  Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

项目摘要/摘要 而“面向多样性”、“面向生物学”和“面向类比”的合成有助于 温德呼吁“面向功能的合成”，即整体合成努力与结构的同时对齐 活动关系(SAR)研究尚未得到充分认识。对于天然产品来说尤其如此，在 几乎没有搜索到的信息存在。提出关于目标天然产品的药效团的假设 进入整个合成工作的逆向合成计划阶段将大大加快识别 简化的生物活性衍生物作为治疗干预的先导化合物。 我们对具有广泛细胞效应的天然产物的化学和生物学研究将 以以下问题为指导：总的合成努力，特别是在有限的SAR和未知细胞的情况下 靶点，通过靶向设计的具有 在合成后规划阶段的假想药效团，以便进行搜救研究 在去天然产品的路上？我们的研究将开发一种创新的逆向综合分析方法， 将全面的合成努力与同时进行的生物学研究紧密结合起来。我们称这一策略为药效团- 定向逆合成(PDR)强调考虑假想的药效团的重要性 总的综合工作的反综合计划阶段。这一方法将重要地导致识别 天然产物的简化版本，具有相似的效力或潜在的新功能 产品。虽然这种方法增加了天然产物全合成的挑战， 当代目标，包括原子经济、阶梯和氧化还原效率以及保护群体避免， 值得注意的是，它将极大地加速基础细胞天然产物的海量信息量的获取 生物和医学。这一策略始于一种生物活性天然产品的假想药效团。 为反合成策略提供信息和指导。逐步、有条不紊地将复杂性引入 假想的药效团实现了并行的合成孔径雷达数据收集，进而通知细胞探针 综合。一组卓有成效的持续合作伙伴，包括分子、细胞、癌症生物学家和化学 生物学家将利用我们以天然产物为基础的探针，为细胞生物学的根本进步做出贡献。 总体而言，我们提议的合成研究，与合作的生物学研究相结合，将开启新的 新疗法的途径，并有助于更好地了解所涉及的基本细胞机制 在人类疾病中，包括细菌感染、炎症、心血管疾病、阿尔茨海默病和癌症。 拟议的研究将证明密切参与总体合成工作的重要性 天然产物的生物研究处于后合成规划阶段。我们将演示 PDR用于天然产物的反向化学遗传探索，以识别新的药物先导和 新的细胞靶点对于发现影响人类健康的新途径至关重要。

Project Summary/Abstract While ‘diversity-oriented,’ ‘biology-oriented,’ and ‘analogue-oriented’ syntheses have contributed to Wender’s call for ‘function-oriented synthesis,’ the simultaneous alignment of total synthesis efforts with structure activity relationship (SAR) studies has not been fully realized. This is particularly true with natural products where little to no SAR information exists. Bringing hypotheses regarding a targeted natural product's pharmacophore into the retrosynthetic planning stages of a total synthesis effort would dramatically accelerate the identification of simplified, bioactive derivatives as lead compounds for therapeutic intervention. Our chemical and biological studies of natural products possessing a broad range of cellular effects will be guided by the following inquiry: Can total synthesis efforts, in particular with limited SAR and unknown cellular targets, be more closely aligned to biological studies by targeting designed derivatives possessing a hypothesized pharmacophore during the retrosynthetic planning stages to enable SAR studies to be conducted en route to the natural product? Our study will develop a type of innovative retrosynthetic analysis that more closely aligns total synthesis efforts with concurrent biological studies. We term this strategy ‘pharmacophore- directed retrosynthesis’ (PDR) to emphasize the importance of considering hypothesized pharmacophores at the retrosynthetic planning stage of a total synthesis effort. This approach will importantly lead to the identification of simplified versions of the natural product with similar potency or potentially new functions in route to the natural product. While this approach increases the challenges of natural product total synthesis beyond important, contemporary goals, including atom-economy, step and redox efficiency, and protecting group avoidance, significantly it will greatly accelerate harvesting of the vast information content of natural products for basic cell biology and medicine. This strategy begins with a hypothesized pharmacophore for a bioactive natural product which informs and directs the retrosynthetic strategy. Stepwise, methodical introduction of complexity to the hypothesized pharmacophore enables concurrent SAR data collection which in turn informs cellular probe synthesis. A fruitful group of ongoing collaborators, including molecular, cell, and cancer biologists and chemical biologists will utilize our natural product-based probes to contribute to fundamental advances in cell biology. Overall, our proposed synthetic studies, combined with collaborative biological studies, will both open new avenues for novel therapeutics, and contribute to a greater understanding of basic cellular mechanisms involved in human disease including bacterial infection, inflammation, cardiovascular, Alzheimer’s disease, and cancer. The proposed research will demonstrate the importance of closely engaging total synthesis efforts with biological studies of natural products at the retrosynthetic planning stages. We will demonstrate the utility of PDR for reverse chemical genetic explorations of natural products towards identification of new drug leads and novel cellular targets critical to uncovering new avenues to impact human health.