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

药效团导向的逆合成应用于生物活性天然产物，为作用研究机制提供信息

• 批准号: 10078959
• 负责人: DANIEL ROMO
• 金额: $ 39.97万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078959
• 关键词: Alzheimer' s Disease; Bacterial Infections; Biological; Biology; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Chemicals; Communicable Diseases; Data Collection; Development; Goals; Harvest; Health; Human; Inflammation; Intervention; Lead; Malignant Neoplasms; Malignant neoplasm of brain; Medicine; Methods; Molecular; Natural Products; Oxidation-Reduction; Proteins; Research; Route; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; analog; base; bioactive natural products; cellular targeting; chemical genetics; design; human disease; innovation; malignant breast neoplasm; new therapeutic target; next generation; novel; novel strategies; novel therapeutics; pharmacophore; small molecule; therapeutic lead compound

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.

项目摘要/摘要 而“以生物学为导向的多样性”和“以模拟为导向”的合成有助于 Wender呼吁“以功能为导向的合成”，简单的整体合成工作与结构 活动关系（SAR）研究尚未完全实现。天然产品尤其如此 几乎没有SAR信息。提出有关靶向天然产品的假设的假设 进入整体合成工作的转回合成计划阶段将大大加速识别 简化的生物活性衍生物作为治疗干预的铅化合物。 我们对具有广泛细胞作用的天然产物的化学和生物学研究将 受到以下查询的指导：可以完全合成工作，尤其是有限的SAR和未知的细胞 靶标，通过靶向具有A 假设的在循环合成计划阶段期间的药效团使SAR研究能够进行 在前往天然产品的途中？我们的研究将开发一种创新的循环分析，更多 将全合成工作与并发的生物学研究紧密结合。我们称这种策略是“药效团” 指示反性合成'（PDR）强调考虑假设的药算归的重要性 全合成工作的递归合成计划阶段。这种方法将重要的是导致识别 天然产品的简单版本具有相似的效力或潜在的自然途径的新功能 产品。尽管这种方法将天然产物总合成的挑战越来越重要，但 当代目标，包括原子经济，步骤和氧化还原效率，以及保护群体的避免， 值得注意的是，它将大大加速基本细胞天然产品的广泛信息含量 生物学和医学。该策略始于生物活性天然产品的假设药效团 它为循环策略提供了信息并指导。逐步，有条不紊地引入复杂性 假设的药效团可实现并发的SAR数据收集，这又为细胞探针提供了信息 合成。一群富有成果的正在进行的合作者，包括分子，细胞和癌症生物学家和化学 生物学家将利用我们的基于天然产品的问题来促进细胞生物学的基本进展。 总体而言，我们提出的合成研究以及合作生物学研究将开放新的 新治疗的途径，并有助于对涉及的基本细胞机制有更多的了解 在人类疾病中，包括细菌感染，感染，心血管，阿尔茨海默氏病和癌症。 拟议的研究将证明与与 天然产物的生物学研究阶段阶段。我们将演示 PDR用于逆向化学遗传探索天然产物的识别新药铅和 新颖的细胞靶标对于发现新途径以影响人类健康至关重要。