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: 10314044
• 负责人: DANIEL ROMO
• 金额: $ 39.01万
• 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/10314044
• 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.

项目概要/摘要 虽然“以多样性为导向”、“以生物学为导向”和“以类似物为导向”的合成有助于 文德呼吁“以功能为导向的综合”，即总体综合工作与结构的同时协调 活性关系（SAR）研究尚未完全实现，对于天然产品尤其如此。 几乎不存在关于目标天然产物药效团的假设。 进入全合成工作的逆合成规划阶段将极大地加速识别 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 可以遵循以下询问：全合成工作，特别是有限的 SAR 和未知的细胞 目标，通过针对具有以下特征的设计衍生物，与生物学研究更加紧密地结合 在逆合成计划阶段获取药效团以进行 SAR 研究 正在走向天然产物？我们的研究将开发一种创新的逆合成分析 将全合成工作与同时进行的生物学研究紧密结合起来，我们将这种策略称为“药效基团”。 定向逆合成”（PDR）强调了考虑药效团的重要性 全合成工作的逆合成规划阶段将重要地导致识别。 具有相似效力或潜在新功能的天然产品版本 虽然这种方法增加了天然产物全合成的挑战，但其重要性不言而喻。 当代目标，包括原子经济性、阶跃和氧化还原效率以及保护基团避免， 显着地，它将大大加速对基础细胞天然产物的大量信息内容的收获 该策略始于生物活性天然产品的开创性药效团。 它为逆合成策略提供信息和指导，逐步、有条理地引入复杂性。 突袭药效团可同时收集 SAR 数据，从而通知细胞探针 一个富有成果的持续合作者团队，包括分子、细胞和癌症生物学家和化学家。 生物学家将利用我们基于天然产物的探针为细胞生物学的根本进步做出贡献。 总体而言，我们提出的综合研究与合作生物学研究相结合，都将开辟新的领域 新疗法的途径，并有助于更好地理解所涉及的基本细胞机制 人类疾病，包括细菌感染、炎症、心血管、阿尔茨海默病和癌症。 拟议的研究将证明与全合成工作密切相关的重要性 我们将在逆合成规划阶段展示天然产物的生物学研究。 PDR 用于天然产物的逆向化学遗传探索，以鉴定新药先导物和 新的细胞靶标对于发现影响人类健康的新途径至关重要。