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: 10545741
• 负责人: DANIEL ROMO
• 金额: $ 36.01万
• 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/10545741
• 关键词: Acceleration; 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; Molecular; Natural Products; Oxidation-Reduction; Proteins; Research; Route; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; analog; 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.

项目总结/摘要 虽然“多样性导向”，“生物学导向”和“类比导向”的综合有助于 Wender呼吁“功能导向的合成”，即同时将整体合成工作与结构结合起来 活性关系（SAR）研究尚未完全实现。天然产品尤其如此， 几乎没有SAR信息。提出关于目标天然产物药效团的假设 进入全面综合工作的逆向综合规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 受以下调查的指导：总合成的努力，特别是有限的SAR和未知的细胞 目标，通过靶向设计的衍生物， 在逆合成计划阶段假设药效团，以进行SAR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合成分析， 将全合成努力与同时进行的生物学研究紧密结合。我们称之为“药效团- 定向逆合成”（PDR）强调考虑假设药效团的重要性， 总体综合工作的逆向综合计划阶段。这一方法将有助于确定 具有类似效力或潜在新功能的天然产物的简化版本， 产品虽然这种方法增加了天然产物全合成的挑战， 当代的目标，包括原子经济性，步骤和氧化还原效率，和保护基团避免， 值得注意的是，它将大大加快基础细胞天然产物的巨大信息含量的收获。 生物学和医学。这一策略始于一个生物活性天然产物的假设药效团 其通知并指导逆合成策略。逐步地，有条不紊地将复杂性引入到 假设药效团使得能够同时收集SAR数据，这反过来通知细胞探针 合成.一个富有成效的小组正在进行的合作者，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。 总的来说，我们提出的合成研究，结合合作的生物学研究，都将开辟新的 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、阿尔茨海默病和癌症。 拟议的研究将表明，全面综合努力与 天然产物的生物学研究处于逆合成计划阶段。我们将展示 PDR用于天然产物的反向化学遗传学探索，以识别新药先导， 新的细胞靶点对于发现影响人类健康的新途径至关重要。