Total Synthesis of Bioactive Indole Alkaloids and Application as Agrochemicals

生物活性吲哚生物碱的全合成及其农药应用

• 批准号: 10620698
• 负责人: Kerry E. Jones
• 金额: $ 1.3万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620698
• 关键词: Agriculture; Agrochemicals; Alkaloids; Aphids; Biological; Biological Assay; Biological Testing; Calcium Channel; Calcium Channel Agonists; Calcium Channel Inhibition; Chemicals; Complex; Cyclization; Derivation procedure; Development; Diels Alder reaction; Disease; Ensure; Evaluation; Exhibits; Food production; Foundations; Future; Health Food; In Vitro; Indole Alkaloids; Indoles; Industrialization; Industry; Insecta; Insecticides; Libraries; Marketing; Modification; Monoterpenes; Natural Products; Peach; Peripheral; Pesticides; Phenotype; Resistance; Resistance development; Route; Scheme; Series; Skeleton; Source; Structure-Activity Relationship; Therapeutic; Time; Work; adduct; analog; farmer; forging; inhibitor; interest; nervous system disorder; novel; oxidation; pesticide resistance; pharmacophore; piperidine; screening

PROJECT SUMMARY/ABSTRACT Agrochemicals are used in industrial food production to ensure the world has access to ample, healthy food. One major problem that drives development of novel agrochemicals is pesticide resistance. As a result, novel mechanisms of action (MoA) are highly sought-after in order to circumvent resistance to existing agrochemicals. To this end, natural products often serve as sources for identifying compounds active toward these novel MoAs. Calcium channels have been identified as under-exploited targets for insecticides and serve as viable, novel MoAs. Scholarinine A, an akuammiline monoterpenoid indole alkaloid, has been identified as a platform for the development of insecticides with novel MoAs due to its’ ability to inhibit calcium channels. A synthesis campaign towards this natural product and structurally related indole alkaloids will enable initial screening toward an insect calcium channel inhibitor. These studies will be accomplished through three specific aims: 1) completing the total synthesis of scholarinine A, 2) synthesizing structurally related natural products and performing initial biological assays, and 3) derivatizing the indole alkaloids to conduct structure activity relationship studies through collaborative efforts with Corteva AgriSciences. The total synthesis of scholarinine A and other akuammiline indole alkaloids will be pursued through the execution of a key cyclization cascade to forge the carbocyclic framework of the natural products, followed by late-stage peripheral functionalizations. Development of a divergent route to structurally related indole alkaloids will allow for biological evaluation of these compounds for application as insecticides. Additionally, development of a synthetic route will lay the foundation for biological testing of these compounds as therapeutics for neurological disorders associated with calcium channel dysregulation in the future. In the end, synthesis and biological testing of these indole alkaloids will provide crucial information on the calcium channel inhibitory capabilities of these compounds.

项目摘要/摘要 农产品用于工业粮食生产，以确保世界获得充足的健康食品。 推动新型农产品发展的一个主要问题是农药耐药性。结果，新颖 作用机理（MOA）是高度扫描之后的，以规避对现有农化学的抵抗。 为此，天然产品通常是识别对这些新型MOA的活跃化合物的来源。 钙通道已被确定为杀虫剂的探索量不足，并且是可行的，新颖的 莫斯。 Scholarinine A，一种akuamminine单键型吲哚生物碱，已被确定为该平台 由于其抑制钙通道的能力，具有新型MOA的杀虫剂的发展。综合运动 朝向这种天然产物和结构相关的吲哚生物碱将使初始筛选朝着绝缘 钙通道抑制剂。这些研究将通过三个具体目标来完成：1）完成总计 学术氨酸A，2）合成相关的天然产物的合成并进行初始生物学 测定和3）衍生吲哚生物碱以通过 与Corteva Agrisciences的合作努力。 学术氨酸A和其他阿库米氨酸吲哚生物碱的总合成将通过 执行关键环化级联以伪造天然产品的碳框架，其次是 晚期外周功能化。发展到与结构相关的吲哚生物碱的不同途径 将允许对这些化合物作为杀虫剂的生物学评估。另外，发展 合成途径的一项将为这些化合物的生物学测试奠定基础 未来与钙通道失调相关的神经系统疾病。最后，合成和 这些吲哚生物碱的生物学测试将在钙通道抑制作用上提供关键信息 这些化合物的能力。