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: 10462970
• 负责人: Kerry E. Jones
• 金额: $ 3.85万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462970
• 关键词: Agricultural Development; Agriculture; Agrochemicals; Alkaloids; Aphids; Biological; Biological Assay; Biological Testing; Calcium Channel; Calcium Channel Agonists; Calcium Channel Inhibition; Chemicals; Complex; Cyclization; Development; Diels Alder reaction; Disease; Ensure; Evaluation; Exhibits; Food production; Foundations; Future; Health Food; In Vitro; Indole Alkaloids; Indoles; Industrialization; Industry; Insecta; Insecticides; Lead; Libraries; 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 农业化学品用于工业食品生产，以确保世界获得充足的健康食品。 推动新型农用化学品开发的一个主要问题是农药抗性。因此，小说 为了避免对现有农用化学品的抗性，作用机制（MoA）是非常受欢迎的。 为此，天然产物通常用作鉴定对这些新型MoA具有活性的化合物的来源。 钙通道已被确定为杀虫剂的未开发目标，并作为可行的，新颖的 MoAs。Scholarinine A是一种阿库阿米林单萜吲哚生物碱，已被鉴定为药物代谢的平台。 由于其抑制钙通道的能力，开发具有新型MoAs的杀虫剂。综合运动 对这种天然产物和结构上相关的吲哚生物碱的研究将能够对昆虫进行初步筛选， 钙通道抑制剂这些研究将通过三个具体目标来完成：1）完成总的 2）合成结构上相关的天然产物，并进行初始生物活性 测定，和3）将吲哚生物碱衍生化以进行构效关系研究， 与Corteva AgriSciences合作。 将通过以下步骤来进行曲马宁A和其他阿库阿米林吲哚生物碱的全合成： 执行关键环化级联以形成天然产物的碳环框架，然后 晚期外周功能化结构相关的吲哚生物碱的不同路线的开发 将允许对这些化合物作为杀虫剂的应用进行生物学评价。此外，发展 合成路线的研究将为这些化合物作为治疗药物的生物学测试奠定基础。 神经系统疾病与钙通道失调的未来。最后，综合和 这些吲哚生物碱的生物学测试将提供关于钙通道抑制剂的关键信息。 这些化合物的能力。