Chemo-Divergent Cationic Cascades for the Synthesis of Biologically Active Alkaloids

用于合成生物活性生物碱的化学发散阳离子级联

• 批准号: 10388002
• 负责人: Jackson J Hernandez
• 金额: $ 3.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388002
• 关键词: Aldehydes; Alkaloids; Analgesics; Antineoplastic Agents; Biological; Biological Testing; Boronic Acids; Caffeine; Cancer cell line; Cations; Chemicals; Chemistry; Collaborations; Complex; Coupling; Cyclization; Development; Drug Targeting; Electrostatics; Exhibits; Generations; Halogens; Hydrogen Bonding; Indenes; Internet; Ions; Lead; Libraries; Medical center; Methodology; Modification; Molecular Weight; Morphine; Natural Product Drug; Natural Products; Nicotine; Nitrogen; Noscapine; Pathway interactions; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Plants; Process; Property; Reaction; Route; Scheme; Series; Source; Stimulant; Sulfonamides; System; Testing; Thiourea; Universities; Work; analog; catalyst; cheminformatics; design; drug biological activity; drug development; drug discovery; high throughput screening; improved; interest; ionization; novel; scaffold; tool

Project Summary: Alkaloids are an important class of nitrogen-containing, low-molecular weight compounds that are ubiquitous in plants.1 These compounds exhibit a wide range of pharmacological activities; ranging from antineoplastics (like noscapine) to analgesics (like morphine), or stimulants (like caffeine, or nicotine).2 Given their medicinal properties, the development of new methodologies that give access to libraries of new and complex alkaloids will aid in drug discovery efforts. In addition, the newly developed strategies will represent novel synthetic disconnections, which will facilitate the efficient synthesis of natural products and drug targets. This proposal will provide a facile and efficient route for the synthesis of structurally complex alkaloids from simple and inexpensive starting materials. One of the projects uses a halide-trapped aza-Prins cyclization to form a nitrogen-containing heterocycle with vinyl halide functional handle. These products can be ionized to give a series of structurally interesting products, depending on the reaction conditions and substrate design. The second project involves an intramolecular, π-trapped aza-Prins cyclization, giving access to two new rings and a new stereocenter in a one pot process. This chemistry is attractive for asymmetric studies using chiral thioureas to obtain enantioenriched products. This would be the first example of an enantioselective, alkynyl Prins cyclization. Synthesized libraries of compounds will be analyzed using online cheminformatics tools to determine which operationally simple transformations can be performed to increase the potential for bioactivity in our substrates. These modified substrates will be submitted to a number of high throughput screening centers for testing against various cancer cell lines, as well as used in collaborations with the University of Rochester Medical Center.

项目概要： 生物碱是一类重要的含氮低分子量化合物 植物中普遍存在。1 这些化合物具有广泛的药理作用 活动;从抗肿瘤药（如诺斯卡品）到镇痛药（如吗啡），或 兴奋剂（如咖啡因或尼古丁）。2 鉴于其药用特性，开发 提供新的和复杂的生物碱库的新方法将有助于 在药物发现工作中。此外，新开发的策略将代表新颖的 合成断开，这将促进天然产物的高效合成 和药物靶点。该提案将为合成提供一种简便有效的路线 从简单且廉价的起始原料中合成结构复杂的生物碱。之一 该项目使用卤化物捕获的氮杂王子环化形成含氮化合物 具有卤乙烯功能手柄的杂环。这些产品可以被电离以产生 一系列结构有趣的产物，取决于反应条件和 基板设计。第二个项目涉及分子内 π 捕获的 aza-Prins 环化，在一锅法中获得两个新的环和一个新的立体中心。 这种化学对于使用手性硫脲获得的不对称研究很有吸引力 对映体富集的产品。这将是对映选择性炔基的第一个例子 普林斯环化。将使用在线分析合成的化合物库 化学信息学工具可确定哪些操作简单的转化可以 进行以增加我们的底物的生物活性潜力。这些修改过的 底物将被提交给多个高通量筛选中心进行测试 针对各种癌细胞系，以及与英国大学合作使用 罗切斯特医疗中心。