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 这些化合物表现出广泛的药理学活性， 活动;从抗过敏塑料（如诺斯卡品）到镇痛剂（如吗啡），或 兴奋剂（如咖啡因或尼古丁）。2鉴于其药用特性， 新的方法，使进入图书馆的新的和复杂的生物碱将有助于 在药物发现方面的努力。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有效合成 药物靶点这一建议将为合成提供一条简便、有效的路线 结构复杂的生物碱从简单和廉价的原料。之一 该项目使用卤化物捕获的氮杂-Prins环化反应形成含氮的 具有卤代乙烯官能柄杂环。这些产物可以被电离以给出 一系列结构上令人感兴趣的产物，这取决于反应条件和 基板设计第二个项目涉及分子内的π-捕获的aza-Prins 环化，从而在一锅法中获得两个新的环和一个新的立构中心。 这种化学对于使用手性硫脲的不对称研究是有吸引力的， 对映体富集的产物。这将是对映选择性炔基 Prins环化。合成的化合物库将使用在线分析 化学信息学工具，以确定哪些操作简单的转换可以 进行，以增加在我们的基板的生物活性的潜力。这些改性 基质将被提交到多个高通量筛选中心进行测试 针对各种癌细胞系，以及用于与大学合作， 罗切斯特医疗中心。