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

基本信息

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
项目类别：
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

项目摘要

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性；从抗肿瘤药（如那可品）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此外，新开发的策略将代表新颖。合成断开，这将促进天然产物的高效合成该提案将为合成提供简便有效的途径。从简单且廉价的起始原料中合成结构复杂的生物碱。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乙烯基卤化物官能团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构中心。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这将是对映选择性炔基的第一个例子。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。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。