Inspired by Nature: Rapid Syntheses and Applications of Propellane-Type Michael Acceptors and Biomimetic Syntheses of Hitorins

受自然启发：螺旋桨型迈克尔受体的快速合成和应用以及 Hitorins 的仿生合成

• 批准号: 9812885
• 负责人: Ting Wang
• 金额: $ 46.35万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812885
• 关键词: Alkenes; Anabolism; Area; Biological; Biology; Biomedical Research; Biomimetics; Cancer cell line; Chemicals; Comprehension; Coupling; DNA; Data; Development; Environment; Feedback; Future; Gastrointestinal Diseases; Grant; Hydrogen Peroxide; Investigation; Japan; Laboratories; Lactones; Lead; Libraries; Methodology; Methods; Modification; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Outcome; Pharmaceutical Preparations; Proteins; Publishing; Reaction; Reporting; Research; Science; Source; Speed; Structure; Time; Traditional Medicine; Training; analog; anti-cancer; base; bioactive natural products; cancer cell; carbene; career; drug discovery; functional group; programs; small molecule; undergraduate student

Covalent modifications of biomolecules, such as DNA and proteins, by natural products or their analogs are the mechanism of action of a number of current drugs. The syntheses of these covalent modifiers, such as propellane-type α-methylene-γ-lactones in this proposal, rely on the methodologies in our current synthetic toolbox. Inspired by the biosynthesis of natural products, we propose to generalize the key transformations to enlarge our synthetic toolbox. Meanwhile, natural products have served as the main source of current drugs due to their structural diversity. About one half of current small-molecule drugs on the market are natural products or their synthetic analogs. Natural product synthesis has benefited drug discovery by providing a supply alternative to the natural source, and by making more active analogs. In this R15 proposal, we aim to develop the synthesis of propellane-type α-methylene-γ-lactones inspired by our biomimetic syntheses of hitorins A and B. Hitorins A and B were isolated from the Chloranthus japonicas, a species that was a traditional medicine to treat gastrointestinal disorders in Japan. This proposal is divided into three Specific Aims. In Aim 1 (Biomimetic synthesis of hitorins A and B based on our modified biosynthetic proposal), we modified the current biosynthetic proposal of hitorins A and B into a radical cascade reaction. Our preliminary results strongly support our new proposal. Aim 2 (A general method to synthesize propellane-type α-methylene-γ-lactones): a cascade reaction was found to synthesize propellane-type α-methylene-γ-lactones during our exploration of Aim 1. The detailed mechanism and a broad synthetic capability will be explored in Aim 2. In Aim 3 (Biological studies of a focused library of propellane-type α-methylene-γ-lactones), we will collaborate with biologists to screen our library of synthetic propellane-type α-methylene-γ-lactones against different cancer cell lines. We aim to find a lead compound to further investigate the interaction between that compound and biomolecules in the cancer cells. From the proposed research, we will have an in-depth understanding of organic reactions and fundamental chemical principles. My undergraduate co-workers will receive comprehensive training in synthetic organic chemistry. This R15 grant will also be beneficial to SUNY-Albany for a better research environment.

通过天然产物或其类似物的生物分子的共价修饰，例如DNA和蛋白质 许多当前药物的作用机理。这些共价修饰符的合成，例如 在该提案中，丙烷型α-甲基-γ-乳元酮依赖于我们当前合成中的方法 工具箱。受天然产品的生物合成的启发，我们建议将关键转换推广到 放大我们的合成工具箱。同时，天然产品已成为当前药物的主要来源 到它们的结构多样性。市场上大约一半的市场上的小分子药物是天然产品或 它们的合成类似物。天然产品合成通过提供供应替代方案使药物发现受益 通过自然来源，并制作更活跃的类似物。在此R15提案中，我们旨在开发合成 丙烷型α-甲基-γ-内乳元受到我们的仿生合成蛋白A和B. hitoriins a的启发 和b从氯藻藻（Chloranthus japonicas）中分离出来，这种物种是一种传统药物治疗 日本的胃肠道疾病。该提议分为三个具体目标。在AIM 1（仿生）中 基于我们修改的生物合成建议的Hitorins A和B的合成），我们修改了电流 Hitorins a和b的生物合成建议成一个根治性的级联反应。我们的初步结果大力支持 我们的新建议。 AIM 2（一种合成丙烷型α-甲基-γ-lactones的一般方法）：A 发现级联反应在我们探索AIM期间合成丙烷型α-甲基-γ-乳元酮 1。将在AIM 2中探索详细的机制和广泛的合成能力。在AIM 3（生物学） 研究丙烷型α-甲基 - γ-内酯的重点库），我们将与生物学家合作 为了筛选我们的合成丙烷型α-亚甲基 - γ-linc酮的库，以不同的癌细胞系。我们 旨在找到铅化合物，以进一步研究该化合物与生物分子之间的相互作用 癌细胞。从拟议的研究中，我们将对有机反应有深入的了解和 基本化学原理。我的本科同事将接受合成的全面培训 有机化学。 R15赠款也将对SUNY-Albany有益于更好的研究环境。