Method and Strategy Development for the Synthesis of Physiologically Important Natural Products

合成具有生理重要性的天然产物的方法和策略开发

• 批准号: 10132361
• 负责人: JOHN L WOOD
• 金额: $ 29.78万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132361
• 关键词: Acids; Aldehydes; Alkaloids; Alkynes; Anti-Inflammatory Agents; Antibiotics; Antifungal Agents; Antiviral Agents; Architecture; Area; Benign; Biological; Biomedical Research; Bromides; Cancer cell line; Carbon; Chemistry; Collaborations; Collection; Complex; Coupling; Development; Elements; FDA approved; Grant; Hand; Health; Hepatitis C virus; Human; Hydrogenation; Hydroxamic Acids; In Situ; Investigation; Ketones; Laboratories; Lead; Learning; Methodology; Methods; Molecular; Natural Products; Nature; Nitrogen; Oxygen; Pharmaceutical Preparations; Physiological; Preparation; Production; Property; Protocols documentation; Reaction; Research Personnel; Resolution; Route; Science; Securinega; Solvents; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Techniques; Technology; Terpenes; Therapeutic; United States National Institutes of Health; Work; anti-cancer; cyclic ketone; cycloaddition; cytotoxicity; diketopiperazine; drug development; falls; functional group; graduate student; member; novel; novel therapeutics; research and development; scaffold; screening; skills

PROJECT SUMMARY/ABSTRACT Over the past three decades, 28% of all new FDA approved drugs have been natural products, or derived from natural products, while 27% have been entirely synthetic in origin. Thus, the pursuit of new synthetic methods and strategies to access complex molecules is not only a worthy pursuit, but a critical component of biomedical research and drug development that also contributes novel elements of synthetic strategy and methods to the lexicon of synthetic chemistry. The studies proposed within this application describe the pursuit of six different natural products that fall into three general classes (diketopiperazine, alkaloid, and terpenoid). These compounds possess a range of biological activities including: leishmanicidal, NO production inhibition, anti- inflamatory, antiinsectan, antifungal, antiviral, cytotoxicity against a variety of cancer cell lines, as well as anti- proliferative activity. For the diketopiperazine and alkaloid projects we are aiming to develop ring expansion technology that will enable efficient access to imbedded hydroxamic acid intermediates. More specifically: Aim 1, entails syntheses of the N-hydroxy-2,5-diketopiperazine-derived (NHDKP) natural products haenamindole, raistrickindole A, and 14-hydroxyterezine D. This aim also includes the development of a regioselective ring expansion of tetramic acids that will enable the direct acces of to highly functionalized NHDKP’s. Aim 2 focuses on syntheses of phyllantidine and flueggeacosine B, two members of a securinega alkaloid subset that contain N-O bonds. The scope of the optimized ring-expansion chemistry developed in Aim-1 will be expand in this aim to deliver key intermediates in both syntheses. Aim 3 is a departure from aims 1 and 2 and turns toward further development of keteniminium chemistry by its application in a complex synthetic setting. At present, work toward each aim is at a different stage of development and this development will continue to evolve over the course of the grant period. As with all of our synthetic endeavors, collections of intermediates will be submitted to the NIH for SAR studies and once materials are in hand further collaborations are sought. In addition to direct contributions to biomedical science afforded by the latter, our synthetic efforts have (and will continue to) educate graduate students and postdoctoral researchers in the planning and execution of complex molecule synthesis.

项目摘要/摘要 在过去的三十年中，所有新的FDA批准药物中有28％是天然产品，或者源自 天然产物，而27％的起源完全是合成的。那，追求新的合成方法 获取复杂分子的策略不仅是一种宝贵的追求，而且是生物医学的关键组成部分 研究和药物开发也为合成策略和方法的新元素和方法贡献给了 合成化学的词典。本应用程序中提出的研究描述了对六种不同的追求 天然产物属于三个通用类别（二酮替代，生物碱和萜类化合物）。这些 化合物具有一系列的生物学活性，包括：利什曼尼剂，无生产抑制，抗 发炎，抗真菌，抗真菌，抗病毒，细胞毒性针对多种癌细胞系，以及抗 增殖活动。对于Diketoperazine和生物碱项目，我们旨在开发戒指扩展 将有效访问嵌入的羟丙酸中间体的技术。更具体地说：目标 1，需要N-Hydroxy-2,5-diketoperaperazine衍生的（NHDKP）天然产品Haenamindole的合成， Raistrickindole A和14-羟基嗪D。此目标还包括开发监管环 四酸的膨胀将使能够直接进入高度功能化的NHDKP。目标2 侧重于phyllantidine和flueggecasine b的合成，这是Securinega生物碱子集的两个成员 包含N-O键。在AIM-1中开发的优化环膨胀化学的范围将扩大 这个目的是在两个合成中提供关键的中间体。 AIM 3是偏离目标1和2的偏离 通过在复杂的合成环境中应用其进一步开发酮氨基化学。在 现在，针对每个目标的工作都是在不同的发展阶段，这种发展将继续 在整个赠款期间的演变。与我们所有的合成努力一样，中间体的集合 将提交给NIH进行SAR研究，一旦材料掌握在材料中，就寻求进一步的合作。 除了对后者提供的生物医学科学的直接贡献外，我们的合成努力也（并且 将继续）教育研究生和博士后研究人员在计划和执行方面 复杂的分子合成。