Modular synthesis of bioactive polycyclic polyprenylated acyl phloroglucinols by a symmetry-guided approach

通过对称引导方法模块化合成生物活性多环聚异戊二烯化酰基间苯三酚

• 批准号: 10387314
• 负责人: Trevor William Butcher
• 金额: $ 6.68万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-03 至 2025-02-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387314
• 关键词: 3-hydroxybutanal; Adamantane; Affect; Alkylation; Anti-Inflammatory Agents; Antidepressive Agents; Antioxidants; Attention; Clinical; Communities; Complex; DNA-Directed DNA Polymerase; Development; Doxorubicin; Exhibits; FDA approved; Goals; Health; Human; Hypericum perforatum; Lead; Left; Medicine; Metals; Methods; Natural Products; Organic Synthesis; Outcome; Pharmaceutical Preparations; Pharmacology; Phloroglucinol; Phosgene; Play; Positioning Attribute; Reaction; Reporting; Research; Role; Route; Scheme; Structure; Structure-Activity Relationship; Topoisomerase-I Inhibitor; Type I DNA Topoisomerases; analog; anti-cancer; anticancer activity; antimicrobial; appendage; base; bioactive natural products; drug development; drug discovery; enolate; hyperforin; nonane; novel; prenyl; scaffold; stereochemistry

PROJECT SUMMARY Natural products continue to play an important role in pharmacology by serving as potent medicines and new lead compounds for drug discovery. A particularly important class of bioactive natural products are the polycyclic polyprenylated acylphloroglucinols (PPAPs), which are known for their diverse bioactivities including anticancer, antiviral, anti-inflammatory, antidepressant, antimicrobial, antioxidant, and neuroprotective activities. The most well-known PPAP, hyperforin, is the active constituent of St. John’s wort, an herbal antidepressant approved for clinical use in the UK and available over-the-counter worldwide. PPAPs are characterized by a highly oxygenated, polycyclic core decorated by prenyl-derived substituents. Because the range of bioactivities offered by these compounds is controlled by the precise identity, position, and configuration of these substituents, modular syntheses of PPAPs that enable the rapid synthesis of numerous natural and unnatural PPAPs have been highly sought after. Although PPAPs have attracted significant attention from the synthetic community, nearly all efforts have been devoted to the synthesis of PPAPs containing a bicyclo[3.3.1]nonane-2,4,9-trione core. This proposal discloses the first modular route to tricyclic PPAPs and the first route to PPAPs containing a bicyclo[3.3.1]nonane-2,8-dione core. The tricyclic PPAPs are more complex than bicyclic PPAPs and consequently have not been prepared in a modular fashion. Several natural products with impressive bioactivities lie within the class of molecules we will target, including garcixanthochymones A and B, which exhibit antiproliferative activities comparable to the FDA-approved chemotherapeutic doxorubicin, and plukenetione A, which exhibits antitumor activity by inhibiting DNA polymerase and topoisomerase I. To achieve these syntheses, we have outlined a plan that defers the installation of each of the substituents to the end of the synthesis, thereby harnessing the hidden symmetry of adamantane-type PPAPs and bicyclo[3.3.1]nonane-2,8-dione-type PPAPs. In the context of this synthesis, we will develop new desymmetrizations that set quaternary stereocenters, directed asymmetric conjugate additions, and bridgehead metalations. These methods will have broad applications in organic synthesis beyond the field of natural product synthesis. The proposed research will positively affect human health by expanding the availability of complex, bioactive PPAPs, ultimately accelerating the discovery of new treatments based on these privileged scaffolds.

项目摘要 天然产品通过作为有效的药物和新的药物来继续在药理学中发挥重要作用 药物发现的铅化合物。一类特别重要的生物活性天然产品是多环 聚集烯基化的酰氯葡萄醇（PPAP），以其潜水生物活性，包括抗癌药，包括抗癌， 抗病毒，抗炎，抗抑郁药，抗菌，抗氧化剂和神经保护活性。最多 众所周知的PPAP Hyperforin是圣约翰最差的活跃成分，它是一种批准的草药抗抑郁药 英国的临床用途，在全球范围内可用。 PPAP的特征是高度氧化的多环状核心，该核心由前衍生的亚电位装饰。 因为这些化合物提供的生物活性范围由精确的身份，位置和 这些子登录的配置，PPAP的模块化合成，使许多人能够快速合成多种 自然和不自然的PPAP受到了极大的追捧。尽管PPAP引起了极大的关注 从合成社区中，几乎所有的努力都致力于合成包含一个的PPAP bicyclo [3.3.1] nonane-2,4,9-trione核心。该提案揭示了前往三轮车PPAP和 通往包含bicyclo [3.3.1] nonane-2,8-二酮核心的PPAP。三轮车PPAP更为复杂 比生物学ppap，因此没有以模块化的方式制备。几种天然产品 具有令人印象深刻的生物活性在我们将靶向的分子中，包括甲状腺素a 和B，暴露于与FDA批准的化学治疗性阿霉素相当的抗增殖活性 和Plumenetione A，通过抑制DNA聚合酶和拓扑异构酶。表现出抗肿瘤活性。 为了实现这些综合，我们概述了一个计划，该计划违反了每个子电视的安装 到综合的尽头，从而利用了阿甘坦型PPAP的隐藏对称性 bicyclo [3.3.1] nonane-2,8-dione型PPAP。在这种综合的背景下，我们将开发新的 设定第四纪立体中心，定向不对称结合添加和桥梁的幻想化 金属。这些方法将在自然产品领域以外的有机合成中广泛应用 合成。拟议的研究将通过扩大复杂的可用性，对人类健康的积极影响 生物活性PPAP，最终加速了基于这些特权脚手架的新疗法的发现。