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 天然产物继续发挥重要作用，药理学作为有效的药物和新的 药物发现的先导化合物。一类特别重要的生物活性天然产物是多环 聚异戊二烯化酰基间苯三酚（PPAP），其已知具有多种生物活性，包括抗癌， 抗病毒、抗炎、抗抑郁、抗微生物、抗氧化和神经保护活性。最 众所周知的PPAP，贯叶金丝桃素，是圣约翰草的活性成分，圣约翰草是一种草药抗抑郁药，被批准用于 在英国临床使用，在全球范围内非处方。 PPAP的特征在于由异戊二烯基衍生的取代基修饰的高度氧化的多环核。 因为这些化合物提供的生物活性范围由化合物的精确身份、位置和结构控制， 这些取代基的结构，PPAP的模块化合成，使许多快速合成 天然的和非天然的PPAP一直备受追捧。虽然PPAP引起了人们的极大关注， 从合成社区来看，几乎所有的努力都致力于PPAP的合成， 双环[3.3.1]壬烷-2，4，9-三酮核。该提案公开了三环PPAP的第一个模块化路线， 第一种制备含有双环[3.3.1]壬烷-2，8-二酮核的PPAP的途径。三环PPAP更复杂 而不是双环PPAP，因此没有以模块化方式制备。几种天然产物 具有令人印象深刻的生物活性，属于我们将靶向的分子类别，包括garcixanthochymones A 和B，其表现出与FDA批准的化疗阿霉素相当的抗增殖活性， 和通过抑制DNA聚合酶和拓扑异构酶I而显示抗肿瘤活性的plukenetion A。 为了实现这些合成，我们已经概述了一个推迟每个取代基安装的计划 到合成结束，从而利用金刚烷型PPAP的隐藏对称性， 双环[3.3.1]壬烷-2，8-二酮型PPAP。在这一综合的背景下，我们将开发新的 去对称化，设置四元立体中心，定向不对称共轭加成和桥头 金属化这些方法将在天然产物领域之外的有机合成中有广泛的应用 合成.拟议的研究将通过扩大复杂的， 具有生物活性的PPAP，最终加速基于这些特殊支架的新治疗方法的发现。