Synthesis of Complex Terpenes From Simple Precursors

从简单前体合成复杂萜烯

• 批准号: 9705683
• 负责人: Thomas John Maimone
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9705683
• 关键词: Anti-Bacterial Agents; Antibiotics; Antimalarials; Apoptotic; Architecture; Artemisinins; Biological; Biological Assay; Breathing; Cardamom; Cellular biology; Chemicals; Chemistry; Collaborations; Complex; Coupled; Cyclization; Development; Disease; Diterpenes; Drug resistance; Effectiveness; Event; Family; Family member; Felis catus; Goals; Immunosuppressive Agents; Lead; Malaria; Manganese; Medicine; Metals; Methods; Modification; Molecular; Molecular Biology; National Institute of Allergy and Infectious Disease; Natural Products; Organic Chemistry; Organic Synthesis; Oxygen; Paclitaxel; Pathway interactions; Pattern; Peroxides; Pharmaceutical Chemistry; Polyenes; Process; Property; Reaction; Research; Route; Sesquiterpenes; Structure; Students; Synthesis Chemistry; System; Technology; Terpenes; Thapsigargin; Therapeutic; Therapeutic Agents; Training; United States National Institutes of Health; Work; anti-cancer; anticancer activity; antiproliferative agents; career; cell type; chemical synthesis; cost; design; drug discovery; exhaustion; graduate student; human disease; interest; member; neoplastic cell; novel; novel therapeutics; ophiobolins; prenyl; programs; scaffold; sesterterpenes; small molecule; success; wasting

PROJECT SUMMARY From Taxol™ to artemisinin, complex terpenes have had a profound impact on both the treatment and understanding of human disease. Despite their enormous medicinal relevance, however, most complex terpene architectures are not optimal starting points for exhaustive medicinal and chemical biological studies, and unlike many small molecule drug discovery programs, it is difficult to easily mix- and-match structural fragments. The proposed research program seeks to discover and develop simple, modular synthetic pathways to access complex, medicinally relevant terpenoid natural products. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple prenyl-derived units and chiral pool materials in concert with controlled, non-biomimetic cyclization events and polyoxygenation strategies. The targets chosen for this program represent both state of the art challenges for complex molecule synthesis as well as potential next-generation therapeutics. Complex terpenes featuring 5/8/n-fused ring systems (n = 5,6) have attractive and potent anticancer, antibacterial, and immunesuppressant properties, yet the lack of efficient synthetic methods to construct such systems has greatly hampered in-depth structure/function studies. The ophiobolin family of sesterterpenes in particular has resisted efficient chemical synthesis for several decades and new strategies are needed to efficiently construct this diverse and growing class of natural products. This work will undoubtedly lead to an enhanced SAR picture with respect to structure and function relating to their anticancer properties. Periconicins represent an emerging (and largely unexplored) class of antibacterial agents with activity against both gram positive and negative strains. Despite effort, the complex immunosuppressant variecolin has not been synthesized signifying a gap in current technologies. Highly oxygenated guaianolide terpenes represent state of the art challenges for organic synthesis and potential next generation therapeutics. Finally, terpenoid peroxides represent proven therapeutics for the treatment of malaria and are emerging as a promising class of pro-apoptotic agents for the treatment of various diseases. We have developed a remarkably simple way to construct terpene peroxide scaffolds using efficient, metal-catalyzed tandem reactions. Overall this program seeks to use advances in synthetic chemistry coupled with the inspiration of natural product architectures to construct biologically active small molecules with unprecedented efficiency and diversity. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.

项目概要 从紫杉醇™到青蒿素，复杂的萜烯对治疗和治疗都产生了深远的影响。 对人类疾病的了解。然而，尽管它们具有巨大的医学意义，但最复杂的 萜烯结构并不是详尽的医学和化学生物学研究的最佳起点， 与许多小分子药物发现计划不同，很难轻松地混合和匹配结构 碎片。拟议的研究计划旨在发现和开发简单的模块化合成 获取复杂的、药用相关萜类天然产物的途径。该提案的核心是 希望通过使用简单的异戊烯基衍生单元和手性池材料来大大简化萜烯合成 与受控的非仿生环化事件和多氧合策略相协调。选定的目标 该项目代表了复杂分子合成的最先进挑战以及潜在的 下一代疗法。具有 5/8/n-稠环系统 (n = 5,6) 的复杂萜烯具有吸引力 以及有效的抗癌、抗菌和免疫抑制特性，但缺乏有效的合成方法 构建此类系统的方法极大地阻碍了深入的结构/功能研究。蛇毒灵 尤其是二倍萜烯家族，几十年来一直无法有效地进行化学合成，而新的 需要制定策略来有效地构建这一多样化且不断增长的天然产品类别。这项工作将 毫无疑问，它们在抗癌相关的结构和功能方面增强了 SAR 图像 特性。 Periconicins 代表一类新兴的（且很大程度上未经探索的）抗菌剂， 对革兰氏阳性和阴性菌株均具有活性。尽管付出了努力，复杂的免疫抑制剂 variecolin 尚未合成，这表明当前技术存在差距。高氧愈创木酚内酯 萜烯代表了有机合成和潜在的下一代疗法的最新挑战。 最后，萜类过氧化物代表了治疗疟疾的行之有效的疗法，并且正在成为一种新兴的治疗方法。 一类有前途的促凋亡剂，用于治疗各种疾病。我们开发了一个 使用高效的金属催化串联构建萜烯过氧化物支架的非常简单的方法 反应。总体而言，该计划旨在利用合成化学的进步以及以下方面的灵感： 天然产物结构以前所未有的效率构建生物活性小分子 多样性。在这项工作的过程中，学生将受到严格的、智力上的刺激 合成化学培训。