Synthesis of Complex Terpenes From Simple Precursors

从简单前体合成复杂萜烯

• 批准号: 9901555
• 负责人: Thomas John Maimone
• 金额: $ 27.75万
• 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/9901555
• 关键词: Anti-Bacterial Agents; Antibiotics; Apoptotic; Architecture; Artemisinins; Biological; Biological Assay; Breathing; Cellular biology; Chemicals; Chemistry; Collaborations; Complex; Coupled; Cyclization; Development; Disease; Diterpenes; Drug resistance; Effectiveness; Event; Family; Family member; 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; 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; member; neoplastic cell; novel; novel therapeutics; ophiobolins; prenyl; programs; public health relevance; scaffold; sesterterpenes; small molecule; success; wasting

DESCRIPTION (provided by applicant): From Taxol(tm) 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. Periconicin 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.

描述（由申请人提供）：从紫杉醇（TM）到青蒿素，复杂的萜烯对人类疾病的治疗和理解产生了深远的影响。然而，尽管它们具有巨大的药用相关性，但大多数复杂的萜烯结构并不是详尽的药用和化学生物学研究的最佳起点，并且与许多小分子药物发现计划不同，很难容易地混合和匹配结构片段。拟议的研究计划旨在发现和开发简单的，模块化的合成途径，以获得复杂的，药用相关的萜类天然产物。该提议的核心是希望通过使用简单的异戊二烯基衍生的单元和手性池材料与受控的非仿生环化事件和多加氧策略相结合来大大简化萜烯合成。为该计划选择的靶点代表了复杂分子合成的最新挑战以及潜在的下一代治疗方法。具有5/8/n-稠环系统（n = 5，6）的复杂萜烯具有吸引人的和有效的抗癌、抗菌和免疫抑制剂性质，然而缺乏有效的合成方法来构建此类系统极大地阻碍了深入的结构/功能研究。特别是二倍半萜的蛇孢菌素家族几十年来一直抵抗有效的化学合成，需要新的策略来有效地构建这种多样化和不断增长的天然产物。这项工作无疑将导致一个增强的SAR图片的结构和功能有关的抗癌性能。Periconicin代表了一类新兴的（并且在很大程度上未开发的）抗菌剂，其对革兰氏阳性和阴性菌株都具有活性。尽管努力，复杂的免疫抑制剂variecolin尚未合成，这表明当前技术存在差距。高度氧化的愈创木单萜代表了有机合成和潜在的下一代治疗剂的最新挑战。最后，萜类过氧化物代表了治疗疟疾的成熟疗法，并且正在成为治疗各种疾病的一类有前途的促细胞凋亡剂。我们已经开发了一种非常简单的方法来构建萜烯过氧化物支架使用高效的，金属催化的串联反应。总的来说，该计划旨在利用合成化学的进步以及天然产物结构的灵感，以前所未有的效率和多样性构建具有生物活性的小分子。在这项工作的过程中，学生将在合成化学提供严格和智力刺激的培训。