Synthesis and Study of Dimeric Diketopiperazine Alkaloids

二聚二酮哌嗪生物碱的合成与研究

• 批准号: 8009874
• 负责人: Mohammad Movassaghi
• 金额: $ 38.67万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009874
• 关键词: Alkaloids; Architecture; Biological; Biological Factors; Biology; Breathing; Chemicals; Chemistry; Collaborations; Complement 3a; Complex; Development; Dimerization; Evaluation; Family; Future; Grant; Human; Hydroxyl Radical; Investigation; Link; Longitudinal Studies; Methodology; Molecular; Play; Preparation; Reaction; Research; Research Activity; Role; Route; Sampling; Secure; Solutions; Staging; Structure; Testing; Therapeutic; Tryptophan; Validation; asperazine; base; chaetocin; design; diketopiperazine; insight; interest; men; migration; novel therapeutics; oxidation; programs; public health relevance; stereochemistry; tool; verticillin A

DESCRIPTION (provided by applicant): The detailed study of the chemistry and biology of complex natural products at a fundamental level provides insight that is key to understanding their mode of action and development of new therapeutics for treatment of various human ailments. This research program aims to develop efficient and concise total syntheses of structurally complex and biologically active natural products through the discovery, development, and application of new strategies and methodologies. In this program, biogenetic considerations provide inspiration for development of new generalizable strategies to rapidly build molecular complexity. A key feature of the planned syntheses is the development of new highly chemoselective and stereoselective transformations. Of particular interest is development of new methodologies allowing advanced stage functionalization using the inherent reactivity of intermediates. Targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, ample opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. This program will focus on synthetic studies of the rich family of dimeric diketopiperazine alkaloids. The core structures of these alkaloids are adjoined by either Csp3-alkyl (sp3-sp3) or Csp3-aryl (sp3-sp2) bond connectivity at quaternary stereocenters. The program will focus on potently bioactive epidithiodiketopiperazines, including the verticillin alkaloids, and will develop generalizable methodologies for rapid assembly and functionalization of dimeric diketopiperazines containing vicinal quaternary stereocenters connected via a Csp3-Csp3 bond. We will also study a late stage highly stereoselective oxidation-migration sequence using bisindole structures to access the Csp3-aryl (sp3-sp2) bond connectivity found in a variety of alkaloids. This program will result in synthetic samples of rare and precious compounds for structure validation and exploration of their chemistry and biology. Given the rich biological activity of diketopiperazines and epidithiodiketopiperazines under investigation, related intermediates and derivatives also hold great promise as mechanistic tools and new bioactive compounds, and thus will be subject to various tests through our collaborative activities. PUBLIC HEALTH RELEVANCE: The study of the fundamental chemical and biological mechanism of action of natural products continues to play an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new and unique strategies and methodologies for preparation of bioactive and complex natural molecules and related designed derivatives. While the immediate result is direct access to samples of extremely rare and precious compounds for structure validation, collaborative biological evaluation, and mechanistic studies, the longer term and broader impact of this program is the establishment of precedence for the application of these new chemistries to other targets and potential therapeutics both natural or rationally designed.

描述（由申请人提供）：在基础水平上对复杂天然产物的化学和生物学的详细研究提供了洞察力，这是理解其作用模式和开发用于治疗各种人类疾病的新疗法的关键。该研究计划旨在通过发现，开发和应用新的策略和方法来开发结构复杂和生物活性天然产物的高效和简洁的全合成。在这个程序中，生物遗传学的考虑提供了新的可推广的策略，以快速建立分子的复杂性的发展灵感。计划合成的一个关键特征是开发新的高度化学选择性和立体选择性的转化。特别令人感兴趣的是开发新的方法，允许使用中间体的固有反应性进行高级官能化。目标的选择是基于分子结构的新奇，缺乏先前的合成研究，充分的机会，发展新的战略和方法，拥有显着的生物活性，以及未来的化学和生物机制研究的潜力。该计划将侧重于二酮哌嗪生物碱丰富的家庭的合成研究。这些生物碱的核心结构通过Csp 3-烷基（sp3-sp3）或Csp 3-芳基（sp3-sp2）键连接在季立体中心处邻接。该计划将重点关注具有潜在生物活性的epidithiodiketopiperazines，包括verticillin生物碱，并将开发可推广的方法，用于快速组装和功能化含有通过Csp 3-Csp 3键连接的邻位四元立体中心的二聚二酮哌嗪。我们还将研究后期高度立体选择性的氧化迁移序列，使用双吲哚结构，以访问各种生物碱中发现的Csp 3-芳基（sp3-sp2）键连接。该计划将产生稀有和珍贵化合物的合成样品，用于结构验证和化学和生物学探索。鉴于正在研究的二酮哌嗪和epidithiodiketopiperazines的丰富生物活性，相关中间体和衍生物也具有很大的前景，作为机械工具和新的生物活性化合物，因此将通过我们的合作活动进行各种测试。 公共卫生相关性：对天然产物的基本化学和生物学作用机制的研究在开发各种人类疾病的新疗法方面继续发挥重要作用。该计划旨在发现，开发和应用新的和独特的策略和方法来制备生物活性和复杂的天然分子和相关的设计衍生物。虽然直接的结果是直接获得极其稀有和珍贵的化合物的样品进行结构验证，合作生物学评价和机理研究，但该计划的长期和更广泛的影响是建立优先将这些新化学物质应用于其他目标和潜在的天然或合理设计的治疗方法。