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: 7765821
• 负责人: Mohammad Movassaghi
• 金额: $ 40.47万
• 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/7765821
• 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; Research Design; Role; Route; Sampling; Secure; Solutions; Staging; Structure; Testing; Therapeutic; Tryptophan; Validation; asperazine; base; chaetocin; design; diketopiperazine; insight; interest; 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品的化学和生物学的详细研究提供了洞察力，这是了解它们的作用模式和开发治疗各种人类疾病的新疗法的关键。这项研究计划旨在通过发现、开发和应用新的战略和方法，开发高效、简洁的结构复杂和具有生物活性的天然产物的全合成。在这个项目中，生物遗传学的考虑为快速构建分子复杂性的新的可推广策略的开发提供了灵感。计划合成的一个关键特征是开发了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，允许使用中间体固有的反应性进行高级阶段功能化。目标的选择是基于分子结构的新颖性、先前合成研究的匮乏、开发新战略和方法的充足机会、拥有重要的生物活性以及未来化学和生物机制研究的潜力。这项计划将重点研究丰富的二聚体二酮基哌嗪生物碱家族的合成研究。这些生物碱的核心结构在四元立体中心由Csp3-烷基(Sp3-Sp3)或Csp3-芳基(Sp3-sp2)键连接而成。该计划将专注于具有潜在生物活性的二硫代二酮基哌嗪，包括轮回西林生物碱，并将开发可推广的方法，用于快速组装和功能化含有通过Csp3-Csp3键连接的邻位四元立体中心的二聚二酮基哌嗪。我们还将研究后期的高度立体选择性的氧化-迁移序列，使用双吲哚结构来访问在各种生物碱中发现的Csp3-芳基(sp3-sp2)键连接性。该计划将产生稀有和珍贵化合物的合成样品，用于结构验证和对其化学和生物学的探索。鉴于所研究的二酮基哌嗪和二硫代二酮基哌嗪具有丰富的生物活性，相关的中间体和衍生物作为机械工具和新的生物活性化合物也很有希望，因此将通过我们的合作活动接受各种测试。 与公共健康相关：对天然产品的基本化学和生物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战略和方法，以制备具有生物活性的复杂天然分子和相关设计的衍生物。虽然直接的结果是直接获得极其稀有和珍贵的化合物样本，用于结构验证、合作生物学评估和机制研究，但该计划的长期和更广泛的影响是为将这些新化学应用于其他目标和潜在的治疗方法建立优先地位，无论是天然的还是合理设计的。