New Methods and Strategies for the Synthesis of ETP Natural Products

ETP天然产物合成新方法和新策略

• 批准号: 8087471
• 负责人: Sarah Elizabeth Reisman
• 金额: $ 27.97万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087471
• 关键词: Anti-Bacterial Agents; Antibiotics; Antiviral Agents; Biological; Biological Factors; Biology; Cancer Center; Carbon; Chemistry; Cities; Collaborations; Collection; Communicable Diseases; Complex; DNA-Directed RNA Polymerase; Development; Disease; Exhibits; Family; Foundations; Future; Gliotoxin; Glycols; Goals; In Vitro; Indoles; Institutes; Kinetics; Malignant neoplasm of prostate; Methicillin; Methodological Studies; Methods; Organic Chemistry; Organometallic Chemistry; Preparation; Property; Reaction; Research; Staging; Staphylococcus aureus; Therapeutic Studies; Tin; Transition Elements; analog; aranotin; cancer cell; cancer therapy; chemical reaction; chemical synthesis; cycloaddition; inhibitor/antagonist; innovation; insight; monomer; quinolone resistance; stereochemistry; verticillin A; viral RNA

DESCRIPTION (provided by applicant): Epidithiodiketopiperazine (ETP) natural products are a class of structurally complex fungal metabolites that exhibit biological properties including antiviral, antiproliferative, and antibacterial activities. The goal of the proposed research is to develop new synthetic methods and strategies for the synthesis of dihydrooxepine and pyrrolidinoindoline ETP natural products. The development of efficient chemical syntheses of ETP natural products is expected to facilitate the study of their biological properties, and demands innovative new methods to prepare dihydrooxepine and pyrrolidinoindoline core motifs. The proposed research comprises two projects, the first of which targets the natural products aranotin (2) and MPC1001B (5), and is expected to contribute new transition-metal catalyzed methods for the preparation of dihydrooxepines. In addition, the first comprehensive studies of ETP formation in the presence of a dihydrooxepine moiety will be carried out. The specific aims are: 1.1) to develop transition metal-catalyzed cycloisomerization reactions to prepare dihydrooxepines; 1.2) to complete a total synthesis of the antiviral natural project aranotin (2); 1.3) to complete a total synthesis of the antiproliferative natural product MPC1001B (5). The second project targets pyrrolidinoindoline ETPs such as 11-deoxybionectin A (8). To this end, a new enantioselective formal [3+2] cycloaddition to prepare pyrrolidinoindolines directly from indoles will be developed. The specific aims are: 2.1) to develop catalytic asymmetric formal [3+2] cycloaddition reactions to prepare pyrrolidinoindolines; 2.2) to study and elucidate the mechanism of catalytic asymmetric pyrrolidinoindoline formation; 2.3) to complete a total synthesis of 11-deoxybionectin A (8). Synthetic access to ETPs such as 2, 5, and 8, is expected to permit studies aimed at deepening our understanding of the underlying mechanisms of their biological properties. Through collaborations with the City of Hope Cancer Center and the Broad Institute of Harvard and MIT, these natural products and synthetic derivatives will be evaluated as biological probes and potential therapeutics for the study and treatment of cancer and infectious disease. It is anticipated that these studies will result in the development of new chemical reactions, further our fundamental understanding of organic and organometallic chemistry, and contribute valuable information on the chemistry and biology of two distinct families of ETP natural products. PUBLIC HEALTH RELEVANCE: Epidithiodiketopiperazine (ETP) natural products are a structurally diverse group of fungal metabolites that exhibit an array of promising biological properties, including antibiotic, antiviral, and antiproliferative activities. This proposal aims to develop new chemical reactions and synthetic strategies for the chemical synthesis of ETP natural products. These studies will contribute valuable information about the chemistry and biology of ETP natural products, and in so doing, will facilitate the study and treatment of disease.

描述(申请人提供)：表二硫代二酮基哌嗪(ETP)天然产物是一类结构复杂的真菌代谢物，具有抗病毒、抗增殖和抗菌等生物学活性。这项研究的目标是开发新的合成方法和策略，用于合成二氢奥西平和吡咯烷吲哚乙二醇醚的天然产物。高效的ETP天然产物化学合成的发展有望促进其生物学性质的研究，这就需要创新的方法来制备二氢奥西平和吡咯烷吲哚的核心模体。拟议的研究包括两个项目，第一个项目针对天然产物芳香胺(2)和MPC1001B(5)，预计将为二氢奥施平的制备提供新的过渡金属催化方法。此外，还将开展在二氢奥西平存在的情况下形成ETP的首次全面研究。具体目标是：1.1)发展过渡金属催化的环异构化反应以制备二氢奥西平；1.2)完成抗病毒天然项目阿拉伯酸苷(2)的全合成；1.3)完成抗增殖天然产物MPC1001B(5)的全合成。第二个项目针对的是吡咯烷吲哚类ETP，如11-脱氧生物连接素A(8)。为此，将开发一种新的由吲哚直接合成吡咯烷吲哚的不对称形式[3+2]环加成反应。具体目标是：2.1)开展催化不对称形式[3+2]环加成反应，合成吡咯烷吲哚；2.2)研究和阐明催化不对称吡咯烷吲哚形成机理；2.3)完成11-脱氧生物素A(8)的全合成。合成获得ETP，如2，5和8，有望使旨在加深我们对其生物学特性的潜在机制的理解的研究成为可能。通过与希望之城癌症中心以及哈佛大学和麻省理工学院博德研究所的合作，这些天然产品和合成衍生品将被评估为研究和治疗癌症和传染病的生物探针和潜在疗法。预计这些研究将导致新的化学反应的发展，加深我们对有机和有机金属化学的基本了解，并为两个不同的ETP天然产物家族的化学和生物学提供有价值的信息。 与公共卫生相关：Epidithiodiketopiperazine(ETP)天然产物是一组结构多样的真菌代谢物，表现出一系列有前景的生物学特性，包括抗生素、抗病毒和抗增殖活性。这项提议旨在开发新的化学反应和合成策略，用于ETP天然产物的化学合成。这些研究将提供有关ETP天然产物的化学和生物学方面的有价值的信息，这样做将有助于疾病的研究和治疗。