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（由申请人提供）：表皮二邻苯二甲酸（ETP）天然产物是一类结构复杂的真菌代谢物，具有抗病毒，抗增殖和抗细菌活性在内的生物学特性。拟议的研究的目的是开发新的合成方法和策略，以合成二羟基氧和吡咯烷迪迪洛丁氨酸ETP天然产物。 ETP天然产物有效的化学合成的发展有望促进其生物学特性的研究，并需要创新的新方法来制备二羟氧气和吡咯烷迪诺迪迪丁洛琳核心基序。 拟议的研究包括两个项目，其中第一个针对天然产物Aranotin（2）和MPC1001B（5），并有望为制备二羟氧气的准备新的过渡金属催化方法。此外，将在存在二氢昔epine部分的情况下对ETP形成的首次综合研究。具体目的是：1.1）开发过渡金属催化的环化反应以制备二氢氧果； 1.2）完成抗病毒天然项目Aranotin的总合成（2）； 1.3）完成抗增殖性天然产物MPC1001b的总合成（5）。第二个项目靶向吡咯啶丁迪ETP，例如11-脱氧辅维蛋白A（8）。为此，将开发出一种新的对映选择性的正式[3+2]环加成，以直接从indoles中制备吡咯烷二丹岛。具体目的是：2.1）开发催化不对称的形式[3+2]环加成反应，以制备吡咯烷迪迪顿； 2.2）研究和阐明催化不对称吡咯烷丁寄生的机理； 2.3）完成11-脱氧副毒素A（8）的总合成。预期获得2、5和8等ETP的合成访问允许研究加深我们对其生物学特性的潜在机制的理解。通过与Hope Cance Center中心以及哈佛大学和麻省理工学院的广泛研究所的合作，这些天然产物和合成衍生物将被评估为研究和治疗癌症和传染病的生物学探针和潜在的治疗剂。预计这些研究将导致新的化学反应的发展，进一步我们对有机和有机金属化学的基本理解，并为ETP天然产品的两个不同家族的化学和生物学提供宝贵的信息。 公共卫生相关性：二硫代二甲苯嗪（ETP）天然产物是一组结构上多样的真菌代谢产物，它们表现出一系列有希望的生物学特性，包括抗生素，抗病毒和抗增殖活性。该建议旨在为ETP天然产物的化学合成开发新的化学反应和合成策略。这些研究将贡献有关ETP天然产品的化学和生物学的有价值信息，并且这样做将有助于疾病的研究和治疗。