Total Synthesis of Alsmaphorazine A, an Alkaloid Natural Product Inhibitor of Nit

尼特生物碱天然产物抑制剂阿司马佛拉嗪 A 的全合成

• 批准号: 8395931
• 负责人: Allen Y. Hong
• 金额: $ 4.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-14 至 2016-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395931
• 关键词: Affect; Aldehydes; Alder plant; Alkaloids; Alstonia; Alzheimer' s Disease; Biological; Biological Factors; Cardiovascular system; Cell Survival; Cells; Cessation of life; Chemicals; Collection; Complex; Development; Disease; Dose; Enzymes; Evaluation; Family; Future; Generations; Goals; Human; Immune system; Indole Alkaloids; Inhibitory Concentration 50; Link; Lipase; Malignant Neoplasms; Medical Research; Methods; Modification; Monoterpenes; Nervous system structure; Neurodegenerative Disorders; Nitric Oxide Synthase; Phase; Plant Sources; Play; Preparation; Process; Protein Isoforms; Reaction; Research; Research Project Grants; Respiratory System; Role; Route; Secure; Series; Stroke; Structure; Therapeutic; Ursidae Family; analog; chemical reaction; cycloaddition; enzyme activity; flexibility; human NOS2A protein; human disease; indoline; inhibitor/antagonist; macrophage; member

DESCRIPTION (provided by applicant): Nitric oxide synthase plays an essential role in the proper functioning of vital processes in respiratory, cardiovascular, nervous, and immune systems, and recent advances have shown that improper enzyme function has been linked to the onset of cancer, stroke, and neurodegenerative diseases. Isoform-selective nitric oxide synthase inhibitors have been shown to modulate the activity of these enzymes and help treat numerous human diseases. Alsmaphorazine A, a monoterpene indole alkaloid isolated in small quantities from Alstonia pneumatophora, has shown promising inducible nitric oxide synthase inhibition in lipase stimulated LPS-stimulated J774.1 macrophage cells (IC50=49.2 ¿M) in a dose-dependent manner without affecting cell viability. No members of the alsmaphorazine family have been prepared by total synthesis since their discovery, so synthetic access to these compounds and unnatural analogs would enable their evaluation as nitric oxide synthase inhibitors or potential therapeutics for other diseases. This proposal describes a concise approach to the total synthesis of the unique hexacyclic core of alsmaphorazine A from simple starting materials and outlines the extension of the synthetic route to alsmaphorazine B and numerous synthetic derivatives. The approach employs an intramolecular Diels-Alder, intra- or intermolecular Heck, and (1,3)-dipolar cycloaddition to secure the caged heterocyclic framework which bears 1,2-oxazinane, isoxazolidine, and indoleneine moieties. This flexible synthetic route enables rapid evaluation of key transformations and facile modification for asymmetric synthesis or preparation of unnatural alkaloid analogs.

描述（由适用提供）：一氧化氮合酶在呼吸，心血管，神经和免疫系统中重要过程的适当运作中起着至关重要的作用，并且最近的进步表明，酶功能不当已与癌症，中风和神经降解性疾病的发作有关。同工型选择性一氧化氮合酶抑制剂已显示可调节这些酶的活性并有助于治疗许多人类疾病。 Alsmaphorazine A是一种与肺炎肺炎少量分离的单二烯吲哚生物碱，已显示出有望在脂肪酶刺激的LPS刺激的LPS刺激的J774.1巨噬细胞中诱导的诱导型一氧化氮合酶抑制（IC50 = 49.2€M），而无需影响Dose的依赖性。自发现以来，没有通过总合成来制备Alsmaphorazine家族的成员，因此合成对这些化合物和不自然的类似物的访问将使他们作为一氧化氮合酶抑制剂或对其他疾病的潜在治疗方法进行评估。该提案描述了一种简洁的方法，用于从简单的起始材料中完全合成Alsmaphorazine A独特的六边性核心，并概述了合成途径扩展到Alsmaphorazine B和许多合成衍生物。该方法采用分子内二烷级，分子内或分子间的heck，（1,3） - 多极环加成，以确保带有1,2-氧化烷，异沙唑醇和吲哚胺的笼中的笼中的杂环框架。这种灵活的合成途径可以快速评估关键转化和轻松修饰，以进行不对称的合成或制备不自然的生物碱类似物。