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

描述（由申请人提供）：一氧化氮合酶在呼吸、心血管、神经和免疫系统的重要过程的正常功能中起着至关重要的作用，最近的进展表明，酶功能不正常与癌症、中风和神经退行性疾病的发病有关。同种异构体选择性一氧化氮合酶抑制剂已被证明可以调节这些酶的活性，并有助于治疗许多人类疾病。Alsmaphorazine A是一种从Alstonia pneumatophhora中少量分离出来的单萜吲哚生物碱，在脂酶刺激的lps刺激的J774.1巨噬细胞（IC50=49.2¿M）中显示出有希望的诱导型一氧化氮合酶抑制（IC50=49.2¿M），且剂量依赖方式不影响细胞活力。自alsmaphorazine家族的成员被发现以来，还没有通过全合成方法制备过，因此这些化合物和非天然类似物的合成途径将使它们能够作为一氧化氮合酶抑制剂或其他疾病的潜在治疗药物进行评估。本提案描述了一种从简单的起始材料全合成alsmaphorazine a独特的六环核心的简明方法，并概述了将合成路线扩展到alsmaphorazine B和许多合成衍生物。该方法采用分子内Diels-Alder，分子内或分子间Heck和(1,3)-偶极环加成来确保含有1,2-恶嗪烷，异恶唑烷和吲哚胺部分的笼状杂环框架。这种灵活的合成路线能够快速评估关键转化和不对称合成或制备非天然生物碱类似物的简易修饰。

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.