Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

• 批准号: 8266483
• 负责人: Armen Zakarian
• 金额: $ 38.17万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266483
• 关键词: Achievement; Address; Antigens; Area; Biological Factors; Carbon Dioxide; Chemicals; Chemistry; Claisen rearrangement; Complex; Detection; Development; Disease Outbreaks; Drug Compounding; Environment; Esters; Event; Exhibits; Family; Foundations; Goals; Health; Human; Imines; Immunoassay; Intoxication; Ireland; Marine Toxins; Methodology; Methods; Monitor; Organic Chemistry; Organic Synthesis; Pharmaceutical Chemistry; Pharmacologic Substance; Prevention; Property; Public Health; Reaction; Relative (related person); Research; Seafood; Shellfish; Solutions; Source; Structure; Toxin; Work; base; chemical synthesis; drug discovery; external ear auricle; gymnodimine; improved; innovation; marine natural product; member; pharmacophore; pinnatoxin A; programs

DESCRIPTION (provided by applicant): The main objective of our research program is the development of new synthetic methods using complex natural products to identify new challenges. Our endeavors in total synthesis and resulting access to natural products will also provide the basis for research in the area of bioorganic chemistry. The new synthetic methods will find further utility in pharmaceutical and medicinal research, serving for the benefit of public health through improved preparation of drugs and bioactive substances. The specific targets pursued in this application are marine toxins containing a spiroimine ring. This is an expanding group of complex marine natural products that presently includes pinnatoxins, pteriatoxins, spirolides, spiro-prorocentrimine, and gymnodimine. The unique spiroimine fragment has been determined to be critical for their bioactivity. Some of these natural products have been implicated in several global seafood intoxication events. The proposed synthetic strategy is general and can be applied for the synthesis of pinnatoxins, spirolides, and gymnodimine. The most challenging part of the target structures is the spiroimine fragment. We developed a method that enables stereoselective Ireland-Claisen rearrangement of alpha-branched allylic esters. Typically, poor diastereoselectivity is observed in these reactions. Employing our method, both diastereomers can be accessed with excellent diastereoselectivity. This is the central method that we use in the synthesis of the spiroimine fragments. We anticipate that our efforts in the area of chemical synthesis of complex natural products will enrich the arsenal of synthetic methods in general, facilitating research in the fields of medicinal chemistry and drug discovery. More specific to this application, the marine toxins featured herein are directly related to the public health issue of seafood intoxication. It is noted that a major problem in the development of precise methods for detection of algal toxins is the lack of pure standards. Thus, the targets of our syntheses will serve as pure standards for the development of detection probes for marine toxins. PUBLIC HEALTH RELEVANCE Developments in organic synthesis have long benefited human health by providing methods for drug discovery and pharmaceutical research. The total synthesis of complex natural products is a major branch of organic chemistry that defines the current state-of-the-art, stimulates innovation and discovery, and identifies new challenges to be addressed. The research proposed in this application will enrich synthetic methodology through total synthesis of complex natural products. In addition, we will develop sensitive immunoassays for the detection of marine toxins in the environment. This will benefit human health by prevention of certain types of seafood intoxication, which has become a global phenomenon.

描述（由申请人提供）：我们研究计划的主要目标是使用复杂的天然产物开发新的合成方法来识别新的挑战。我们在全合成和由此获得天然产物方面的努力也将为生物有机化学领域的研究提供基础。新的合成方法将在制药和医学研究中得到进一步的应用，通过改进药物和生物活性物质的制备来造福公众健康。本申请追求的具体目标是含有螺胺环的海洋毒素。这是一组不断扩大的复杂海洋天然产物，目前包括pinnatoxins、pteriatoxins、spirolides、spiro-prorocentrimine 和gynodimine。独特的螺胺片段已被确定对其生物活性至关重要。其中一些天然产品与多起全球海鲜中毒事件有关。所提出的合成策略是通用的，可应用于pinnatoxins、spirolides 和gynodimine 的合成。目标结构中最具挑战性的部分是螺胺片段。我们开发了一种能够对 α 支链烯丙酯进行立体选择性爱尔兰-克莱森重排的方法。通常，在这些反应中观察到较差的非对映选择性。采用我们的方法，可以以优异的非对映选择性获得两种非对映异构体。这是我们用于合成螺胺片段的核心方法。我们预计，我们在复杂天然产物化学合成领域的努力将丰富合成方法的库，促进药物化学和药物发现领域的研究。更具体地，对于该应用，本文所描述的海洋毒素与海鲜中毒的公共卫生问题直接相关。值得注意的是，开发用于检测藻类毒素的精确方法的一个主要问题是缺乏纯净的标准。因此，我们的合成目标将作为开发海洋毒素检测探针的纯标准。公众健康相关性 有机合成的发展为药物发现和药物研究提供了方法，长期以来一直造福于人类健康。复杂天然产物的全合成是有机化学的一个主要分支，它定义了当前的最先进水平，刺激创新和发现，并确定需要解决的新挑战。本申请提出的研究将通过复杂天然产物的全合成丰富合成方法。此外，我们将开发灵敏的免疫测定法来检测环境中的海洋毒素。这将通过预防某些类型的海鲜中毒而有益于人类健康，这已成为一种全球现象。