Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

• 批准号: 8259264
• 负责人: Armen Zakarian
• 金额: $ 0.94万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259264
• 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)：我们研究项目的主要目标是开发新的合成方法，使用复杂的天然产品来识别新的挑战。我们在全合成和由此获得的天然产品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进一步发挥作用，通过改进药物和生物活性物质的制备来造福公众健康。本申请中追求的具体目标是含有螺亚胺环的海洋毒素。这是一个不断扩大的复杂海洋天然产品组，目前包括品纳毒素、翼状毒素、螺内酯、螺丙三胺和裸子藻二胺。独特的螺氨酸亚胺片段已被确定为对其生物活性至关重要。其中一些天然产品与几起全球海鲜中毒事件有关。所提出的合成策略具有一定的通用性，可用于合成品那毒素、螺内酯和裸甲二胺。靶结构中最具挑战性的部分是螺氨酰亚胺片段。我们开发了一种方法，使α-支链烯丙酸酯的立体选择性爱尔兰-克莱森重排成为可能。通常，在这些反应中观察到较差的非对映选择性。使用我们的方法，这两个非对映异构体都可以以极好的非对映选择性进行访问。这是我们在合成螺氨酸亚胺片段时使用的中心方法。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总体武器库，促进药物化学和药物发现领域的研究。更具体地说，这里描述的海洋毒素与海鲜中毒的公共卫生问题直接相关。人们注意到，发展精确的藻毒素检测方法的一个主要问题是缺乏纯粹的标准。因此，我们合成的目标将作为开发海洋毒素检测探针的纯标准。公共卫生相关性有机合成的发展长期以来为药物发现和药物研究提供了方法，从而使人类健康受益。复杂天然产物的全合成是有机化学的一个主要分支，它定义了当前的最新技术，刺激了创新和发现，并确定了需要解决的新挑战。本申请中提出的研究将通过复杂天然产物的全合成来丰富合成方法学。此外，我们会发展灵敏的免疫分析方法，以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造福人类健康，这已成为一种全球现象。