SYNTHESES OF BIOLOGICALLY ACTIVE MARINE ALKALOIDS

具有生物活性的海洋生物碱的合成

• 批准号: 2392198
• 负责人: DAVID A. HORNE
• 金额: $ 21.1万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2392198
• 关键词: alkaloids; biological products; chemical synthesis; heterocyclic compounds; imidazole; saltwater environment

DESCRIPTION: The plan of this revised application is to develop new synthetic methodologies and strategies for the construction of 2- aminoimidazole- and guanidine-based marine natural products possessing important biological activities. It is indicated that notable representatives include the tricyclic marine pigments zoanthoxanthins (1) and (2), the C11N5 family of oroidin alkaloids (3-7), dimeric oroidin alkaloids (8-10) and the red-tide toxins, saxitoxin (11) and gonyautoxins (12). It is reported that collectively, these and other structurally related compounds possess potent pharmacological properties that include antiviral, antileukemic, antineoplastic, antiserotonergic as well as alpha-adrenoceptor and ion-channel blocking activities and that in addition, a rare example of ATPase stimulating activities of myosin and actomyosin has recently been observed. The principal investigator notes that although each class of metabolites is structurally unique, they represent, however, a collection of structures whose diversity is related by the rich chemistry that they share in common. The proposed research is to focus on developing methodologies and strategies that involve oxidative and non-oxidative transformations of 2-aminoimidazoles that will have general applicability to synthesis of the above heterocycles. It is noted that in particular, the utility of these methods is delineated in the proposed synthesis of the bicyclic oroidin alkaloid hymenialdisines (6), the dimeric oroidin alkaloids, ageliferin (8) (R=H) and sceptrin (9), and the potent neurotoxins saxitoxin (11) and gonyautoxin (12). The principal investigator indicates that the proposed methods and routes are essentially devoid of protecting groups and are based on biogenetic considerations. He suggests that an integral feature of the research plan is a criterion for substantiating possible biosynthetic pathways. It is indicated that the synthetic plan calls for the development of methods for transforming 2- aminoimidazole into key intermediates for the synthesis of the naturally occurring compounds and that the preparation of these intermediates and the facility of the ensuing molecular rearrangements would tend to support or disclaim the biogenetic hypothesis. It is suggested that versatile and efficient syntheses of these metabolites would provide access to structurally modified or specifically labeled substrates for biomedical research.

描述：此修订后的应用程序的计划是开发新的 的综合方法和战略， 基于氨基咪唑和胍的海洋天然产物， 重要的生物活动。 值得注意的是， 代表物包括三环海洋色素zoanthoxanthins（1） 和（2），C_（11）N_5家族的oroidin生物碱（3-7）， 生物碱（8-10）和赤潮毒素石房蛤毒素（11）， gonyautoxins（12）. 据报道，这些和其他 结构上相关的化合物具有有效的药理学性质 包括抗病毒，抗白血病，抗肿瘤，抗肿瘤 以及α-肾上腺素受体和离子通道阻断活性， 此外，一个罕见的ATP酶刺激活性的例子， 最近观察到肌球蛋白和肌动球蛋白。 校长 研究人员指出，虽然每类代谢物都是 结构独特，但它们代表了一个结构的集合， 它们的多样性是由它们所共有的丰富的化学物质联系在一起的， 共同拟议的研究将侧重于制定方法， 涉及氧化和非氧化转化的策略， 2-氨基咪唑类化合物的合成具有普遍的适用性， 上述杂环。 值得注意的是，特别是， 这些方法描述于所提出的双环 （6），二聚的鸢尾素生物碱， ageliferin（8）（R=H）和scettrin（9），以及强效神经毒素 石房蛤毒素（11）和gonyautoxin（12）。 主要研究者 表明所提出的方法和路线基本上缺乏 保护基团，并基于生物遗传学的考虑。 他 表明，研究计划的一个组成部分是一个标准， 证实可能的生物合成途径。 表明该 综合计划要求开发转化2- 氨基咪唑合成天然药物的关键中间体 存在的化合物，并且这些中间体和 随后的分子重排的便利性将倾向于 支持或否认生物起源假说。 建议在 这些代谢物的通用和有效的合成将提供 获得结构修饰的或专门标记的底物， 生物医学研究