SYNTHESES OF BIOLOGICALLY ACTIVE MARINE ALKALOIDS

这项调查的计划具有双重性质。总目标 是开发简明高效的合成和合成 技术上具有挑战性的生物碱，具有重要的生物 活动。目前的重点是开发新的合成材料 2-氨基咪唑类化合物的合成方法和策略 和相关的金刚烷基海洋天然产物具有独特的 药典实体。这一生物碱族的著名代表 包括三环海洋颜料黄黄嘌呤和偶氮酰胺， C11N5家族的Oroidin生物碱，二聚Oroidin生物碱，以及 赤潮毒素包括麻黄毒素和刚尾藻毒素。总的来说，这些和 其他结构上相关的化合物具有无数的强效 药理作用包括抗病毒，抗生素， 抗白血病，抗肿瘤，抗5-羟色胺，免疫抑制， 细胞毒性、α-肾上腺素能受体和离子通道阻断 活动。此外，一个罕见的ATPase刺激例子 观察到肌球蛋白和肌动球蛋白的活性。尽管每个人 一类代谢物在结构上是独特的，然而，它们代表着， 其多样性与富人相关的结构的集合 它们共有的化学反应。 拟议的研究侧重于制定方法和战略。 这将对上述化合物的合成具有普遍适用性 代谢物及相关类似物。特别是，这些工具的效用 方法描述在建议的合成中的花环 生物碱，二溴琼脂糖苷和琼脂糖苷，二聚体冬凌草苷 强效神经毒素--老年生物碱、麦角碱和帕劳胺 黑曲霉毒素和弓形虫毒素。建议的方法和路线是 本质上缺乏保护团体，并且基于松散的 生物遗传学方面的考虑。 研究计划的一个整体特征是 证实可能的生物合成途径。综合计划呼唤 开发将2-氨基咪唑转化为 合成天然产物的关键中间体 化合物。这些中间体的制备和制备 随后的分子重排将倾向于支持或否认 生物发生假说。这些化合物的多用途和高效合成 代谢物将提供获得结构修饰或 用于生物医学研究的特别标记的底物。

The plan of this investigation is twofold in nature. The overall goal is to develop concise and efficient syntheses of synthetically and technically challenging alkaloids possessing important biological activities. The current focus is on the development of new synthetic methodologies and strategies for the construction of 2-aminoimidazole- and related guanidine-based marine natural products having unique pharmacophoric entities. Notable representatives of this alkaloid group include the tricyclic marine pigments zoanthoxanthins and zoamides, the C11N5 family of oroidin alkaloids, the dimeric oroidin alkaloids, and the red-tide toxins saxitoxin and gonyautoxins. Collectively, these and other structurally related compounds possess a myriad of potent pharmacological effects that include antiviral, antibiotic, antileukemic, antineoplastic, antiserotonergic, immunosuppressive, cytotoxic as well as alpha-adrenoceptor and ion-channel blocking activities. In addition, a rare example of ATPase stimulating activities of myosin and actomyosin has been observed. 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 focuses on developing methodologies and strategies that will have general applicability to synthesis of the above metabolites and related analogs. In particular, the utility of these methods is delineated in the proposed syntheses of the oroidin alkaloids, dibromoagelaspongin and agelastatin, the dimeric oroidin alkaloids ageliferin, sceptrin, and palau amine, the potent neurotoxins saxitoxin and gonyautoxins. The proposed methods and routes are essentially devoid of protecting groups and are based loosely on biogenetic considerations. An integral feature of the research plan is a criterion for substantiating possible biosynthetic pathways. The synthetic plan calls for the development of methods for transforming 2-aminoimidazoles into key intermediates for the synthesis of the naturally occurring compounds. The preparation of these intermediates and the facility of the ensuing molecular rearrangements would tend to support or disclaim the biogenetic hypothesis. Versatile and efficient syntheses of these metabolites would provide access to structurally modified or specifically labeled substrates for biomedical research.