Synthetic/Mechanistic Studies of Bioactive Marine Agents

产品描述（申请人提供）：本次更新计划的目的是对海洋天然产物axinellamine A、帕劳'amine、gymnodimine、phakellstatin、pateamine A和thiolyngbyan进行合成和生物机制研究，这些天然产物具有新颖的结构和强大的生物学效应。具有有效和特异性细胞效应的天然产物仍然是用于解剖参与各种细胞功能的信号转导途径的分子机制的有用的生化探针。Pateamine A和帕劳'amine是有效的免疫抑制剂，有望成为发现参与细胞信号传导的细胞事件的有用生化探针，与Jun Liu（John霍普金斯）的持续合作将继续提供这一领域的见解。这些天然产物可能会为器官移植治疗带来新的治疗靶点，但也可能为癌症、糖尿病、多发性硬化症和类风湿性关节炎带来新的治疗靶点。裸甲亚胺是一种具有独特螺环亚胺结构的海洋毒素，其毒性机制尚不清楚。海洋毒素已被证明在离子通道、蛋白磷酸酶和神经递质受体的研究中是有用的。此外，需要在我们的海洋监测有害藻华驱动我们的兴趣，在开发gymnodimine同源独立的免疫测定，这将是在得克萨斯州A&M包括丽莎坎贝尔（TAMU-海洋学）的跨学科团队合作进行。已经提出法克林是在其来源的海绵提取物中观察到的强大抗生素作用的原因，而密切相关的法克林他汀是一种结构新颖的抗肿瘤剂。在与Justin Du Bois实验室（斯坦福大学）的合作努力中，我们寻求开发用于合成这些和相关的oroidin生物碱的C-H插入策略。在与Coran Watanabe（TAMU-Chemistry）的合作中，我们将筛选抗肿瘤和其他活性，如果活性需要，则阐明phakellstatins和axinellamines的作用机制。在符合后者的兴趣，我们将探讨潜在的热敏聚合物作为可溶性支持天然产物。Thiolyngbyan是一种新型抗真菌药物，具有独特的五元环状二硫键结构。与比尔·格威克实验室（俄勒冈州）的合作努力试图确认结构并确定其绝对立体化学。在我们的总合成努力中，一个自然结合的目标是开发新的合成策略，以简明地合成这些目标。在这方面，几个独特的战略概述了天然产物的目标提出的合成。

DESCRIPTION (provided by applicant): The objectives of this renewal proposal include synthetic and biomechanistic studies of the marine natural products axinellamine A, palau'amine, gymnodimine, phakellstatin, pateamine A and thiolyngbyan, which possess novel structure and exhibit potent biological effects. Natural products with potent and specific cellular effects continue to be useful biochemical probes for dissecting molecular mechanisms of signal tansduction pathways involved in various cellular functions. Pateamine A and palau'amine are potent immunosuppressive agents that promise to be useful biochemical probes for discovery of cellular events involved in cell signaling and continued collaborations with Jun Liu (John Hopkins) will continue to provide insights in this area. These natural products may potentially lead to new therapeutic targets for organ transplantation therapy, but also cancer, diabetes, multiple sclerosis, and rheumatoid arthritis. Gymnodimine is a potent marine toxin that possesses an unusual spirocyclic imine moiety and its molecular mechanism of toxicity has not been elucidated although it appears to be unique. Marine toxins have proven useful in the study of ion channels, protein phosphatases, and neurotransmitter receptors. Furthermore, the need to monitor harmful algal blooms in our oceans drives our interest in developing congener independent immunoassays for gymnodimine and this will be pursued in collaboration with an interdisciplinary team at Texas A&M including Lisa Campbell (TAMU-Oceanography). Phakellin has been proposed to be responsible for the powerful antibiotic effects observed in extracts from its sponge of origin while the closely related phakellstatin is a structurally novel antitumor agent. In collaborative efforts with Justin Du Bois' laboratory (Stanford), we seek to develop a C-H insertion strategy for the synthesis of these and related oroidin alkaloids. In collaborative efforts with Coran Watanabe (TAMU-Chemistry) we will screen for antitumor and other activities and, if warranted by activity, elucidate the mechanism of action of the phakellstatins and the axinellamines. In line with this latter interest, we will explore the potential of thermoresponsive polymers as soluble support for natural products. Thiolyngbyan is a novel antifungal agent with a proposed unique 5-membered cyclic disulfide moiety. Collaborative efforts with Bill Gerwick's laboratory (Oregon State) seek to confirm the structure and determine its absolute stereochemistry. A naturally conjoined objective in our total synthesis efforts is the development of new synthetic strategies for the concise synthesis of these targets. In this regard, several unique strategies are outlined for the synthesis of the natural product targets proposed.