Synthetic/Mechanistic Studies of Bioactive Marine Agents

描述(申请人提供)：这项更新建议的目标包括合成和生物力学研究海洋天然产物紫杉胺A、帕劳胺、裸子二胺、phakellstatin、帕特明A和硫代龙边胺，它们具有新的结构和显示出强大的生物效应。天然产物具有强大的和特定的细胞作用，仍然是有用的生化探针，用于剖析参与各种细胞功能的信号转导途径的分子机制。帕特胺A和帕劳胺是有效的免疫抑制剂，有望成为发现细胞信号中涉及的细胞事件的有用生化探针，与刘军(约翰·霍普金斯饰)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，但也会导致癌症、糖尿病、多发性硬化症和类风湿性关节炎。绞股蓝是一种强效海洋毒素，具有独特的螺环亚胺结构，其毒性的分子机制尚不清楚。海洋毒素在离子通道、蛋白磷酸酶和神经递质受体的研究中已被证明是有用的。此外，监测海洋有害藻华的需要促使我们对开发类似的独立免疫分析方法产生兴趣，这将与包括Lisa Campbell(TAMU-海洋学)在内的德克萨斯A&M的一个跨学科团队合作进行。Phakellin被认为是从其来源的海绵提取物中观察到强大的抗生素作用的原因，而与其密切相关的phakellstatin是一种结构新颖的抗肿瘤药物。在与Justin Du Bois的实验室(斯坦福)的合作中，我们寻求开发一种C-H插入策略来合成这些和相关的oroidin生物碱。在与Coran Watanabe(TAMU化学)的合作中，我们将筛选抗肿瘤和其他活性，如果活性得到保证，还将阐明phakellstatins和axinellamines的作用机制。根据后者的兴趣，我们将探索热响应性聚合物作为天然产品的可溶性载体的潜力。Thiolyngbyan是一种新型抗真菌药物，具有独特的5元环二硫结构。与比尔·格里克的实验室(俄勒冈州立大学)的合作努力试图确认该结构并确定其绝对立体化学。在我们的全部合成努力中，一个自然相连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，提出了几种独特的合成天然产物目标的策略。

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.