Synthetic/Mechanistic Studies of Bioactive Marine Agents

描述（由申请人提供）：本更新提案的目标包括海洋天然产物axinellamine A， palau'amine, gymnodimine, phakellstatin， pateamine A和thiolybyan的合成和生物力学研究，这些天然产物具有新颖的结构和强大的生物效应。具有强大和特异性细胞效应的天然产物仍然是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。帕特胺A和帕劳胺是有效的免疫抑制剂，有望成为有用的生化探针，用于发现参与细胞信号传导的细胞事件，与刘军（约翰霍普金斯大学）的持续合作将继续在这一领域提供见解。这些天然产物可能会成为器官移植治疗的新靶点，也可能用于癌症、糖尿病、多发性硬化症和类风湿性关节炎。裸子二胺是一种具有不同寻常的螺环亚胺部分的强效海洋毒素，其毒性的分子机制尚未阐明，尽管它似乎是独特的。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被证明是有用的。此外，监测海洋中有害藻华的需要促使我们对开发裸子二胺的同源独立免疫测定方法感兴趣，这将与德克萨斯州农工大学的一个跨学科团队合作，其中包括丽莎坎贝尔（tamu -海洋学）。Phakellin被认为是在其来源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phakellstatin是一种结构新颖的抗肿瘤药物。在与Justin Du Bois实验室（斯坦福大学）的合作努力下，我们寻求开发一种碳氢键插入策略，用于合成这些和相关的鹿角苷类生物碱。在与TAMU-Chemistry的Coran Watanabe合作的努力中，我们将筛选抗肿瘤和其他活性，如果活性得到保证，阐明phakell他汀类药物和axinellamine的作用机制。根据后一种兴趣，我们将探索热响应聚合物作为天然产物可溶性载体的潜力。硫柳氰是一种新型抗真菌剂，具有独特的5元环二硫段。与Bill Gerwick的实验室（俄勒冈州）合作，试图确认其结构并确定其绝对立体化学性质。我们全面合成努力的一个自然结合的目标是为简明地合成这些目标制定新的合成战略。在这方面，概述了几种独特的策略来合成所提出的天然产物目标。

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.