SYNTHETIC/MECHANISTIC STUDIES OF BIOACTIVE MARINE AGENTS

描述：(主要调查人员摘要)提案的目标 包括海洋天然材料的全合成和生物力学研究 产品帕特明A、帕劳胺、裸子胺和扁桃体蛋白 结构新颖，并显示出强大的生理效应。天然产物 具有强烈的和特定的细胞效应已被证明是强大的 剖析信号转导分子机制的生化探针 参与各种细胞功能的通路。帕特胺A和帕劳胺 是一种有效的免疫抑制剂，有望成为有用的生化药物 用于阐明与免疫反应有关的细胞事件的探针。因此， 这些天然产品可能会为NOT带来新的治疗靶点 不仅是器官移植治疗，还有糖尿病、多发性硬化症和 类风湿关节炎。绞股蓝是一种有效的海洋毒素，具有 不寻常的螺环亚胺部分。其确切的毒性分子机制 尚未被阐明，尽管它似乎是独一无二的。海洋毒素有 已证明对研究离子通道、蛋白磷酸酶和 神经递质受体。因此，绞股蓝有望成为一种有用的 用于研究神经元功能的生化探针。Phakellin已经被提议 对其提取物中观察到的强大的抗生素作用负责 海洋海绵Phakellia flabellata。考虑到抗生素的增加 近年来，对新型抗生素的研究愈演愈烈。 四烷基胍结构在褐藻糖蛋白及其同系物中的应用 新的抗生素将被检测出来。 在我们的全部合成工作中，一个自然相连的目标是 为简明合成开发新的合成方法和策略 这些目标中。在这方面，一些新的方法和战略包括 卤代乙烯的甲酰化反应，未活化的Hantzsch并噻唑合成 α-亚甲基内酰胺与乙烯基类化合物的溴酮、Diel-Alder反应 咪唑烷酮，环亚胺合成的单盆内酰胺，以及 分子内氯化/1，2变换序列，以及潜在吡咯的使用 将会被研究。这项研究产生的合成产品将 使我们和我们的合作者刘军教授(麻省理工学院)和克里斯·迈尔斯博士 (农业研究)解决具有生物学意义并因此具有健康意义的问题。

DESCRIPTION: (Principal Investigator's Abstract) The objectives of the proposal include total synthesis and biomechanistic studies of the marine natural products pateamine A, palau'amine, gymnodimine, and phakellin which possess novel structures and exhibit potent physiological effects. Natural products that have strong and specific cellular effects have proven to be powerful biochemical probes for dissecting molecular mechanisms of signal transduction pathways involved in various cellular functions. Pateamine A and palau'amine are potent immunosuppressive agents that promise to be useful biochemical probes for elucidating cellular events involved in the immune response. Thus, these natural products may potentially lead to new therapeutic targets for not only organ transplantation therapy, but also diabetes, multiple sclerosis, and rheumatoid arthritis. Gymnodimine is a potent marine toxin that possesses an unusual spirocyclic imine moiety. Its precise molecular mechanism of toxicity has not been elucidated although it appears to be unique. Marine toxins have proven useful for the study of ion channels, protein phosphatases, and neurotransmitter receptors. Thus, gymnodimine promises to be a useful biochemical probe for studies of neuronal function. Phakellin has been proposed to be responsible for the powerful antibiotic effects observed in extracts from the marine sponge Phakellia flabellata. Considering the rise in antibiotic resistance in recent years, the search for novel antibiotics has intensified. The utility of the tetracylic guanidine structure in phakellin and congeners as new antibiotics will be assayed. A naturally conjoined objective in our total synthesis efforts is the development of new synthetic methods and strategies for the concise synthesis of these targets. In this regard, several new methods and strategies including formylation of vinyl halides, Hantzsch thiazole synthesis with unactivated bromoketones, Diel-Alder reactions of alpha-exomethylene lactams and vinyl imidazolidinones, a single pot lactam to cyclic imine synthesis, an intramolecular chlorination/1,2 shift sequence, and the use of latent pyrroles will be studied. The synthetic products resulting from this research will enable us and our collaborators Prof. Jun Liu (MIT) and Dr. Chris Miles (AgResearch) to address questions of biological and thus health significance.