STRUCTURAL/SYNTHETIC STUDIES OF BIOACTIVE MARINE AGENTS

描述：本提案的目标包括结构 新型海洋天然产物的测定和全合成 显示出强大的生物活性。据说目标包括 双乙酰胺A，一种诱导细胞分化的衣状分离物， 一种具有免疫调节作用的海绵分离物--帕特胺A 性质，以及海洋细菌抗有丝分裂药库拉星A 抑制微管蛋白聚合。 据报道，双乙酰胺A有望成为治疗癌症的一种有用的新工具 细胞分化机制的研究--一种能力丧失 一些癌细胞及其制备方法 适用于X-射线分析的双螺杆胺A的晶型衍生物为 提出作为确定其相对和绝对的一种手段 立体化学。首席调查员指出，一个汇聚者， 提出了立体柔性路线，用于对映体选择性，总 双草胺A合成，其主要特征包括 爱尔兰-克莱森重排和二碘化钐的介导， 顺序酰基取代/氧化还原过程。有消息称， 双菌胺A亲和基质及结构衍生物的合成 将允许对这些组织的行动模式进行初步调查 探员们。 首席调查员表示，作为迈向 了解帕他明A如何发挥其免疫调节作用，以及 与M.Munro教授(大学)合作的初步目标 坎特伯雷。新西兰)是对其亲属和 绝对立体化学通过使用半合成， 天然产物降解，分子模拟，核磁共振波谱和 该结构验证将通过执行 聚合型、对映体选择性合成帕特明。有迹象表明， 综合的收敛性质将允许访问重要的 帕特胺A和结构衍生物的数量 G·费尔布德博士对潜在免疫抑制剂的评价 (美国PharmaMar)，并对其行动机制进行调查。 值得注意的是，一种收敛的，对映体选择性合成的四个 柯拉星A的非对映异构体将使光谱与 这种抗有丝分裂物质的立体化学测定的正品 探员。首席调查员表示， 综合方法包括一种新的Stille型耦合 环丙基锡烷到半胱氨酸衍生物-三氟化噻唑啉到 克拉酸结构独特的环丙基噻唑啉部分的制备 A和分子这一区域的结构变体。这些 对衍生物抑制微管蛋白的能力进行评估 由E.Hamel博士(国家癌症研究所-NIH)进行聚合。它是 暗示这些调查可能会导致一类新的 通过秋水仙碱发挥作用的抗肿瘤药物 与其他已知的微管蛋白抑制剂相比，微管蛋白的结合部位 在长春花碱结合部位发挥作用的聚合反应。

DESCRIPTION: The objectives of this proposal include the structure determination and total synthesis of novel marine natural products displaying potent biological activity. Targets are said to include bistramide A, a tunicate isolate inducing cellular differentiation, pateamine A, a marine sponge isolate exhibiting immunomodulating properties, and curacin A, a marine bacterial antimitotic agent which inhibits tubulin polymerization. It is reported that bistramide A promises to be a useful new tool for the study of mechanisms involved in cellular differentiation, a capacity lost by some cancerous cells and that methods for the preparation of crystalline derivatives of bistramide A suitable for x-ray analysis are proposed as a means to determine its relative and absolute stereochemistry. The principal investigator notes that a convergent, stereoflexible route is proposed for the enantioselective, total synthesis of bistramide A and that key features of the synthesis include an Ireland-Claisen rearrangement and a samarium diiodide mediated, sequential acyl substitution/redox process. It is indicated that the synthesis of structural derivatives and a bistramide A affinity matrix will allow preliminary investigations into the mode of action of these agents. The principal investigator states that as a first step towards understanding how pateamine A exerts its immunomodulating effects, an initial objective in collaboration with Professor M. Munro (University of Canterbury. New Zealand) is determination of its relative and absolute stereochemistry by using a combination of semi-synthesis, natural product degradation, molecular modeling, and NMR spectroscopy and that structural verification is to be accomplished by executing a convergent, enantioselective synthesis of pateamine. It is indicated that the convergent nature of the synthesis will allow access to significant quantities of pateamine A and structural derivatives for further evaluation as potential immunosuppressive agents by Dr. G. Faircloth (PharmaMar, USA) and for investigations into their mechanism of action. It is noted that a convergent, enantioselective synthesis of four diastereomers of curacin A will enable spectroscopic comparison to an authentic sample for stereochemical determination of this antimitotic agent. The principal investigator states that a key step in the synthetic approach includes a novel Stille-type coupling of a cyclopropyl stannane to a cysteine derived- thiazoline triflate to prepare the structurally unique cyclopropyl-thiazoline portion of curacin A and structural variants in this region of the molecule. These derivatives are to be evaluated for their ability to inhibit tubulin polymerization by Dr. E. Hamel (National Cancer Institute-NIH). It is suggested that these investigations may lead to a novel class of antineoplastic agents that exert their effects via the colchicine binding site of tubulin in contrast to other known inhibitors of tubulin polymerization which exert their effects at the vinblastine binding site.