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 显示出强有力的生物活性。据称目标包括 bistramide A，诱导细胞分化的被囊动物分离物， pateamine A，一种表现出免疫调节作用的海绵分离物， 和Curacin A，海洋细菌抗有丝分裂剂， 抑制微管蛋白聚合。 据报道，双酰胺A有望成为一种有用的新工具， 研究细胞分化的机制， 一些癌细胞的作用， 适合于X射线分析的双酰胺A的结晶衍生物是 建议作为一种手段，以确定其相对和绝对 立体化学首席研究员指出， 立体灵活的路线提出了对映选择性，总 合成双甲酰胺A，其主要特征包括 Ireland-Claisen重排和二碘化钐介导， 顺序酰基取代/氧化还原过程。表明该 结构衍生物和双酰胺A亲和基质的合成 将允许对这些行动模式进行初步调查 剂. 首席研究员表示，作为迈向 了解帕特胺A如何发挥其免疫调节作用， 与M教授合作的初步目标。芒罗（大学 在坎特伯雷。新西兰）是确定其相对和 绝对立体化学通过使用半合成的组合， 天然产物降解、分子建模和NMR光谱学， 结构验证将通过执行 收敛的，对映选择性的合成帕丁胺。指出了 综合的收敛性质将允许获得重要的 一定量的帕丁胺A和结构衍生物， 作为潜在免疫抑制剂的评价。费尔布德 （PharmaMar，USA），并用于研究其作用机制。 注意到，四个化合物的会聚的、对映选择性的合成是可能的。 Curacin A的非对映异构体将使光谱比较， 用于该抗有丝分裂剂的立体化学测定的真实样品 剂首席研究员指出， 合成方法包括一种新的Stille型偶联， 环丙基锡烷转化为半胱氨酸衍生的噻唑啉三氟甲磺酸酯， 制备结构独特的Curacin环丙基噻唑啉部分， A和结构变异体在这个区域的分子。这些 评价衍生物抑制微管蛋白的能力 Dr. E。Hamel（国家癌症研究所-NIH）。是 这些研究可能会导致一类新的 通过秋水仙碱发挥作用的抑制剂 与其它已知的微管蛋白抑制剂相比，微管蛋白的结合位点 聚合，其在长春碱结合位点发挥作用。

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.