STRUCTURAL/SYNTHETIC STUDIES OF BIOACTIVE MARINE AGENTS

海洋生物活性剂的结构/综合研究

• 批准号: 2750034
• 负责人: DANIEL ROMO
• 金额: $ 10.27万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750034
• 关键词: Porifera; Tunicata; X ray crystallography; animal extract; antimitotics; antineoplastics; cell differentiation; chemical structure function; cyclization; drug design /synthesis /production; immunomodulators; lactams; molecular rearrangement; nuclear magnetic resonance spectroscopy; saltwater environment; stereochemistry; tubulin; Porifera; Tunicata; X ray crystallography; animal extract; antimitotics; antineoplastics; cell differentiation; chemical structure function; cyclization; drug design /synthesis /production; immunomodulators; lactams; molecular rearrangement; nuclear magnetic resonance spectroscopy; saltwater environment; stereochemistry; tubulin

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.

描述：该提案的目标包括结构 新型海洋天然产品的确定和总合成 表现出强大的生物学活性。据说目标包括 双二酰胺A，一个诱导细胞分化的皮肤分离物， Pateamine A，海绵分离物，表现出免疫调节 特性和素蛋白A，一种海洋细菌抗菌丝剂，该剂 抑制小管蛋白聚合。 据报道，Bistramide A承诺将成为一个有用的新工具 研究涉及细胞分化的机制，容量损失 通过某些癌细胞，以及制备的方法 Bistramide的晶体衍生物适合X射线分析是 提议作为确定其相对和绝对的手段 立体化学。主要调查员指出，一种收敛， 为对映选择性，总计提出了立体式途径 Bistramide A的合成以及合成的关键特征包括 爱尔兰 - 克莱森重排和二碘化物介导的samarium diiodide， 顺序酰基取代/氧化还原过程。表明 结构衍生物的合成和双胺A亲和矩阵的合成 将允许对这些行动方式进行初步调查 代理商。 主要研究人员指出，作为迈向的第一步 了解pateamine如何施加其免疫调节作用，一个 与M. Munro教授合作的最初目标（大学 坎特伯雷。新西兰）是其相对和 通过使用半合成的组合，绝对立体化学 天然产物降解，分子建模和NMR光谱和 该结构验证应通过执行 pateamine的收敛性，对映选择性合成。表明 合成的收敛性将允许访问重要 数量的Pateamine A和结构衍生物以进一步 评估G. Faircloth博士作为潜在的免疫抑制剂 （美国Pharmamar）和对其作用机理进行调查。 注意到，四个的收敛性，对映选择性合成 素蛋白A的非映异构体将使光谱镜比较与 正宗样品，用于立体化学测定该抗魔法 代理人。主要研究者指出， 合成方法包括一种新颖的Stille型耦合 环丙烷stannane到半胱氨酸衍生的噻唑啉三烯酸酯至 准备结构独特的环丙基 - 噻唑氨酸属素的部分 A分子该区域中的A和结构变体。这些 衍生物应评估其抑制微管蛋白的能力 E. Hamel博士（NIH国家癌症研究所）聚合。这是 建议这些调查可能导致一类新颖 通过秋水仙碱发挥作用的抗塑料剂 小管蛋白的结合位点与其他已知的微管蛋白抑制剂相反 聚合将其作用在长文碱结合位点上发挥作用。