SYNTHESIS OF ANTICANCER AGENTS

抗癌剂的合成

• 批准号: 7357462
• 负责人: K. C. NICOLAOU
• 金额: $ 49.47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7357462
• 关键词: 9,10-anthraquinone; Acids; Alkylation; Anthraquinones; Antineoplastic Agents; Applications Grants; Area; Biological; Biological Factors; Biomimetics; Carbon; Chemotherapy-Oncologic Procedure; Cleaved cell; Crowding; Development; Dihydroxyacetone; Dimerization; Esters; Evaluation; Generations; Monitor; Numbers; Pliability; Process; Production; Research; Screening procedure; Technology; Work; analog; antitumor agent; cytoskyrin A; drug discovery; tetrahydrothiophene

This grant application describes the proposed total syntheses of a number of potent antitumor agents of natural origin, namely lomaiviticins A and B, cytoskyrin A, amphidinolide N and caribenolide I, as well as a number of related molecules for biological screening. The proposed total synthesis of the lomaiviticins would involve the dimerization of an advanced a-halo enone intermediate to generate the C2-symmetric polycyclic framework. Further elaboration of the sterically crowded central core would then be facilitated by the temporary incorporation of a bridging cyclic tether. Two alternative such tethers have been devised, namely a tetrahydrothiophene and a carbocycle bearing a pendant ester group, increasing the flexibility of the overall strategy. Once the required structural motifs are installed, either of these bridges could be oxidatively cleaved to reveal the necessary functionalities for completion of the target molecules. For cytoskyrin A, a biomimetic cascade process to furnish the cage-like framework of the target molecule has been experimentally demonstrated. Involving the acid-catalyzed dimerization of an anthraquinone derivative followed by a bis-enolization/ double intramolecular Michael addition sequence, careful monitoring of this cascade allows for the selective generation of the central core of not only cytoskyrin A, but also that of a number of other structurally related biologically active natural products. This cascade process would be amenable to the production of not only these natural products themselves, but also to that of specifically targeted analogs, which would be screened for antitumor activity. The proposed syntheses of amphidinolide N and caribenolide I feature a unified, highly convergent strategy involving the sequential asymmetric alkylation of a chiral 1,3-dihydroxyacetone equivalent to establish the complete carbon framework of the target molecules, followed by a highly selective macrolactonization to generate the 26-membered ring in each case. The significance of the proposed work will lie specifically in the area of cancer chemotherapy research, and in the development of new synthetic strategies and technologies for general use in the drug discovery and development process.

这项拨款申请描述了一些有效的抗肿瘤药物的拟议全合成。 天然来源，即罗麦维菌素A和B、胞苷A、两性内酯N和卡里本内酯I，以及a 用于生物筛选的相关分子的数量。提议的洛麦维菌素的全合成将 涉及先进的a-卤代烯酮中间体的二聚化，以生成C2对称的多环 框架。然后，对空间密集的中央核心的进一步阐述将由 临时加入桥接循环系绳。已经设计了两种替代的这种系绳，即 四氢噻吩环和含侧链酯基的碳环，增加了整体的柔韧性 策略。一旦安装了所需的结构基序，这些桥中的任何一个都可能被氧化 裂解以揭示完成目标分子所需的功能。对于细胞分裂素A，a 提供目标分子笼状骨架的仿生级联过程已经被 实验证明。涉及酸催化的一种蒽醌衍生物的二聚反应 然后是双烯醇化/双分子内Michael加成序列，仔细监测 CASCADE不仅允许选择性地产生细胞分裂蛋白A的中心核心，而且还允许选择性地产生 其他结构相关的生物活性天然产物的数量。这一级联过程将是 不仅可以生产这些天然产品本身，而且还可以生产特定的 靶向类似物，将对其进行抗肿瘤活性筛选。两面针内酯的合成研究进展 N和Caribenolide I具有统一的、高度收敛的策略，涉及序列不对称 手性1，3-二羟基丙酮的烷基化反应建立完整的碳骨架 目标分子，随后进行高度选择性的大内酯化以生成26元环 每一箱都是。拟议工作的意义将具体体现在癌症化疗领域。 研究和开发新的合成策略和技术，用于药物的普遍使用 发现和发展的过程。