SYNTHESIS OF ANTICANCER AGENTS

抗癌剂的合成

• 批准号: 7568872
• 负责人: K. C. NICOLAOU
• 金额: $ 50.84万
• 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/7568872
• 关键词: 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; Process; Production; Research; Screening procedure; Technology; Work; analog; antitumor agent; cytoskyrin A; drug discovery; flexibility; 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.

该拨款申请描述了多种有效抗肿瘤药物的全合成 天然来源，即 lomaiviticins A 和 B、cytoskyrin A、amphidinolide N 和 caribenolide I，以及 用于生物筛选的相关分子的数量。拟定的 Lomaiviticins 的全合成将 涉及先进的α-卤代烯酮中间体的二聚化以生成C2对称多环 框架。然后，将有助于进一步阐述空间拥挤的中央核心 暂时并入桥接环状系链。已经设计了两种替代的此类系绳，即 四氢噻吩和带有侧酯基团的碳环，增加了整体的灵活性 战略。一旦安装了所需的结构基序，这些桥中的任何一个都可以被氧化 裂解以揭示完成目标分子所需的功能。对于细胞分裂蛋白 A， 仿生级联过程提供目标分子的笼状框架 实验证明。涉及蒽醌衍生物的酸催化二聚化 随后是双烯醇化/双分子内迈克尔加成序列，仔细监测该序列 级联不仅允许选择性生成 cytoskyrin A 的中央核心，还允许选择性生成 许多其他结构相关的生物活性天然产物。这个级联过程将是 不仅适合这些天然产品本身的生产，还适合特定产品的生产 靶向类似物，将对其进行抗肿瘤活性筛选。氨吡啶内酯的拟议合成 N 和 caribenolide I 具有统一的、高度收敛的策略，涉及顺序不对称 手性 1,3-二羟基丙酮等价物的烷基化以建立完整的碳框架 目标分子，然后进行高度选择性的大环内酯化以生成 26 元环 每个案例。拟议工作的意义特别在于癌症化疗领域 研究，以及开发药物通用的新合成策略和技术 发现和开发过程。