SYNTHESIS OF ANTICANCER AGENTS

抗癌剂的合成

• 批准号: 7090326
• 负责人: K. C. NICOLAOU
• 金额: $ 48.28万
• 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/7090326
• 关键词: antineoplastics; biomimetics; biotherapeutic agent; chemical addition; chemical models; chemical reaction; chemical structure; chemical synthesis; chromatography; diazo compound; drug design /synthesis /production; intermolecular interaction; model design /development; oxidation; quinones; small molecule

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本拨款申请描述了多种天然来源的强效抗肿瘤药物的全合成，即洛马维霉素 A 和 B、胞嘧啶 A、amphidinolide N 和 caribenolide I，以及多种相关分子生物筛选。所提出的 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，通过暂时并入桥接环状系绳，可以促进空间拥挤的中央核心的进一步精细化。已经设计了两种替代的此类系链，即四氢噻吩和带有侧酯基团的碳环，增加了总体策略的灵活性。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 cytoskyrin A，已通过实验证明了提供目标分子笼状框架的仿生级联过程。涉及蒽醌衍生物的酸催化二聚化，然后是双烯醇化/双分子内迈克尔加成序列，仔细监测该级联不仅可以选择性地生成 cytoskyrin A 的中央核心，还可以选择性地生成许多细胞的中央核心。其他结构相关的生物活性天然产物。这种级联过程不仅适用于这些天然产物本身的生产，而且适用于特定目标类似物的生产，这些类似物将被筛选抗肿瘤活性。所提出的amphidinolide N和caribenolide I的合成具有统一、高度收敛的策略，涉及手性1,3-二羟基丙酮等价物的连续不对称烷基化，以建立目标分子的完整碳框架，然后进行高度选择性的大内酯化以生成每种情况都是 26 元环。拟议工作的意义将具体体现在癌症化疗研究领域，以及开发新的合成策略和技术以供药物发现和开发过程中通用。