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）：该赠款申请描述了许多有效的自然起源抗肿瘤剂的总合成，即洛氏素毒素A和B，Cytoskyrin A，Amphidinolide N和Caribenolide I以及许多相关分子用于生物学筛查。提出的洛氏素蛋白的总合成将涉及高级A-HALO ENONE中间体的二聚化，以生成C2-对称的多环形框架。然后，通过暂时融合桥接的循环系绳，将进一步阐述在空间拥挤的中心核心。已经设计了两个替代方案，即四氢噻吩和一个带有吊坠酯基的碳循环，从而提高了整体策略的灵活性。一旦安装了所需的结构基序，这些桥梁中的任何一个都可以被氧化裂解以揭示目标分子完成的必要功能。对于细胞kyr蛋白A，已经在实验中证明了一个仿生级联反应过程，用于提供目标分子的笼子样框架。涉及蒽醌衍生物的酸催化二聚化，然后进行双溶解/双分子内迈克尔添加序列，仔细监测该级联反应，可以选择性地生成细胞肌蛋白A的中心核心，而且还可以选择许多其他结构相关的生物学活性自然产物。这种级联过程不仅可以生产这些天然产品本身，而且还可以针对特定靶向类似物的生产，这些产品将被筛选以进行抗肿瘤活性。 I涉及统一的，高度收敛的策略的提议的合成策略，涉及手性1,3-二羟基乙酸的顺序不对称烷基化等效于建立靶分子的完整碳框架，然后在高度选择性的大分子化中产生26分。拟议工作的重要性将特别在于癌症化学疗法研究领域，以及开发新的合成策略和技术，用于药物发现和开发过程中。