SYNTHESIS OF ANTICANCER AGENTS

描述(申请人提供)：这项拨款申请描述了一些天然来源的有效抗肿瘤药物的拟议全合成，即洛麦维菌素A和B、胞嘧啶A、两性内酯N和卡里本内酯I，以及一些用于生物筛选的相关分子。建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对称的多环骨架。然后，通过临时加入桥接环链，将有助于进一步细化空间密集的中心核心。已经设计了两种替代的这种系链，即四氢噻吩环和带有侧酯基团的碳环，增加了整体战略的灵活性。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切割，以揭示完成目标分子所需的功能。对于细胞分裂蛋白A，一个仿生级联过程已经被实验证明，以提供目标分子的笼状骨架。通过酸催化的二聚化和双烯醇化/双分子内的Michael加成序列，仔细监测这一级联反应，不仅可以选择性地生成胞嘧啶A的中心核心，而且可以选择性地生成许多其他结构相关的生物活性天然产物。这一级联过程不仅适用于这些天然产品本身的生产，也适用于特定目标类似物的生产，这些类似物将被筛选出抗肿瘤活性。所提出的两性内酯N和加勒比苯内酯I的合成具有统一的、高度收敛的策略，包括手性1，3-二羟基丙酮等效物的顺序不对称烷基化以建立目标分子的完整碳骨架，然后分别进行高选择性的大内酯基化以生成26元环。拟议工作的意义将具体体现在癌症化学研究领域，以及开发新的合成战略和技术，供药物发现和开发过程中普遍使用。

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.