SYNTHESIS OF ANTICANCER AGENTS

描述（由申请人提供）：该资助申请描述了一些天然来源的强效抗肿瘤药物的拟议全合成，即lomaiviticins a和B， cytoskyrin a， amphidinolide N和caribenolide I，以及一些用于生物筛选的相关分子。提议的全合成lomaivitticins将涉及先进的a-halo烯酮中间体的二聚化，以产生c2对称的多环框架。然后，通过临时加入桥接循环系绳，将有助于进一步设计空间拥挤的中央核心。已经设计了两种可选择的系链，即四氢噻吩和带有垂坠酯基的碳环，增加了整体策略的灵活性。一旦所需的结构基序被安装，这些桥可以被氧化裂解，以揭示完成目标分子的必要功能。对于cytoskyrin A，实验证明了一种仿生级联过程可以提供靶分子的笼状框架。包括酸催化的蒽醌衍生物的二聚化，然后是双烯醇化/双分子内迈克尔加成序列，仔细监测这一级联不仅可以选择性地产生细胞skyrin a的中心核心，还可以选择性地产生许多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，而且适用于专门针对的类似物的生产，这些类似物将被筛选为抗肿瘤活性。两苯乙烯内酯N和羰基内酯I的合成采用统一的、高度聚合的策略，包括手性1,3-二羟基丙酮等价物的顺序不对称烷基化，以建立目标分子的完整碳框架，然后进行高选择性的大内酯化，在每种情况下生成26元环。所提议的工作的意义将特别在于癌症化疗研究领域，以及在药物发现和开发过程中普遍使用的新合成策略和技术的发展。

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.