Chemistry and Biology of Salicylate Natural Products

描述：(申请者描述)水杨酰胺A是第一个成员 一类新的复杂的大环水杨酸酯，并显示出独特的 美国国家癌症研究所60细胞的不同细胞毒性谱 LINE人体肿瘤检测。自从1997年首次发现它们以来，越来越多的 已分离出结构相关的代谢物，包括洛巴胺 A-F、蜂胶A、草亚胺I-II、CJ12、950和SCH351448。观察到的 它们中的每一个似乎都能在哺乳动物细胞中诱导一种独特的反应， 因此为治疗剂的开发提供了独特的新线索， 这为合成化学在这一领域的发展奠定了基础。建立在 高效合成水杨基卤胺和针叶蜂大环核， 拟议研究的一部分旨在提供合成材料， 否则无法访问，用于结构-活动和行动模式研究。 它们常见但不稳定的烯胺侧链的合成替代品将是 除了合成光亲和，放射性标记，和 生物素标记的探针。 建议的其余研究涉及与以下物质相关的化学 羟咪胺、CJ-12、950和SCH 351448。达到完全合成的目的 将探索多种交叉偶联的方法来安装奥西米 一种非常不寻常的共轭E，Z，Z-三烯亚基，嵌入在1个2-成员中 苯唑内酯。用于确定相对和绝对 CJ-12,950的立体化学，尚不清楚，一种有效的合成 提出了苯并内酯核心的精选立体异构体，作为 通过Mitsunobu化学实现立体异构体快速相互转化的平台。核磁共振 光谱学将成为关联这些物质的光谱指纹的工具 高级中间体与CJ-12,950。最后，一个简短的、高度收敛的 大环聚酮双内酯SCH351448的合成 利用一种新的串联分子间/分子内烯烃，提出了相同的酸 化合策略。最终，拟议的研究将提供 除了新的治疗方法外，发现生物学的小分子探针 线索。

DESCRIPTION: (Applicant's Description) Salicylihalamide A is the first member of a novel class of complex macrocyclic salicylates and displays a unique differential cytotoxicity profile in the National Cancer Institute's 60-cell line human tumor assay. Since their initial discovery in 1997, a growing number of structurally related metabolites have been isolated, including lobatamides A-F, apicularen A, oximidines I-II, CJ 12,950 and SCH351448. The observation that each one of them seems to induce a unique response in mammalian cells, and as such represent unique new leads for the development of therapeutic agents, warrants the development of synthetic chemistry in this area. Building on an efficient synthesis of the salicylihalamide and apicularen macrocyclic cores, part of the proposed research is intended to provide synthetic materials, otherwise not accessible, for structure-activity and mode-of-action studies. Synthetic substitutes for their common, but labile enamide side-chain will be explored in addition to the synthesis of photoaffinity, radiolabeled, and biotinylated probes. The remainder of the proposed research deals with chemistry related to oximidine, CJ- 12,950 and SCH 351448. To achieve a total synthesis of oximidine, a variety of cross- coupling approaches will be explored to install a highly unusual conjugated E,Z,Z-triene subunit embedded within a 1 2-membered benzolactone. For the determination of the relative and absolute stereochemistry of CJ-12,950, which remains unknown, an efficient synthesis of a selected stereoisomer of the benzolactone core is proposed, serving as a platform for rapid stereoisomer interconversion via Mitsunobu chemistry. NMR spectroscopy will be the tool to correlate spectroscopic fingerprints of these advanced intermediates with CJ-12,950. Finally, a short, highly convergent synthesis of SCH351448, a macrocyclic polyketide bis-lactone composed of two identical acids, is proposed using a novel tandem inter-/intramolecular olefin metathesis strategy. Ultimately, the proposed studies will provide small-molecule probes for discovery biology in addition to new therapeutic leads.