Chemistry and Biology of Salicylate Natural Products

描述：（申请人描述）水杨基卤酰胺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 在国家癌症研究所的60个细胞中， 线人肿瘤测定。自1997年首次发现以来， 已分离出结构相关的代谢物，包括洛巴他酰胺 A-F，apicularen A，oximidines I-II，CJ 12，950和SCH 351448。观察 它们中的每一种似乎都能在哺乳动物细胞中引发独特的反应， 因此代表了开发治疗剂的独特的新先导物， 这就要求在这一领域发展合成化学。建立在 高效合成水杨卤酰胺和apicularen大环核， 所提议的研究的一部分旨在提供合成材料， 否则无法获得，用于结构-活性和作用模式研究。 合成替代品，其共同的，但不稳定的烯酰胺侧链将是 探索除了光亲和，放射性标记， 生物素化探针。 拟议研究的其余部分涉及与以下方面有关的化学： 羟脒，CJ-12，950和SCH 351448。为了实现全面的综合， 为了安装奥昔亚胺，将探索各种交叉耦合方法 一个非常不寻常的共轭E，Z，Z-三烯亚基嵌入在一个12-元 苯内酯。用于确定相对和绝对 CJ-12，950的立体化学，这仍然是未知的，有效的合成 提出了苯并内酯核的一种选择的立体异构体， 通过Mitsunobu化学快速立体异构体相互转化的平台。NMR 光谱学将是将这些光谱指纹 CJ-12950的高级中间体最后，一个简短的，高度收敛的 SCH 351448的合成，SCH 351448是由两个大环聚酮双内酯组成的大环聚酮双内酯 相同的酸，提出使用新的串联分子间/分子内烯烃 复分解策略最终，拟议的研究将提供 用于发现生物学小分子探针以及新的治疗方法 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.