A General Route to Anti-tumor Angucycline/Angucyclinones

描述（由申请人提供）：本提案中概述的研究目标是研究使用1，3-二卤代-2-（三烷基甲硅烷基）苯作为1，3-苯并二炔前体作为苯并[a]蒽核心的一般途径的范围。使用一次性系链使环加成在分子内进行将控制苯炔环加成的区域化学。产生的苯并[a]蒽核将进一步加工成天然产物rubiginone B1、urdamycinone B和IB-00208，它们是来自angucycline/angucyclinone家族天然产物的有效抗肿瘤化合物。该反应将进行调查，并将扩大范围的1，3-苯并二炔环加成，通过使用正交方法产生所需的苯炔中间体。这将允许苯炔的受控产生和反应以产生适当官能化的苯并[a]蒽核。使用所提出的3-苯并二炔方法通过灵活的路线进行有效的化学合成将提供用于合成多种结构相似的angucycline/angucyclinone天然产物的一般合成策略，所述天然产物已被鉴定为癌症、抗菌剂、抗病毒剂和酶抑制剂的治疗领域中的潜在药物。

DESCRIPTION (provided by applicant): The goal of the research outlined in this proposal is to investigate the scope of using 1,3-dihalo-2- (trialkylsilyl) benzenes as 1,3-benzadiyne precursors as a general route to the benz[a]anthracene core. Using disposable tethers to render the cycloadditions intramolecular will control the regiochemistry of the benzyne cycloadditions. The benz[a]anthracene cores produced will be further elaborated into the natural products rubiginone B1, urdamycinone B, and IB-00208, which are potent antitumor compounds from the angucycline/angucyclinone family of natural products. The reaction will be investigated and will expand the scope of 1,3-benzadiyne cycloadditions by using orthogonal methods of generating the requisite benzyne intermediates. This will allow for a controlled generation and reaction of benzyne to produce appropriately functionalized benz[a]anthracene cores. Efficient chemical syntheses by flexible routes using the proposed, 3-benzadiyne methodology will provide a general synthetic strategy for the synthesis of a multitude of structurally similar angucycline/angucyclinone natural products, which have been identified as potential pharmaceuticals in the therapeutic areas of cancer, anti-bacterials, anti-virals, and enzyme inhibitors.