Biomimetic Synthesis of Complex Natural Products

描述（由申请人提供）：拟议的研究反映了主要研究者John A.小波尔科和他的小组在新的化学反应的发展和生物相关分子的合成使用的方法的灵感来自复杂的天然产物的生物成因。他们的目标是为许多重要的天然产物目标类别开发合成方法，包括azaphilones，rocaglamide和来自植物属Aglaia的相关化合物，以及ansamycin tetrapetalone A。为实现项目目标而开发的新反应方法包括azaphilones的环异构化路线，制备rocaglamide和相关抗肿瘤化合物的光化学偶极环加成，以及安莎霉素tetrapetalone A和同系物的跨环氧化环化方法。他们将与Guilford Jones教授的实验室（波士顿大学）合作，进行光物理研究，以阐明新的光化学转化机制。他们将与美国国家癌症研究所（NCI），Cerylid Biosciences和麦吉尔University的研究人员合作，评估合成化合物的生物活性。除了方法学的发展，结构复杂和生物活性的天然产品和类似物的合成将继续进行。拟议项目的目的是：  开发azaphilone类天然产物的不对称合成方法，并将该方法应用于端粒酶抑制剂diazaphilonic acid、p53/MDM 2抑制剂chlorofusin和脂肪酸合成酶抑制剂CT 2108 A的合成。  从米仔兰中合成rocaglamide和相关化合物，包括抗肿瘤剂glaistatin和最近分离的强效细胞毒性剂silvestrol。  基于酰胺基对苯二酚和二烯的独特的[4+3]跨环氧化环化，追求安莎霉素四瓣内酯A的糖苷配基的仿生方法。 与公共卫生的相关性：复杂天然产物的拟生物合成与公共卫生的相关性需要鉴定新的生物活性剂。这些药物应该在与各种病理学（包括各种人类癌症）相关的药物发现中发挥关键作用。

DESCRIPTION (provided by applicant): The proposed research reflects the interest of the Principal Investigator, John A. Porco, Jr., and his group in new chemical reaction development and the synthesis of biorelevant molecules using approaches inspired by the biogenesis of complex natural products. Their goal is to develop synthetic methodologies for a number of important natural product target classes, including the azaphilones, the rocaglamides and related compounds from the plant genus Aglaia, and the ansamycin tetrapetalone A. New reaction methodologies developed to accomplish the project aims include cycloisomerization routes to the azaphilones, photochemical dipolar cycloaddition to prepare the rocaglamides and related antitumor compounds, and transannular oxidative cyclization approaches to the ansamycin tetrapetalone A and congeners. In collaboration with Professor Guilford Jones' laboratory (Boston University), they will conduct photophysical studies to elucidate the mechanisms of novel photochemical transformations. They will evaluate the biological activity of synthetic compounds in specific biological collaborations with investigators from the National Cancer Institute (NCI), Cerylid Biosciences, and McGill University. In addition to methodology development, the synthesis of structurally complex and biologically active natural products and analogues will be pursued. The aims of the proposed project are to:  Develop approaches to the asymmetric synthesis of the azaphilone class of natural products, and apply the methodologies towards the synthesis of the telomerase inhibitor diazaphilonic acid, the p53/MDM2 inhibitor chlorofusin, and the fatty acid synthase inhibitor CT2108A.  Synthesize the rocaglamides and related compounds from Aglaia, including the antitumor agent aglaiastatin and the recently isolated, potent cytotoxic agent silvestrol.  Pursue a biomimetic approach to the aglycone of the ansamycin tetrapetalone A based on a unique [4+3] transannular oxidative cyclization of an amido-hydroquinone and diene. Relevance to Public Health: The relevance to public health of the planned biomimetic syntheses of complex natural products entails identification of novel, biologically active agents. Such agents should play a key role in drug discovery related to various pathologies, including a variety of human cancers.