Biomimetic Synthesis of Complex Natural Products

描述（由申请人提供）：提议的研究反映了首席研究员John A. Porco, Jr.和他的团队在新化学反应开发和生物相关分子合成方面的兴趣，这些方法受到复杂天然产物生物发生的启发。他们的目标是开发一些重要的天然产物目标类的合成方法，包括氮唑啉酮，来自Aglaia植物属的rocaglamides和相关化合物，以及ansamycin tetrapetalone a。为完成项目目标而开发的新反应方法包括氮唑啉酮的环异构化路线，光化学偶极环加成制备rocaglamides和相关抗肿瘤化合物。和跨环氧化环化方法的安纳霉素四apetalone A和同系物。他们将与吉尔福德·琼斯教授的实验室（波士顿大学）合作，进行光物理研究，以阐明新型光化学转化的机制。他们将与美国国家癌症研究所（NCI）、Cerylid生物科学公司和麦吉尔大学的研究人员合作，评估合成化合物的生物活性。除了方法学发展之外，还将进行结构复杂和具有生物活性的天然产物和类似物的合成。拟议项目的目的是：

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.