Biomimetic Synthesis of Complex Natural Products

描述 拟议的研究反映了首席调查员小约翰·A·波尔科和他的 在新的化学反应开发和生物降解剂分子的合成方面的小组 受复杂天然产品生物发生的启发而采取的方法。他们的目标是开发合成的 一些重要的天然产品目标类的方法学，包括氮杂环丙酮、 从仙人掌属植物中分离得到的岩藻酰胺类化合物和相关化合物，以及阿萨霉素四氢呋喃甲素A。 为实现该项目目标而开发的新反应方法包括环异构化路线 以氮杂环酮为原料，光化学偶极环加成反应制备罗格酰胺类化合物及相关化合物 抗肿瘤化合物及其跨环氧化环化合成安沙霉素四氢呋喃的方法 A和同系物。与吉尔福德·琼斯教授的实验室(波士顿大学)合作，他们将 进行光物理研究，以阐明新的光化学转化的机制。 他们将在特定的生物学合作中评估合成化合物的生物活性 来自国家癌症研究所(NCI)、Cerylid生物科学公司和麦吉尔大学的研究人员。在……里面 除了方法学开发，合成结构复杂和具有生物活性的化合物 将寻求天然产品和类似物。拟议项目的目的是： 开发不对称合成氮杂环丙酮类天然产物的方法，以及 将该方法应用于端粒酶抑制剂二氮杂环酸的合成， P53/MDM2抑制剂氯氟菌素和脂肪酸合成酶抑制剂CT2108A。 从仙人掌中合成罗格拉胺及其相关化合物，包括抗肿瘤药物 阿格司他丁和最近分离的有效细胞毒剂西尔维斯特罗。 基于一种独特的生物仿生学方法研究氨沙霉素四氢呋喃甲素的苷元。 [4+3]氨基对苯二酚和二烯的跨环氧化环化反应。 与公共卫生的相关性： 计划中的复杂天然产品仿生合成与公众健康的相关性需要 新的生物活性物质的鉴定。这类药物应该在药物发现中发挥关键作用。 与各种病理有关，包括各种人类癌症。

Description 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.