基于手性源的DTS策略对天然产物Neobraclactone A的全合成、探针化和分子编辑的研究

化学生物学作为具有举足轻重作用的交叉学科，是推动化学学科和生命科学发展的重要动力，也是一项非常有挑战的研究领域。本项目以基于手性源的DTS策略对天然产物Neobraclactone A的全合成为基础，进行“探针化”和“分子编辑”，以发现靶标及活性先导化合物。本项拟解决的关键科学问题是：以手性源左旋香芹酮出发，应用Fries重排串联环化或分子间苯炔环化策略，汇聚式地完成Neobraclactone A的对映选择性全合成；合成探针分子，并对其进行细胞水平活性筛选，应用生物学技术确定与其作用的靶标蛋白；通过“分子编辑”合成结构简化的衍生物，建立化合物库；将计算机辅助药物设计与活性测试相结合，寻找结构简单、活性良好的先导化合物。本项目拟以目标分子的合成为契机，解决天然产物来源有限、改造困难、难以获取靶标蛋白的难题，其有效实施有助于促进多学科领域的交叉与融合，推动分科知识融通发展为完整的知识体系。

Chemical biology is a discipline spanning the fields of chemistry and biology, therefore it is highly interdisciplinary. It has been an important driving force for the development of chemistry and life sciences, and it has become increasingly challenging. Based on the DTS strategy using a chiral pool, we propose to perform the total synthesis of the natural product Neobraclactone A, to develop chemical probes and to carry out "molecular editing" to find its target and some bioactive lead compounds. The key scientific problems to be solved are as follows: starting from the chiral pool of L-Carvone, Fries rearrangement will be utilized to go through tandem cyclization or intermolecular benzyne cyclization and convergently complete the total synthesis of Neobracactone A enantioselectively. Then we will synthesize its probes and screen for its biological activity at the cellular level. We will apply various techniques to determine the target protein. We will also try to simplify the complex natural product by synthesizing simply structural derivatives via "molecular editing" to construct a compound library. Computer-aided drug design technique will be used as an integral part of the research to explain their mode of action and help design simpler compounds with better activities. In summary, this proposal will seek to complete the synthesis of target molecule and to solve the problems of limited sources of natural products, difficulty in modification and target protein identification, which will be helpful to develop novel compounds. The successful implementation of the proposal will promote our understanding of the efficient synthesis of Neobracactone A and its applications in chemical biology as well as drug discovery and development.