基于DOS/CtD策略挖掘特色傣药来源的新型类天然产物的研究

天然产物（NPs）的结构复杂性和多样性赋予其独特的生物活性，是创新药物发现的重要源泉。然而，NPs含量低且分离难度大又限制了其可持续的多样性，延缓了药物的发现历程。从复杂性到多样性的类天然产物合成（CtD），即易得NPs为起点的结构多样性导向合成（DOS），为解决该瓶颈提供了有效途径。遵循该思路，项目组围绕云南特色傣药资源开展了前期探索：通过长期药效物质基础研究，初步锁定了傣药锅拢良、克楞和摆埋丁别中3类目标分子，并借助CtD策略获取了3种新类型的腊肠素二聚体。鉴于前期重要进展，本项目拟从3方面开展系统研究：依托腊肠素筛选高效的CtD策略，如金属或光电催化；对关键起始原料开展富集制备；基于CtD策略系统挖掘3类目标分子的化学空间，构建相应的类天然产物分子库，为后续药理研究奠定基础。该项目的实施可能为发现傣药来源的新型先导化合物提供有益探索，亦可能为发展高效的DOS/CtD策略提供科学依据。

Natural products (NPs), which possess wide-ranging biological activities due to their structural complexity and diversity, are considered as significant sources of innovative drug discoveries. However, the difficulties associated with the isolation of large numbers of NPs enormously restrict the sustainable structural diversity and delay the process of the drug discoveries. Complexity-to-diversity (CtD) approach, which means a structural diversity-oriented synthesis (DOS) using easily accessible NPs as starting points, provides an effective way to solve this problem. In the light of the above ideas, we have carried out a preliminary exploration around Yunnan Dai traditional medicines. At first, studying on therapeutic material basis of several Dai traditional medicines, we have selected three suitable molecules (cassiarin A, ingol and echitaminic acid) isolated from three Dai traditional medicines (Goulongliang, Keleng and Baimaidingbie). Furthermore, based on DOS/CtD approach, we have obtained three novel types of dimeric alkaloidis using cassiarin A as starting materials. According to these important results, we will initiate this project from three aspects. Firstly, using cassiarin A as the raw materials, we will screen out the effective DOS/CtD strategies, such as transition metal catalysis, photochemical or electrochemical reactions. Secondly, we will prepare the main constituents in multi-gram quantities from Keleng and Baimaidingbie. At last, we will explore the chemical spaces of the three related molecules and establish their natural-like products molecular library, which may lay a foundation for the subsequent pharmacological studies. This research may provide a useful exploration for developing innovative lead compounds with new carbon skeletons derived from Dai traditional medicines and may also provide scientific evidence for the development of effective DOS/CtD strategies.