天然药物新型微量活性成分的发现与功能研究

Taking minor constituents as a breakthrough point, by integrative application, functional development, and method establishment based on various high-effective and high-sensitive technologies including CombiFlash, and HPLC-DAD-MS/MS-NMR, etc. several technical bottleneck problems with investigation of the minor constituents in complex systems of the natural medicines, e.g. difficult to identify, difficult to obtain, and difficult to evaluate, have been solved Meanwhile, from 18 traditional Chinese medicines, of which functional constituents are unknown, a number of minor chemical constituents possessing novel or unique structure features and significant activities and functions were found, which proves that the minor components may be important functional substances of the natural medicines and lead compounds of new drug development. Based on the results and accumulation, this project will further investigate 10-15 traditional Chinese medicines which are mainly used for treatment of nervous and cardiovascular diseases: to discovery and obtain new bioactive minor chemicals, to elucidate their precise structures, to synthesize the new bioactive chemicals and their derivatives via transformation, and to evaluate in-depth their bio-functions. It is expected that more than 200 new minor compounds, including more than 30 compounds with significant bioactivities, will be discovered, that 5-10 bioactive isolates and more than 100 derivatives will be synthesized via transformation, and that more than 2 lead compounds with unique functions will be obtained by in-depth evaluation, which will provides basis for new drug development and supportive scientific evidences for clinical functions of these natural medicines.

前期以微量成分为切入点，通过CombiFlash和HPLC-DAD-MS/MS-NMR等高效灵敏新技术整合运用、功能开发和方法建立，结合生源关联的转化合成及计算机模拟和分子对接等，解决了天然药物复杂体系中微量活性成分“难识别、难获取、难评价”等主要技术瓶颈问题，并从18种药效成分尚不明确天然药物中，发现众多微量成分具有新颖结构及显著生物活性与功能，证明新型微量活性成分是天然药物的重要功效物质及研发新药的先导化合物。基于上述研究结果和积累，拟继续重点针对用于神经和心脑血管系统疾病等治疗的10-15种中草药进行深入系统研究：发现获取新型微量活性成分、阐明其精确结构、转化合成制备微量活性成分及其衍生物、深入评价其活性和功能。预期发现、获取和鉴定>200个新颖结构微量成分，筛选发现>30个强活性成分，转化合成5-10个强活性成分及衍生物>100个，获得>2个先导化合物。

对用于神经和心脑血管系统疾病等治疗的附子、羊踯躅、当归、钩藤、三七叶等18种天然药物的微量药效物质进行了较深入系统研究，发现新颖结构类型的微量成分252个，确定了它们的精确结构。基于生源合成联系，从易得的常量成分出发，高效转化合成18个新颖结构类型微量成分及其衍生物116个。通过多模型活性与功能测定和深入评价研究，发现了体内具有显著药效作用微量成分33个和具有体外强活性化合物16个，优选出药物先导化合物5个。主要结果已申请专利20项，获授权专利10项；部分内容已在本领域有重要影响的国内外学术期刊发表研究论文48篇（第一标注31篇）。项目组成员晋升研究员和副研究员各1人，培养西部之光人才1名，培养研究生18名。全面完成了项目计划书的研究工作，阐明了相关天然药物中的部分微量药效物质的结构，揭示了微量成分相互之间以及与常量成分之间的生源联系，确证并实现了易得常量成分高效转化获得微量成分及其衍生物，发现了微量成分及其制备衍生物的活性、构效关系和功能特点及其与传统功效的联系，获得了候选药物；为药物合成、合成生物学和有机合成化学等研究提供了具有新颖骨架的新型目标活性分子，为基于天然药物微量成分的新型药物研发奠定了基础，为部分天然药物的临床应用提供了科学依据，为丰富和全面诠释这些传统天然药物临床功效的科学内涵奠定基础。