基于联烯多样反应性能的核苷衍生物的合成、生物活性和荧光性能研究

5-Substituted pyrimidine nucleoside derivatives are emerging as a rich source in the search for new lead compounds since many of them are biologically active and intrinsically fluorescent. So far, 5-substituted pyrimidine nucleosides are usually synthesized via palladium catalyzed coupling of 5-iodopyrimidine nucleosides with functionalized organo(metallic) reagents. However, the usage of these coupling reactions are compromised due to difficult-to-obtain and toxic substrates they employed, expensive catalysts they used, and limited categories and amounts of products they could produce. In order to solve these problems and inspired by the diverse reactivity of functionalized allenes, this project aims to establish new synthetic methods toward 5-substituted pyrimidine nucleosides from easily available and economical starting materials without using noble metal catalysts. With these new methods, a privileged structure-guided design and synthesis of structurally diverse 5-membered or 6-membered aromatic (heterocyclic) ring substituted pyrimidine nucleosides and tricyclic pyrimidine nucleosides will be accomplished. All the compounds prepared will be screened as antiviral, anticancer and antiparasitic drug candidates and their fluorescent property will also be studied. It is expected that implementation of the proposed research in this project will result in the discovery of new lead compounds with significant biological activities and promising fluorescent characteristics and help to pave the way toward the development of novel nucleoside drugs and fluorescent probes.

5-取代嘧啶核苷衍生物因具有显著的生物活性和良好的荧光性能而成为新先导化合物发现的重要来源。目前，该类化合物大多通过钯催化下5-碘代嘧啶核苷与官能团化有机（金属）试剂之间的偶联反应来得到。由于这些偶联反应所用的反应底物难合成、毒性大，所用的催化剂价格昂贵，所能提供的核苷衍生物种类及数量有限，使相关的嘧啶核苷类新药及荧光探针试剂的研究与开发工作受到严重制约。为解决上述问题，本项目拟基于官能团化联烯的丰富反应性能，探索并建立从价廉易得的原料出发、在无需使用贵金属催化剂的条件下合成5-取代嘧啶核苷的新方法。利用这些方法，并以优势结构为导向，设计、合成结构多样化的五元、六元芳（杂）环取代嘧啶核苷和三环嘧啶核苷衍生物。通过研究这些核苷衍生物的抗病毒、抗肿瘤、抗寄生虫等生物活性及荧光性能，希望筛选到具有显著生物活性和良好荧光特征的新先导化合物，为核苷类新药和荧光探针试剂的开发做好物质准备。

5-取代嘧啶核苷及其衍生物因具有显著的生物活性和良好的荧光性能而成为新先导化合物发现的重要来源。目前，该类化合物大多通过钯催化下5-碘代嘧啶核苷与官能团化有机金属试剂之间的偶联反应来得到。由于这些偶联反应所用的反应底物难合成、毒性大，所用的催化剂价格昂贵，因此，其所能提供的核苷衍生物种类及数量有限，从而制约了5-取代嘧啶核苷类新药及荧光探针试剂的研究与开发。为解决上述问题，本项目基于官能团化联烯的多样反应性能，首先研究并建立了以联烯酮、联烯醇等为原料、在无需使用贵金属催化剂的条件下合成多取代呋喃、二氢呋喃、呋喃酮、吡唑、异噁唑、吡喃酮、苯并吡喃酮、酰基吲嗪、吡唑并[1,5-a]嘧啶、吡唑并[5,1-a]异喹啉、吡唑并[5,1-a]异吲哚、二氢喹嗪-2-酮、喹嗪-2-酮、多取代苯酚、2-苯基苯酚、二苯并呋喃、二苯并吡喃酮、2,6-二氰基苯胺、环戊烯基酮和环己烯基酮等碳环、杂环和稠杂环类化合物的高效新方法。然后，以上述合成方法为模板，从简单、易得的原料出发，在温和的反应条件下制备了5-位带有呋喃、吡唑、吡咯、异噁唑、吡喃酮、吡唑并[1,5-a]嘧啶、多取代苯酚或2,6-二氰基苯胺等结构单元的嘧啶核苷衍生物。部分完成了所合成嘧啶核苷衍生物的抗肿瘤、抗寄生虫等活性筛选和荧光性能研究，并从中发现了一些有苗头的先导化合物。上述研究结果不仅在一定程度上丰富和拓展了联烯衍生物的反应类型和应用范围，而且为嘧啶核苷衍生物的合成提供了新的思路。基于以上研究结果，目前已发表有基金标注的学术论文28篇，申请中国发明专利15项，其中6项已获得授权。