天然产物水鬼蕉碱导向的TopoI抑制剂的设计、立体选择性全合成及生物活性研究

Pancratistatin is a natural low toxic alkaloid with high anti-cancer activity. Due to the extremely low content in natural plants and difficult to extract, pharmacology study of Pancratistatin is hard to conduct and the application is restricted. Our previous study identified that a new antitumor mechanism of Pancratistatin is TopoI inhibition, and the inhibitory activity against TopoI and anti-proliferative activity of Pancratistatin are much better than Camptothecin. Therefore, Pancratistatin will serve as the lead compound in this project and series of novel TopoI inhibitors will be designed following the basic principle of drug design that combined with computer-aided drug design (CADD). A specific chiral nitro olefin shall be used as the starting material and chiral control source. We plan to exploit a novel, non-toxic residues and structure-oriented stereoselective total synthetic route with a six-step reaction which includes Michael addition reaction, and complete the total synthesis of Pancratistatin-type TopoI inhibitors. The antitumor activities, TopoI inhibitory activities and antitumor mechanism will also be studied in order to obtain one or two highly active and safe Topo I inhibitor(s). This project will provide innovative ideas for overcoming the high toxic problems of Camptothecin-type TopoI inhibitors which are due to the restriction of their structures. Meanwhile, our study will provide important theoretical basis for the development of anti-cancer drugs by targeting TopoI.

水鬼蕉碱是一个高效低毒的抗肿瘤天然生物碱，但因其在植物中含量低，提取困难，使其药理研究不够深入，作用靶标不明晰，其研究和应用受到限制。前期工作中，申请人发现水鬼蕉碱新的抗肿瘤机制：TopoI抑制，且其TopoI抑制活性和肿瘤细胞增殖抑制活性均优于喜树碱。在此基础上，本项目拟以水鬼蕉碱为先导化合物，运用药物设计基本原理，结合计算机辅助药物设计，设计结构新颖的水鬼蕉碱类TopoI抑制剂；再以手性硝基烯为原料和手性控制源，通过Michael加成等六步反应，探索一条新颖、无毒物残留、结构多样性导向的立体选择性合成路线，完成水鬼蕉碱类TopoI抑制剂合成；最后研究该类化合物对TopoI的作用机制，并进行抗肿瘤活性筛选，以期获得1-2个高活性高安全性的TopoI抑制剂。为克服已上市喜树碱类TopoI抑制剂因骨架结构限制造成毒副作用大等缺陷提供新的思路，为以TopoI为靶点的抗肿瘤药物研发提供理论依据。

水鬼蕉碱（Pancratistatin）是一个高效低毒的抗肿瘤天然生物碱，但因其在植物中含量低，提取困难，使其药理研究不够深入，作用靶标不明晰，其研究和应用受到限制。为解决水鬼蕉碱及其类似物物质基础问题，探索结构多样化抗肿瘤小分子合成路线，深入研究该类生物碱抗肿瘤作用机制，申请人依托本项目在三年执行期中，主要开展了以下研究：1.开发了以葡萄糖甲苷作为起始原料，合成得到手性硝基烯为手性控制源，基于高立体选择性分子间Michael加成和分子内Henry反应，完成具有6个连续手性中心的(+)-水鬼蕉碱的合成方法。该方法高效、易于放大、普适性好，可用于合成具有水鬼蕉碱骨架的多种生物碱，为(+)-水鬼蕉碱及其类似物的抗肿瘤机制及药效学研究奠定了物质基础；2.通过DFT计算、原位1H-NMR定点检测实验阐明了分子内Henry反应的机理和进程；3.首次发现了水鬼蕉碱及其类似物具有抑制TopoI活性的作用机制。通过TopoI酶活性实验、细胞克隆形成实验、流式细胞术（FCM）、Western blot、彗星实验、EB/Hoechst 33258荧光竞争实验、琼脂糖凝胶电泳、TARDIS等实验，阐明了水鬼蕉碱类化合物Narciclasine靶向TopoI发挥抗肿瘤作用的分子机制。4.产生成果包括通讯作者发表Organic Letters等高质量论文4篇、申请发明专利3件、入选云南省高层次人才培养计划-青年拔尖人才1人、晋升正高级职称1人、培养研究生4人。本项目工作为克服已上市喜树碱类TopoI抑制剂因骨架结构限制造成毒副作用大等缺陷提供新的思路，为以TopoI为靶点的水鬼蕉碱类抗肿瘤药物研发提供理论依据。

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