三种茜草属植物抗肿瘤萘醌二聚体的发现与作用机制研究

Malignant tumors have been seriously threatening human's life and health, and natural products are one of the important direction for antitumor drug development. Quinones are widespread in the Rubia plants and possess many biological activities. Among them, though naphthohydroquinone dimers have garnered significant attention due to diverse structures and better biological activities, their developments are limited for amounts and bioactive mechanisms. Previously, we investigated the chemical constituents of the roots and rhizomes of R. alata and R. podantha, which led to the isolation of two novel naphthohydroquinone dimers and six ones containing two new ones, respectively. We also evaluated their biological activities against various tumor cell lines and the tumor-associated NF-κB signaling pathway, and found several active compounds. Based on the preliminary results, this project will perform the directional isolation of naphthohydroquinone dimers from the roots and rhizomes of R. podantha, R. cordifolia and R. yunnanensis, and evaluated their biological activities against various tumor cell lines and the tumor-associated NF-κB signaling pathway. Meanwhile, the isolation and activity screening of other quinones from the three Rubia plants will be carried out. Furthermore, we will select the best naphthohydroquinone dimer and investigate how it affects NF-κB signaling pathway, which may contribute to further research for its antitumor mechanism. The implementation of this project will promote the chemical and bioactive studies of naphthohydroquinone dimers derived from the Rubia plants, which will lay a scientific foundation for their future development as new anti-tumor drugs.

恶性肿瘤严重威胁人类生命健康，天然产物是目前抗肿瘤药物研发的重要方向之一。茜草属植物中富含醌类化合物，具有多种生物活性，其中萘醌二聚体结构类型多样，活性较好，引起了天然产物学家的关注，但数量与机制研究较少，制约着该类成分的发展。前期申请者分别从金剑草和柄花茜草中得到两个新骨架萘醌二聚体和六个萘醌二聚体（含两个新结构），并评价其肿瘤细胞毒及NF-κB信号通路活性，发现了活性较好的分子。本项目在已有研究基础上，从三种茜草属药用植物柄花茜草、茜草和紫参的根及根茎中定向挖掘萘醌二聚体，并进行抗肿瘤及NF-κB信号通路活性筛选；同时也开展其它醌类化合物的分离与活性筛选工作。优选目的萘醌二聚体，以作用于NF-κB信号通路机制为突破口，为对其进行深入的抗肿瘤机制研究奠定基础。本项目的实施将促进茜草属植物萘醌二聚体的化学与活性机制研究，为其作为抗肿瘤候选药物的开发利用奠定基础。

恶性肿瘤严重威胁人类生命健康，天然产物是目前抗肿瘤药物研发的重要方向之一，茜草属植物中萘醌二聚体因骨架多变和潜在的抗肿瘤活性而受到关注。本项目开展了柄花茜草、茜草、紫参和钩毛茜草等四种茜草属植物中萘醌二聚体类成分研究，获得了系列萘醌二聚体，其中包括四个新成分，还获得了其它醌类、环肽和萜类等成分。基于UPLC-MS/MS技术，结合已分离得到的化合物和所在团队前期研究积累，在MRM模式下建立了能快速识别茜草属植物来源的45种醌类成分和同时定量其中24种醌类成分的分析方法，用于研究45个野外采集的茜草属植物样品中醌类成分的分布特点。对已分离得到的萘醌二聚体及其它醌类化合物进行肿瘤细胞毒活性筛选和NF-κB信号通路筛选，发现萘醌二聚体rubioncolin C活性最好，并利用荧光素酶双报告基因、Western blotting、ELISA、免疫荧光等多种生化技术，通过研究其对肿瘤细胞凋亡和自噬的影响以及肿瘤相关的Akt/mTOR/P70S6K以及NF-κB信号通路的影响，阐明了rubioncolin C的抗肿瘤新作用机制。此外，还新发现rubioncolin C具有较好的体内外抗肿瘤转移活性。该项目目前已在Phytochemistry，Journal of Natural Products，Journal of Pharmaceutical and Biomedical Analysis，Cells，Journal of Ethnopharmacology，Chemisty & Biodiversity，中国中药杂志等杂志上发表论文14篇，申请中国专利2项（其中1项已授权）。这些研究成果将促进茜草属植物萘醌二聚体的化学与活性机制研究，为其作为抗肿瘤候选药物的开发利用奠定基础。