融合多层次化学结构特征研究钩吻中吲哚生物碱抗乳腺癌的构效关系和作用机制

Traditional herb Gelsemium elegans has a significant anti-tumor effect, but its high toxicity as well as slow progress in mechanism and effective substances study, restricts the application. The major chemical compositions isolated from the Gelsemium elegans are indole alkaloids, with numerous components formed by multi-chiral centers of spirocyclic or fused-cyclic scaffolds. A resonable model based on multi-stereochemical space of the ligands is built by the means of chiral synthetic strategies and CADD. It takes the skeletons, substituents and stereochemistry into structure-activity study, not just considering the existed structures and quantity of components extracted from the herb. Thus, virtual screening and drug design by scaffold-hopping can be realized. Meanwhile, on the basis of MDM2 target, the newfound anti-tumor function of inducing apoptosis is added. Employed by bioinformatics and molecular biology, this project provides deep insight into the molecular mechanism of the indole alkaloids in Gelsemium elegans. It can also disclose the multitarget interaction of TCM more comprehensively. Smooth implementation of this project will improve the mechanism of Gelsemium elegans on microscopic level, and provide a new idea to study the ingredients of Chinese medicine with especially complex stereochemical structures. It is helpful for safely and effectively developing a novel anti-tumor agent guided by Gelsemium elegans.

传统中药钩吻抗肿瘤效果显著，但因其毒性较大、作用机制和药效物质研究进展缓慢而应用受限，钩吻主要活性成分为吲哚生物碱，该类成分含有多个手性中心的复杂螺环或并环母核，故研究其有效成分难度较大。本课题在中医药整体观理论指导下，借助手性不对称合成手段融合CADD技术，构建具有“立体化学结构多样性”的计算模型，该模型克服中药已有成分结构种类和数量固化的局限性，将骨架、取代基和手性等信息均纳入构效关系研究中，兼具虚拟筛选和以骨架跃迁创制新药等功能；同时，前期研究充分证明：钩吻生物碱除作用于靶标MDM2外，诱导凋亡也是其发挥抗肿瘤的重要机制，结合生物信息学、分子生物学等方法，开展钩吻吲哚生物碱抗乳腺癌的分子机制研究，从而深入阐释其药效物质结构与活性规律的根本原因。本课题的开展将完善钩吻多靶点的作用机制，并为研究中药化学成分的立体结构对活性的影响提供新思路，同时为利用钩吻为先导物开发抗肿瘤新药提供基础。

本项目制备了多样性的钩吻吲哚生物碱的小型化合物库，构建钩吻吲哚生物碱的药效团模型和QSAR 模型，阐释钩吻药效物质的构效关系，同时借助生物信息学技术探索钩吻吲哚生物碱抗乳腺肿瘤的药物-靶点关系，并利用现代分子生物学技术研究钩吻吲哚生物碱通过诱导凋亡途径抑制MCF-7 细胞的作用机制。本项目从中药整体效应考察效应成分对活性的贡献，借助现代合成技术和CADD 技术构建基于配体多样性的计算模型，该模型克服中药固有药效成分数据的局限性，兼具解释钩吻吲哚生物碱构效关系和筛选对应抗肿瘤药物等功能；同时，课题组研究证明诱导凋亡钩吻生物碱其发挥抗肿瘤的重要机制，并结合生物信息学、分子生物学等技术，深入研究钩吻中吲哚生物碱抗乳腺癌细胞的分子机制，阐明其多靶点抗肿瘤的科学内涵，并从根本上解释钩吻吲哚生物碱药效物质结构与活性规律。该项目研究期间：共发表基金号标注的SCI收录的研究论文17篇，其中通讯作者论文10篇，并列一作论文2篇，影响因子>5的论文共6篇；第一作者国际学术会议论文1篇（256届美国化学年会，SCI收录论文摘要）；培养硕士研究生8人；联合培养博士研究生4人；2019年获得四川省科技进步一等奖。顺利完成了预期的研究目标。