地胆草属吉玛烷型倍半萜内酯的精准导向分离及调控Hsp90α发挥抗肝癌作用的研究

天然来源的吉玛烷型倍半萜内酯（GSL）因其独特的十元环骨架和显著的抗肿瘤活性，能够为肿瘤治疗药物的开发提供多样化的先导化合物，一直是抗肿瘤药物的重要来源。前期实验表明，地胆草属植物中的GSL对肝癌有着很好的抑制作用，其药理作用机制是通过调控Hsp90α实现的。基于此，本项目将全面挖掘地胆草属GSL的抗肝癌潜力，以期发现新的抗肝癌先导化合物。拟通过GNPS平台构建白花地胆草亚流份的可视化分子网络，以已建立的地胆草属GSL的质谱数据库作为结构参照，快速区分不同类型GSL的分子节点，从而精准获得T类GSL。同时，筛选出通过调控Hsp90α来发挥抗肝癌作用的活性化合物，在细胞和动物水平上完成其药效学评价，多角度阐明该类化合物与Hsp90α作用的分子机制。本项目的顺利完成，不仅可以全面的挖掘地胆草属GSL在抗肝癌方面的价值，同时也为调控Hsp90α的抗肝癌药物的开发提供优选结构。

Natural germacrane-type sesquiterpene lactones (GSL) are an important source of the development of antitumor drug for they have a characteristic 10-membered carbocyclic skeleton and remarkable antitumor activity, which can provide a variety of lead compounds for the development of antitumor drug. The GSL isolated from genus of Elephantopus before which showed potent inhibitory activity on hepatoma cells could play a significant role in the anti-hepatoma effect by regulating Hsp90α according to the previous study. In this project, the anti-hepatoma potential of GSL will be explored comprehensively in order to discover novel anti-hepatoma lead compounds. The visual molecular network for fractions of Elephantopus tomentosus will be established by GNPS. The mass spectral database of previously isolated GSL was used as the structural reference to rapidly distinguish the different structural skeleton of GSL in molecular network node, and it could be helpful for targeted isolation of T-GSL. In addition, the active compounds which showed anti-hepatoma effect by regulating Hsp90α will be screened out and their anti-hepatoma pharmacological effect will be investigated in vitro and in vivo. Furthermore, the detailed molecular mechanism of Hsp90α should also be given. This project not only comprehensively demonstrated the value of the germacranolides from genus of Elephantopus in inhibiting hepatoma, but also provided an optimal structure for the development of Hsp90α inhibitors.