心肌纤维化是多种心血管疾病不断进展最终导致心脏功能障碍的一个重要病理过程。抑制心肌纤维化的发生发展是治疗心血管疾病的重要环节，对降低心血管疾病的致死风险具有重要意义。心肌纤维化作用机制十分复杂，目前尚未发现针对性的治疗药物。前期研究中，我们发现中药南木香的某一提取部位在细胞和动物水平具有显著的抗心肌纤维化活性，其作用机制为对心肌纤维化进程中两个关键信号通路ERK和TGF-beta/Smad的双重抑制。初步化学研究表明，该提取部位主要由大环倍半萜类构成，含多个新化合物，对MAPK信号通路中的ERK信号通路具有选择性的抑制作用，活性强于阳性对照药PD98059。本申请拟在此基础上深入研究南木香抗心肌纤维化活性部位的物质基础，发现靶向ERK和TGF-beta/Smad信号通路对抗心肌纤维化的活性分子并初步阐明其作用机制。通过构效研究、结构改造等为抗心肌纤维化候选药物的研发奠定基础。

Cardiac fibrosis is considered as the major pathologic process of multiple cardiovascular diseases leading to cardiac dysfunction. The inhibition of cardiac fibrosis plays an important role in prevention and treatment of the cardiovascular diseases, which may reduce the risk of lethality of such diseases. The mechanism of cardiac fibrosis is very complex, and so far there is no targeted therapeutic drug for cardiac fibrosis. In our previous study, we found that a fraction of the crude extract of a Traditional Chinese Medicine-Aristolochia yunnanensis exhibited potent antifibrotic effects in both vitro and vivo models. Its mechanism was the inhibition of two important signaling pathways in cardiac fibrosis, ERK and TGF-beta/Smad. Preliminary chemical study revealed that this active fraction was consisted of a group of sesquiterpenoids including several new ones. The in vitro assay verified that several compounds exhibited selective inhibition of the phosphorylation of ERK1/2, being more active than the positive control PD98059. In this proposal, we are aiming to illustrate the chemistry of the active fraction, and to discover some active compounds both targetting ERK and TGF-beta/Smad signaling pathways against carbidac fibrosis. The action mechanism of the active compound will also be roughly explored. After structure-activity relationship study and structure modification, we hopefully find some drug leads, laying a solid foundation for antifibrotic drug research.