Biomimetic Total Synthesis and the Biological Evaluation of Natural Product (−)-Fargesone A as a Novel FXR Agonist

[Image: see text] Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays an important role in maintaining or reversing metabolic homeostasis during the development of liver diseases. However, developing FXR modulators to intervene in FXR-related diseases is still an unmet clinical need. Therefore, it is significant to develop novel small-molecule agonists for drug discovery targeting FXR. Through a high-throughput chemical screen and follow-up biological validations, we first identified the natural product Fargesone A (FA) as a potent and selective FXR agonist. The limited, variable supply of FA from natural product isolation, however, has impeded its biological exploration and potential drug development. Accordingly, we have developed a biomimetic and scalable total synthesis of FA in nine steps that provides a solution to the supply of FA. Enabled by chemical synthesis, the in vivo efficacy of FA has been further investigated. The results showed that FA alleviates hepatocyte lipid accumulation and cell death in an FXR-dependent manner. Moreover, treatment of bile duct ligation (BDL)-induced liver disorder with FA ameliorates pathological features in mice. Therefore, our work lays the foundation to develop new small-molecule FXR agonists as a potential therapy for liver diseases.