Non-Steroidal FXR Agonistic Dimeric 2-Methyl-4-(1-glycerol)furan with Lipid-Lowering Activities from Marine-Derived Nocardiopsis sp. ZSN1.

Five novel 2-methyl-4-(1-glycerol)furan (MGF) dimers, namely nocardifuran A (1), 13-acetyl-nocardifuran A (2), 15-epi-nocardifuran A (3), nocardifuran B (4), and nocardifuran C (5), were isolated from the Gause liquid fermentation of the marine-derived Nocardiopsis sp. ZSN1. Their structures were elucidated through HRESIMS, 1D and 2D NMR spectroscopic data analysis, and ECD calculations. Compounds 1-4 were identified as derivatives of MGF with its rearrangement of furan or pyran derivatives, while compound 5 was identified as the derivative of MGF with an indole derivative. These MGF dimers, representing a new structural class, were isolated from a marine microorganism for the first time, thereby enhancing chemical diversity. Screening for farnesoid X receptor (FXR) agonistic activity revealed that MGF dimers could activate FXR. Furthermore, bioactivity evaluations demonstrated that these types of compounds exhibited lipid-lowering activity with lower cytotoxicity in vitro. Consequently, our findings not only contribute to the chemical diversity of marine-derived MGF-type natural products but also offer potential insights into the development of MGF dimers as lead compounds for FXR agonists in the dysregulation of hepatic lipid metabolism.