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 (<b>1</b>), 13-<i>acetyl</i>-nocardifuran A (<b>2</b>), 15-<i>epi</i>-nocardifuran A (<b>3</b>), nocardifuran B (<b>4</b>), and nocardifuran C (<b>5</b>), were isolated from the Gause liquid fermentation of the marine-derived <i>Nocardiopsis</i> sp. ZSN1. Their structures were elucidated through HRESIMS, 1D and 2D NMR spectroscopic data analysis, and ECD calculations. Compounds <b>1</b>-<b>4</b> were identified as derivatives of MGF with its rearrangement of furan or pyran derivatives, while compound <b>5</b> 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.