New Sesquiterpenoids from the Mangrove-Derived Fungus Talaromyces sp. as Modulators of Nuclear Receptors

Four new sesquiterpenoids, talaroterpenes A-D (<b>1</b>-<b>4</b>), were isolated from the mangrove-derived fungus <i>Talaromyces</i> sp. SCSIO 41412. The structures of compounds <b>1</b>-<b>4</b> were elucidated through comprehensive NMR and MS spectroscopic analyses. The absolute configurations of <b>1</b>-<b>4</b> were assigned based on single-crystal X-ray diffraction and calculated electronic circular dichroism analysis. Talaroterpenes A-D (<b>1</b>-<b>4</b>) were evaluated with their regulatory activities on nuclear receptors in HepG2 cells. Under the concentrations of 200 μM, <b>1</b>, <b>3</b> and <b>4</b> exhibited varying degrees of activation on <i>ABCA1</i> and <i>PPARα</i>, while <b>4</b> showed the strongest activities. Furthermore, <b>4</b> induced significant alterations in the expression of downstream target genes <i>CLOCK</i> and <i>BMAL1</i> of RORα, and the in silico molecular docking analysis supported the direct binding interactions of <b>4</b> with RORα protein. This study revealed that talaroterpene D (<b>4</b>) was a new potential non-toxic modulator of nuclear receptors.