SMART-Guided Isolation and Identification of Seven-Membered Cembranolides with Anti-Inflammation Activity from the Soft Coral Sinularia mollis

The first systematic chemical investigation on <i>Sinularia mollis</i> resulted in the isolation and identification of 36 seven-membered cembranolides, including 14 new compounds named sinumollolides A-N (<b>1</b>-<b>14</b>) and 22 known analogs (<b>15</b>-<b>36</b>) by HSQC-based small molecule accurate recognition technology (SMART). Their structures were characterized by spectroscopic methods (1D/2D NMR and UV), HRESIMS, quantum chemical calculations (DP4+ analysis and ECD calculations), and X-ray diffraction analysis. In zebrafish assays, compounds <b>1</b>, <b>2</b>, <b>4</b>, and <b>5</b> exhibited anti-inflammatory activity at 20 μM by inhibiting the number of macrophages around the neuromasts, with inhibition rates ranging from 30.4% to 45.6%. Moreover, the two most bioactive and less toxic compounds, <b>1</b> and <b>5,</b> featuring a 14-membered macrocyclic lactone scaffold with several hydroxyl groups and a seven-membered <i>α</i>, <i>β</i>-unsaturated lactone moiety, can inhibit inflammation by suppressing the secretion of inflammatory cytokines at 10 μM in LPS-stimulated BV-2 cells.