Nitrogen-Containing Sesquiterpenoids from the Sponge <i>Stellitethya ingens</i> as TRPA1 Antagonists

Biological screening of marine sponge extracts against transient receptor potential ankyrin 1 (TRPA1) identified <i>Stellitethya ingens</i> as a promising source of secondary metabolites with potential antagonistic activity. A comprehensive investigation yielded 13 nitrogen-containing sesquiterpenoids (<b>1</b>-<b>13</b>) and eight glycerophosphocholines (<b>16</b>-<b>23</b>), including four previously undescribed bisabolene-type analogues (<b>3</b> and <b>6</b>-<b>8</b>) and one new phosphatidylcholine derivative (<b>23</b>). Structures were elucidated by extensive NMR and HR-ESIMS/MS analyses. The absolute configuration of <b>6</b> was determined via asymmetric synthesis, while that of <b>7</b> was assigned from NOE correlations and pyridine-induced deshielding effects. Isolated compounds were evaluated for TRPA1 antagonistic activity using a FLIPR-based calcium mobilization assay, and compounds <b>1</b>, <b>3</b>, and <b>12</b> exhibited moderate inhibitory effects without cytotoxicity against HEK cells. This study represents the first report of secondary metabolites from the genus <i>Stellitethya</i> and highlights bisabolene- and pupukeanane-type scaffolds as novel frameworks for TRPA1 antagonists, thereby expanding the chemical diversity of the underexplored order Tethyida and offering new chemotypes with potential relevance to analgesic drug discovery.