| Summary: | Sponge-derived scalaranes are remarkable sesterterpenoids previously found to exhibit profound inhibitory effects against neutrophilic inflammation. In our current work, we constructed the metabolomic profile of marine sponge <i>Lendenfeldia</i> sp. for the first time using a tandem mass spectrometry (MS/MS) molecular networking approach. The results highlighted the rich chemical diversity of these scalaranes, motivating us to conduct further research to discover novel scalaranes targeting neutrophilic inflammation. MS- and NMR-assisted isolation and elucidation led to the discovery of seven new homoscalaranes, lendenfeldaranes K–Q (<b>1</b>–<b>7</b>), characterized by methylation at C-24, together with five known derivatives, lendenfeldarane B (<b>8</b>), 25-nor-24-methyl-12,24-dioxoscalar-16-en-22-oic acid (<b>9</b>), 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (<b>10</b>), felixin B (<b>11</b>), and 23-hydroxy-20-methyldeoxoscalarin (<b>12</b>). Scalaranes <b>1</b>–<b>4</b> and <b>6</b>–<b>12</b> were assayed against superoxide anion generation and elastase release, which represented the neutrophilic inflammatory responses of respiratory burst and degranulation, respectively. The results indicated that <b>1</b>–<b>3</b> and <b>6</b>–<b>12</b> exhibited potential anti-inflammatory activities (IC<sub>50</sub> for superoxide anion scavenging: 0.87~6.57 μM; IC<sub>50</sub> for elastase release: 1.12~6.97 μM).
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