6-Bromoindole Derivatives from the Icelandic Marine Sponge <em>Geodia barretti</em>: Isolation and Anti-Inflammatory Activity
Xiaxia Di | Caroline Rouger | Ingibjorg Hardardottir | Jona Freysdottir | Tadeusz F. Molinski | Deniz Tasdemir | Sesselja Omarsdottir
An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge <i>Geodia barretti</i>. This includes three new metabolites, namely geobarrettin A–C (<b>1</b>–<b>3</b>) and four known compounds, barettin (<b>4</b>), 8,9-dihydrobarettin (<b>5</b>), 6-bromoconicamin (<b>6</b>), and <span style="font-variant: small-caps;">l</span>-6-bromohypaphorine (<b>7</b>)<i>.</i> The chemical structures of compounds <b>1</b>–<b>7</b> were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (<b>1</b>) was assigned by ECD analysis and Marfey’s method employing the new reagent <span style="font-variant: small-caps;">l</span>-<i>N</i><sup>α</sup>-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (<span style="font-variant: small-caps;">l</span>-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both <b>2</b> and <b>3</b> reduced DC secretion of IL-12p40, but <b>3</b> concomitantly increased IL-10 production. Maturing DCs treated with <b>2</b> or <b>3</b> before co-culturing with allogeneic CD4<sup>+</sup> T cells decreased T cell secretion of IFN-γ, indicating a reduction in Th1 differentiation. Although barettin (<b>4</b>) reduced DC secretion of IL-12p40 and IL-10 (IC<sub>50</sub> values 11.8 and 21.0 μM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of <b>4</b> did not affect the ability of T cells to secrete IFN-γ or IL-17, but reduced their secretion of IL-10. These results indicate that <b>2</b> and <b>3</b> may be useful for the treatment of inflammation, mainly of the Th1 type.
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