6-Bromoindole Derivatives from the Icelandic Marine Sponge Geodia barretti: Isolation and Anti-Inflammatory Activity

• Main Authors: Di, Xiaxia, Rouger, Caroline, Hardardottir, Ingibjorg, Freysdottir, Jona, Molinski, Tadeusz F, Tasdemir, Deniz, Omarsdottir, Sesselja
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: eScholarship, University of California 2018
• Subjects: Biomedical and Clinical Sciences; Chemical Sciences; Immunology; Inflammatory and immune system; Alkaloids; Animals; Anti-Inflammatory Agents; Aquatic Organisms; CD4-Positive T-Lymphocytes; Cell Differentiation; Cells; Cultured; Coculture Techniques; Dendritic Cells; Geodia; Humans; Iceland; Indoles; Inhibitory Concentration 50; Interleukin-10; Interleukin-12 Subunit p40; Peptides; Cyclic; Stereoisomerism; 6-bromoindole; Geodia barretti; anti-inflammatory activity; T cell differentiation; Physical Chemistry (incl. Structural); Pharmacology and Pharmaceutical Sciences; Medicinal & Biomolecular Chemistry; Physical chemistry; Arctic
• Online Access: https://escholarship.org/uc/item/10s7c5mb

An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti. This includes three new metabolites, namely geobarrettin A⁻C (1⁻3) and four known compounds, barettin (4), 8,9-dihydrobarettin (5), 6-bromoconicamin (6), and l-6-bromohypaphorine (7). The chemical structures of compounds 1⁻7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (1) was assigned by ECD analysis and Marfey's method employing the new reagent l-Nα-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4⁺ T cells decreased T cell secretion of IFN-γ, indicating a reduction in Th1 differentiation. Although barettin (4) reduced DC secretion of IL-12p40 and IL-10 (IC50 values 11.8 and 21.0 μM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of 4 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 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type.