Abstract
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.
Highlights
Many chronic illnesses, including cancer, neurological diseases, diabetes, and autoimmune diseases, exhibit dysregulation of pathways that have been linked to inflammation [1,2]
We examined whether compounds 2, 3, and 4 affected cytokine secretion by the dendritic cells (DCs) in a a dose-dependent manner
Compounds 2 and 3 inhibited IL-12p40 production by DCs and DCs treated with compounds 2 and 3 reduced IFN-γ secretion by co-cultured T cells, reduced Th1 responses, which are linked to inflammatory disorders and many chronic inflammatory diseases [48,49]
Summary
Many chronic illnesses, including cancer, neurological diseases, diabetes, and autoimmune diseases, exhibit dysregulation of pathways that have been linked to inflammation [1,2]. A vast number of unique marine natural products possessing in vitro and in vivo anti-inflammatory activity. Mar. Drugs 2018, 16, 437; doi:10.3390/md16110437 www.mdpi.com/journal/marinedrugs. Mar. Drugs 2018, 16, 437 have been isolated [3,4], no marine-derived anti-inflammatory agent is currently on the market. The search and development of new natural products to treat chronic inflammatory diseases is of great importance [5,6]. Due to their phenomenal biological and chemical diversity, are considered as a notable source of natural products with potential anti-inflammatory activity [5,7,8]
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