Abstract
Four unusual meroterpenoids, dysivillosins A–D (1–4), were isolated from an organic extract of the marine sponge Dysidea villosa collected from the South China Sea. Their planar structures were determined by 1D and 2D NMR and HRESIMS techniques, while the relative and absolute configurations were elucidated by NOESY experiments and comparison between the calculated and experimental ECD spectra. To the best of our knowledge, dysivillosins A–D are the first examples of terpene-polyketide-pyridine hybrid metabolites from the nature. Anti-allergic activity evaluation showed that compounds 1–4 potently inhibited the release of β-hexosaminidase, a marker of degranulation, in a dose-dependent manner with IC50 values of 8.2–19.9 μM. Additionally, the four meroterpenoids could downregulate the production of lipid mediator leukotrienes B4 (LTB4) and pro-inflammatory cytokine interleukin-4 (IL-4) in the antigen-stimulated RBL-2H3 mast cells. Further biological investigations revealed that dysivillosin A (1) could suppress the phosphorylation of Syk and PLCγ1 in IgE/FcɛRI/Syk signaling pathway, which resulted in the inhibition of degranulation and the downregulation of LTB4 and IL-4 production in mast cells.
Highlights
Mast cells have long been considered as important effector cells in immunoglobulin E (IgE)-associated immune responses1
All the four compounds were evaluated for their anti-allergic activity, they could significantly inhibit β-hexosaminidase and the production of leukotrienes B4 (LTB4) and IL-4 in antigen-stimulated RBL-2H3 mast cells
The IR spectrum indicated the presence of hydroxy (3185 cm−1), carbonyl (1713 and 1662 cm−1), and benzene (1591 and 1440 cm−1) groups7, 8, whereas the UV absorption maxima at 216, 255, and 303 nm were indicative of a 2-pyridone unit9
Summary
Dysivillosin A [1] was isolated as an amorphous powder ([α]D26 + 26.5) and gave a molecular formula of C26H33NO3 with 11 degrees of unsaturation, as determined by HRESIMS data. The aromatic proton H-18 in the hydroquinone unit showed NOESY correlations with H-23 in the 2-pyridone moiety, which suggested the presence of two possible configurations (a and b) of the axial chiral center C-19–C-22 (Fig. 2). Comprehensive analysis of the 1H and 13C NMR data of 3 (Table 1) showed that the only difference between 1 and 3 was the position of 2-pyridone, which tethered at C-18 in 3 rather than at C-19 in 1 This assignment was supported by HMBC correlations of H-19/C-22 and H-23/C-18 as well as the NOESY correlation of H-19/H-23 (Figure S1). These results highlight the potential of dysivillosin A [1] as a new chemotherapeutic scaffold targeting Syk-associated allergy
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