Abstract
Two new polyketide compounds, asperulosins A and B (1–2), and one new prenylated small molecule, asperulosin C (3), along with nine known compounds (4–12), were isolated and identified from a fungus Aspergillus rugulosa. Their structures were extensively elucidated via HRESIMS, 1D, and 2D NMR analysis. The absolute configurations of the new compounds were determined by the comparison of their electronic circular dichroism (ECD), calculated ECD spectra, and the detailed discussion with those in previous reports. Structurally, compounds 1 and 2 belonged to the polyketide family and were from different origins. Compound 2 was constructed by five continuous quaternary carbon atoms, which occur rarely in natural products. All of the isolates were evaluated for anti-inflammatory activity against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Among those, compounds 1 and 5 showed a significant inhibitory effect on NO production with IC50 values of 1.49 ± 0.31 and 3.41 ± 0.85 μM, respectively. Additionally, compounds 1 and 5 markedly increased the secretion of anti-inflammatory cytokine IL10 while suppressing the secretion of pro-inflammatory cytokines IL6, TNF-α, IFN-γ, MCP-1, and IL12. Besides, 1 and 5 inhibited the transcription level of pro-inflammatory macrophage markers IL6, IL1β, and TNF-α while remarkably elevating the anti-inflammatory factor IL10 and M2 macrophage markers ARG1 and CD206. Moreover, 1 and 5 restrained the expression and nuclear translocation of NF-κB, as well as its downstream signaling proteins COX-2 and iNOS. All these results suggest that 1 and 5 have potential as anti-inflammatory agents, with better or comparable activities than those of the positive control, dexamethasone.
Highlights
Small molecular polyketide compounds have been considered commercially valuable for their wide range of functions, structural diversity, and outstanding pharmaceutical activities (González-Medina et al, 2017; Newman and Cragg, 2020)
The 13C NMR and DEPT spectroscopic data (Table 1; Supplementary Figure S2) of 1 revealed 17 carbon resonances that were attributed to four methyls at δC 11.3 (C-14), 12.5 (C-15), 21.4 (C-16), and 19.1 (C-17), three sp3 methylenes at δC 30.1 (C-4), 44.7 (C-11), and 30.0 (C-13), five olefinic methines at δC 121.6 (C-2), 144.7 (C-3), 122.2 (C-6), 138.7 (C-7), and 142.4 (C-9), three sp3 methines at δC 78.6 (C-5), 30.3 (C-10), and 32.2 (C-12), one olefinic quaternary carbon at δC 130.7 (C-8), and one ester carbonyl at δC 164.1 (C-1)
Using the search network SciFinder, compound 1 was determined as a unique linear chain compound with an α, β-unsaturated monocyclic lactone structure originating from the polyketide family
Summary
Small molecular polyketide compounds have been considered commercially valuable for their wide range of functions, structural diversity, and outstanding pharmaceutical activities (González-Medina et al, 2017; Newman and Cragg, 2020). Lovastatin, daunomycin, and tetracycline are all small molecular polyketides (Herkommer et al, 2014; Van Wagoner et al, 2014). Recent studies have shown that uncontrolled chronic inflammation is associated with multiple diseases, including rheumatoid arthritis, metabolic syndrome, diabetes, and cancer (Okamoto et al, 2007). Overproduction of proinflammatory factors including nitric oxide (NO) and cyclooxygenase-2 (COX-2) and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) impulses the inflammatory response (Lee et al, 2016). The activation of the transcription factor nuclear factor-kappa B (NFκB) accelerates the immune response via the transcriptional activation of the pro-inflammatory factors and cytokines mentioned above (Alvarez-Suarez et al, 2017)
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