Penazaphilones J–L, Three New Hydrophilic Azaphilone Pigments from Penicillium sclerotiorum cib-411 and Their Anti-Inflammatory Activity

Abstract

Penazaphilones J–L (1–3), three new hydrophilic azaphilone pigments, as well as six known compounds, were discovered from the filamentous fungus Penicillium sclerotiorum cib-411. Compounds 1–3 were structurally elucidated by the detailed interpretation of their 1D and 2D NMR spectroscopic data. Compound 1 is an unprecedented hybrid of an azaphilone and a glycerophosphate choline. Compounds 2 and 3 each contain an intact amino acid moiety. The bioassay showed that compound 3 exhibited significant anti-inflammatory activity. Concretely, compound 3 significantly suppressed the NO production, the expression levels of COX-2, IL-6, IL-1β, and iNOS mRNA in LPS-stimulated RAW264.7 cells. Moreover, treatment of compound 3 prevented the translocation of NF-κB through inhibiting the phosphorylation of PI3K, PDK1, Akt, and GSK-3β. Thus, the inhibition of compound 3 against LPS-induced inflammation should rely on its inactivation on NF-κB.

Comprehensive Analysis of Penicillium Sclerotiorum: Biology, Secondary Metabolites, and Bioactive Compound Potential─A Review

“…For instance, Peniazaphilone A (27) , (29) , (30) , and compound (43) exhibited moderate activity by reducing nitric oxide (NO) release in LPS-induced RAW264.7 cells, with IC 50 values ranging from 4.71 to 42.23 μmol/L. ,, Penazaphilone L (26) significantly reduced NO generation and COX-2, IL-6, IL-1β, and iNOS mRNA expression. They also inhibited PI3K, PDK1, Akt, and GSK-3β phosphorylation, which stopped NF-κB translocation . Additionally, compounds Sclerketide A (78) , Sclerketide C (64) , and Sclerketide D (80) exhibited significant inhibition of NO production in the range of 2.5–18.0 μM, potentially downregulating iNOS and COX-2 expression at the mRNA level. , Penazaphilones A (15) , (19) , (20) , and (22) demonstrated varying degrees of NO inhibition, while peniscmeroterpenoids A (65) and D (68) showed suppression of NO production and pro-inflammatory mediators. , Also, penicilazaphilones F (36) and G (37) demonstrated inhibitory effects on lipopolysaccharide-induced nitric oxide (NO) production in BV-2 cells, showing IC 50 values of 31.7 and 34.5 μM, respectively .…”

“…They also inhibited PI3K, PDK1, Akt, and GSK-3β phosphorylation, which stopped NF-κB translocation. 32 Additionally, compounds Sclerketide A (78), Sclerketide C (64), and Sclerketide D (80) exhibited significant inhibition of NO production in the range of 2.5−18.0 μM, potentially downregulating iNOS and COX-2 expression at the mRNA level. 44,46 Penazaphilones A (15), ( 19), (20), and ( 22) demonstrated varying degrees of NO inhibition, while peniscmeroterpenoids A (65) and D (68) showed suppression of NO production and proinflammatory mediators.…”

“…Secondary metabolites identified from the P. sclerotiorum extract possess antimicrobial properties. Penicilazaphilone C (33) displayed potent antibacterial effects against Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus, surpassing the antibacterial activity of Penicilazaphilone B (32). 24 This compound emerged as a new azaphilonidal derivative, exhibiting strong antimicrobial properties along with selective cytotoxic effects.…”

“…Some of the methods are by using column chromatography such as Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), High-resolution electrospray ionization mass spectrometry (HRESIMS), Mass Spectroscopy (MS), Nuclear Magnetic Resonance (NMR), X-ray single-crystal diffraction, and Ultraviolet Visible Spectroscopy (UV–vis). ,, In this review, total, 85 secondary metabolites were described to be biosynthesized by this P. sclerotiorum (Table ), encompassing azaphilonidal derivatives, meroterpenoids, polyketides, and peptides. Most of the metabolites that can be extracted and isolated from P. sclerotiorum azaphilones groups such Chlorogeumasnol ( 1 ), epi -geumsanol D ( 2 ), 8a- epi -eupenicilazaphilone C ( 3 ), 8a- epi -hypocrellone A ( 4 ), eupenicilazaphilone C (5) , 5-bromoisorotiorin ( 6 ), 5-bromosclerotiorin (7) , 5-chloro-3-[(1E,3R,4R,5S)-3,4-dihydroxy-3,5-dimethyl-1-hepten-1-yl]-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-(7R,8R,8aS)-6 H -2-benzopyran-6-one (8) , 7-deacetylisochromophilone VI (9) , ((1 E ,3 E )-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (10) , Isochromophilone IV (11) , Isochromophilone H (12) , Isochromophilone J (13) , Ochlephilone (14) , Penazaphilones A–I (15–23) , Penazaphilone J–L (24–26) , , Peniazaphilone A–E (27–31) , ,, Penicilazaphilone B (32) , Penicilazaphilone C (33) , Penicilazaphilones D-E (34–35), Penicilazaphilone F–G (36–37) , Penicilazaphilone I–N (38–43) , Penicilazaphilones H (44) , Penidioxolane C–D (45–46) , Sclerazaphilone A–I (47–55) , Sclerotioramine (56) , Sclerotiorin (57) , Sclerotiorin A–E (58–62) , and Sclerketide B-C (63–64) (Figures –). According to Jiang et al meroterpenoids are a family of secondary metabolites that are frequently discovered in plants, marine creatures, and fungus .…”

“…Several compounds, including Azaphilones Peniazaphilone A (27) , Peniazaphilone C (29) , , Peniazaphilone D (30) , , Penazaphilones L (26) , Penicilazaphilone N (43) , Sclerketide A (78) , Sclerketide C (64) , Sclerketide D (80) , Penazaphilones A (15) , Penazaphilones E (19) , Penazaphilone F (20) , Penazaphilone H (22), peniscmeroterpenoids A (65) and D (68) , penicilazaphilones F (36) and G (37) , Sclerazaphilone E (51), Sclerazaphilone F (52) , and Sclerazaphilone G (53) demonstrated varied but noteworthy anti-inflammatory activities . For instance, Peniazaphilone A (27) , (29) , (30) , and compound (43) exhibited moderate activity by reducing nitric oxide (NO) release in LPS-induced RAW264.7 cells, with IC 50 values ranging from 4.71 to 42.23 μmol/L. ,, Penazaphilone L (26) significantly reduced NO generation and COX-2, IL-6, IL-1β, and iNOS mRNA expression.…”