Bioactive α-Pyrone Derivatives from the Endophytic Fungus Diaporthe sp. CB10100 as Inducible Nitric Oxide Synthase Inhibitors

Abstract

Inducible nitric oxide synthase (iNOS) produces NO from l-arginine and plays critical roles in inflammation and immune activation. Selective and potent iNOS inhibitors may be potentially used in many indications, such as rheumatoid arthritis, pain, and neurodegeration. In the current study, five new compounds, including a dibenzo-α- pyrone derivative ellagic acid B (5) and four α-pyrones diaporpyrone A–D (9–12), together with three known compounds (6–8), were isolated from the endophytic fungus Diaporthe sp. CB10100. The structures of these new natural products were unambiguously elucidated using NMR, HRESIMS or electronic circular dichroism calculations. Ellagic acid B (5) features a tetracyclic 6/6/6/6 ring system with a fused 2H-chromene, which is different from ellagic acid (4) with a fused 2H-chromen-2-one. Both 2-hydroxy-alternariol (6) and alternariol (7) reduced the expression of iNOS at protein levels in a dose-dependent manner, using a lipopolysaccharide (LPS)-induced RAW264.7 cell models. Also, they decreased the protein expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein 1. Importantly, 6 and 7 significantly reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells. Molecular docking of 6 and 7 to iNOS further suggests that both of them may interact with iNOS. Our study suggests that 6 and 7, as well as the alternariol scaffold may be further developed as potential iNOS inhibitors.

Secondary metabolites of Diaporthe sp., isolated from the Cameroonian medicinal plant Trema guineensis (Schumach. & Thonn.) Ficalho

“…Alternariol is a dibenzo-𝛼-pyrone that constitutes an important group of heptaketide coumarin derivatives with a fused tricyclic ring [29]. Dibenzo-𝛼-pyrones are usually isolated from fungi [30,31], mycobionts [15,16], plants [32,33], and animal feces containing the transformed products of plant-derived ellagitannins and ellagic acid by intestinal bacteria [34,35]. They are known for their wide range of biological activities including, antioxidant [34], antiallergic [36], antimicrobial [37],…”

Bioactive α-Pyrone Analogs from the Endophytic Fungus Diaporthe sp. CB10100: α-Glucosidase Inhibitory Activity, Molecular Docking, and Molecular Dynamics Studies

“…CB10100 that was isolated from Sinomenium acutum. These products consist of ellagic acid B, a dibenzo-α-pyrone derivative, and four α-pyrones, diaporpyrones A-D (S1-S4) [17]. strong inhibitory effects on the proliferation of B cells caused by LPS, with IC50 values of 6.7 and 3.8 µM, respectively [11].…”

“…CB10100 that was isolated from Sinomenium acutum. These products consist of ellagic acid B, a dibenzo-α-pyrone derivative, and four α-pyrones, diaporpyrones A-D (S1-S4) [17]. In the present work, further chemical studies were performed with this fungus to identify novel bioactive chemicals.…”

Chemical Investigation of Endophytic Diaporthe unshiuensis YSP3 Reveals New Antibacterial and Cytotoxic Agents

“…Many other species of Diaporthe are reported as non-pathogenic endophytes and recognized as producers of numerous secondary metabolites with a range of biological potencies, including antifungal [ 7 ], antibacterial [ 8 ], cytotoxic [ 9 ], anti-inflammatory [ 10 ], antioxidant [ 11 ], phytotoxic [ 12 ], and anti-influenza A virus (IAV) potencies [ 13 ]. Most of the compounds produced by this genus have been classified into polyketides, including xanthones, chromanones, benzofuranones, quinones, phenols and pyrones, terpenoids, steroids, lactones, alkaloids, and fatty acids [ 14 , 15 ].…”