C-Geranylated Flavanones from Paulownia tomentosa Fruits as Potential Anti-inflammatory Compounds Acting via Inhibition of TNF-α Production

Abstract

Eleven new C-geranylated flavonoids, tomentodiplacones L, M, and N (1, 2, 10), tomentodiplacol B (3), 3',4'-O-dimethyl-5'-hydroxydiplacone (4), mimulones F, G, and H (5, 6, 7), paulowniones A (8) and B (9), tomentone (11), and 3',4',5'-trimethoxyflavanone (12), together with 11 known flavonoids (13-23), were isolated from fruits of Paulownia tomentosa. The structures of the compounds isolated were determined by spectroscopic data interpretation. The ability of compounds 1-23, together with the nonprenylated flavanones eriodictyol (24) and naringenin (25), to reduce the production of the pro-inflammatory cytokine TNF-α in THP-1 cells after bacterial lipopolysaccharide stimulation was evaluated using an in vitro screening test. The preliminary structure-activity relationships of these derivatives were also studied, and the correlation of their TNF-α inhibitory activity with their lipophilicity was investigated. The mechanism of action of compounds with significant antiphlogistic potential (4, 7, 10, 14, 22) was investigated. These compounds reduced both the secretion of TNF-α and the level of its corresponding mRNA. Compounds 4, 7, 10, 14, and 22 inhibited the nuclear translocation of NF-κB, which controls the expression of TNF-α, by blocking the degradation of IκB.

An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever

“…Silybin (silibinin, silymarin) has shown antiviral activity against hepatitis C virus [63] and chikungunya virus [64]. C -geranylated flavanones from Paulownia tomentosa fruits have shown antibacterial [65, 66], cytotoxic [67], and anti-inflammatory [68] activities as well as SARS-CoV protease inhibitory activity [69]. Diplacone showed excellent docking properties with DENV MTase (Table 3 ) and both 3ʹ- O -methyldiplacone and 3ʹ- O -methyldiplacol docked well with the ATP site of DENV helicase (Table 2 ).…”

Paulownia C-geranylated flavonoids: their structural variety, biological activity and application prospects

“…However, if the geranyl side chain was modified by the formation of a pyran ring with a double bond between C-1″ and C-2″, as in the structures of compounds 62 and 57-61, the conjugated chromophoric system between the pyran ring, the ring A and the C-4 carbonyl group in the flavonoid skeleton caused an unusual UV spectrum with two main maximum absorptions at approximately λ 230 and 275 nm, and a shoulder peak at approximately λ 290 and 360 nm. This kind of modified geranyl substituent could clearly influence 19 the UV spectrum obviously (Hanáková et al 2015.…”

“…Compounds 2-5 were all active (EC 50 \10 µM) against breast carcinoma (MCF -7), T-lymphoblastic leukaemia (CEM), multiple myeloma (RPMI 8226 and U266), cervical cancer cells (HeLa), monocytic leukaemia cell lineTHP-1, and the normal BJ fibroblast cell line (Š mejkal et al 2010). Moreover,compounds 1,6,8,10,15,39,56, and 64 also showed potential cytotoxic effects all with IC 50 values\10 μM on the viability of THP-1 cells (Hanáková et al 2015). In addition, paucatalinone A (19) displayed good antiproliferative effects on human lung cancer cells A549 (IC 50 8.9 μM) with a clear increase in the percentage of cells in G1 phase and a decrease in the percentage of cells in S and G2/ M phases in comparison with the control cells (Gao et al 2015).…”

“…In addition, the unmodified geranyl group at the C-6 position seemed to be crucial for these various biological effects in vitro and in vivo (Vochyánová et al 2015) of C-geranylated flavonoids, however, hydroxylation on the distal end of the geranyl substituent decreased the biological activities revealed by different research (Alcaráz et al 2000;Š mejkal et al 2010;Hanáková et al 2017;Ryu et al 2017). The presence of a β-carbon (proximal) OH group on the geranyl chain did not affect the cytotoxicity (Hanáková et al 2015). In addition, the 3,4-dihydro-2H-pyran moiety in some Paulownia C-geranylated flavonoids seemed to be positive for their SARS-CoV PLpro enzyme inhibition .…”

“…In addition, the effects of 21 Paulownia Cgeranylated flavonoids on the secretion of the typical pro-inflammatory cytokine TNF-α in LPS-stimulated THP-1 cell from were evaluated. Compounds 2, 4, 8, 38 and 56 could affect the secretion of TNF-α at 2.0 μM more than prednisone as the positive control, and mimulone H (38) and tomentodiplacone N (56) significantly increased the level of reactive oxygen species (ROS) in the THP-1 cells without LPS stimulation (Hanáková et al 2015). In another biological activity assay on human alveolar basal epithelial cells (A549 cells), compounds 23, 26, 35, 52-54 significantly inhibited TNF-α-induced IL-8 levels at a concentration of 2.5 μM without detectable cell toxicity ).…”