7-Hydroxyflavone

Inhibition of Enterovirus 71 replication by 7-hydroxyflavone and diisopropyl-flavon7-yl Phosphate.[Pubmed: 24664133]

PLoS One. 2014 Mar 24;9(3):e92565.

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which has been continuously prevalent in Asia in recent years. In children, severe cases can lead to death, and no prophylactic or therapeutic measures against EV71 infection are available. The 3C proteases of EV71 play an important role in viral replication and are an ideal drug target. In previous work, we resolved the crystal structure for EV71 3Cpro.
METHODS AND RESULTS:
In this report, we took advantage of the automated docking program AutoDock 4.0 to simulate EV71 3Cpro-ligand conformation. 7-Hydroxyflavone (HF) and its phosphate ester(FIP) were predicted to bind with EV71 3Cpro.In an in vitro protease inhibition assay, FIP inhibited EV71 3Cpro protease activity. Both flavones were highly active against EV71, protecting cells from EV71 infection. Replication of viral RNA and formation of EV71 plaque were all strongly inhibited in cells.
CONCLUSIONS:
These results indicated that HF and FIP may serve as potential protective agents in the treatment of patients with chronic EV71 infection.

Inhibitory effects and underlying mechanism of 7-hydroxyflavone phosphate ester in HeLa cells.[Pubmed: 22574207]

PLoS One. 2012;7(5):e36652.

Chrysin and its phosphate ester have previously been shown to inhibit cell proliferation and induce apoptosis in Hela cells; however, the underlying mechanism remains to be characterized.
METHODS AND RESULTS:
In the present study, we therefore synthesized diethyl flavon-7-yl phosphate (FP, C(19)H(19)O(6)P) by a simplified Atheron-Todd reaction, and explored its anti-tumor characteristics and mechanisms. Cell proliferation, cell cycle progression and apoptosis were measured by MTS, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling techniques, respectively in human cervical cancer HeLa cells treated with 7-Hydroxyflavone (HF) and FP. p21, proliferating cell nuclear antigen (PCNA) and cAMP levels in Hela cells were analyzed by western blot and radioimmunoassay. Both HF and FP inhibited proliferation and induced apoptosis in HeLa cells via induction of PCNA/p21 expression, cleaved caspase-3/poly (ADP-ribose) polymerase (PARP)-1, elevation of cAMP levels, and cell cycle arrest with accumulation of cells in the G0/G1 fraction. The effects of FP were more potent than those of HF. The interactions of FP with Ca(2+)-calmodulin (CaM) and Ca(2+)-CaM-phosphodiesterase (PDE)1 were explored by electrospray ionization-mass spectrometry and fluorescence spectra. FP, but not HF, formed non-covalent complexes with Ca(2+)-CaM-PDE1, indicating that FP is an inhibitor of PDE1, and resulting in elevated cellular cAMP levels. It is possible that the elevated cAMP levels inhibit growth and induce apoptosis in Hela cells through induction of p21 and cleaved caspase-3/PARP-1 expression, and causing down-regulation of PCNA and cell cycle arrest with accumulation of cells in the G0/G1 and G2/M fractions. In conclusion, FP was shown to be a Ca(2+)-CaM-PDE inhibitor, which might account for its underlying anti-cancer mechanism in HeLa cells.
CONCLUSIONS:
These observations clearly demonstrate the special roles of phosphorylated flavonoids in biological processes, and suggest that FP might represent a potential new drug for the therapy of human cervical carcinoma.

Differential roles of 3-Hydroxyflavone and 7-Hydroxyflavone against nicotine-induced oxidative stress in rat renal proximal tubule cells.[Pubmed: 28640852 ]

PLoS One. 2017 Jun 22;12(6):e0179777.

Plant flavonoids are well known as antioxidants against oxidative stress induced by exposure to external pollutants. Nicotine (NIC) is one of those agents which increases renal oxidative stress, an important factor in the pathogenesis of renal epithelial injury in smokers. Although several studies had been conducted on flavonoids and oxidative stress, the mechanism of the protective pathways are not fully understood.
METHODS AND RESULTS:
Here, we present studies on antioxidant properties of two mono-hydroxyflavone isomers, 3-hydroxyflanove (3HF)- and 7-Hydroxyflavone (7HF), against nicotine-associated oxidative stress and injury in cultured renal proximal tubule cells and correlate their antioxidant properties with their chemical structure. Our data clearly demonstrates, for the first time, that while both 3HF and 7HF protect renal cells from NIC-associated cytotoxicity, the mechanism of their action is different: 3HF elicits protective activity via the PKA/CREB/MnSOD pathway while 7HF does so via the ERK/Nrf2/HO-1 pathway. Molecular docking and dynamics simulations with two major signaling pathway proteins showed significant differences in the binding energies of 3HF (-5.67 and -7.39 kcal.mol-1) compared to 7HF (-5.41 and -8.55 kcal.mol-1) in the matrices of CREB and Keap1-Nrf2 proteins respectively, which corroborate with the observed differences in their protective properties in the renal cells.
CONCLUSIONS:
The implications of this novel explorative study is likely to promote the understanding of the mechanisms of the antioxidative functions of different flavones.

Inhibition of pro-inflammatory mediators in RAW264.7 cells by 7-hydroxyflavone and 7,8-dihydroxyflavone.[Pubmed: 28295316 ]

J Pharm Pharmacol. 2017 Jul;69(7):865-874.

Flavonoids are a class of compounds that having the benzo-γ-pyrone skeleton, which possess anti-inflammatory properties in vitro and in vivo. The aim of this study was to investigate the inhibition of two flavonoids 7-Hydroxyflavone (HF) and 7,8-dihydroxyflavone (DHF) on the production of pro-inflammatory mediators in RAW264.7 cells activated by lipopolysaccharides (LPS).
METHODS AND RESULTS:
For this purpose, we selected four pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2 ), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as markers to evaluate the anti-inflammatory activity of HF and DHF. In this regard, we showed that HF and DHF dose-dependently reduced the production of NO, PGE2 , TNF-α and IL-6 through downregulating mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), TNF-α and IL-6, respectively. Moreover, DHF generally possesses more efficient than HF in reducing these markers secretion in this study.
CONCLUSIONS:
Consider together, these findings suggest that DHF and HF can inhibit LPS-induced inflammation via attenuating the production of NO, PGE2 , TNF-α and IL-6, indicating that they may be lead compounds for developing anti-inflammatory agent.

J Phys Chem A. 2014 May 1;118(17):3068-80.

7-hydroxyflavone revisited: spectral, acid-base properties, and interplay of the protolytic forms in the ground and excited states.[Pubmed: 24689737]

Spectral and acid-base properties of 7-Hydroxyflavone (7HF) in the ground and excited states were investigated with a purpose to enable reasonable application of this dye and its derivatives as fluorescent probes.
METHODS AND RESULTS:
Analysis of solvatochromic and solvatofluorochromic ability of 7HF in 20 solvents, investigations of 7HF spectral properties in the frozen solvents, spectrophotometric and spectrofluorimetric titrations in methanol-water (4:1 v/v) in the wide pH/H0 range (from pH = 11.0 to H0 = -4.5), analysis of the 3D fluorescence and time-resolved spectra, as well as quantum-chemical calculations were carried out. It has been found that 7HF can exist in three protolythic forms-neutral, anion, and cation-depending on the environment acidity or basicity. In the excited state, in methanol-water solutions, there are four forms: neutral, cation and anion, which can be formed by direct excitation of the ground-state anion or by photodissociation of the neutral form depending on pH, and only one phototautomer, which appears in the H0 range from 1.3 to -4.5.
CONCLUSIONS:
It has been shown that the mechanism of the phototautomer formation depends on medium acidity. The photoautomer can be formed by cation photodissociation as well as by photoanion protonation. Finally, it was concluded which of the 7HF protolytic forms can be used for fluorescent probing.