Flavone

Inhibitory Effects of Amentoflavone and Orobol on Daclatasvir-Induced Resistance-Associated Variants of Hepatitis C Virus.[Pubmed:29737209]

Am J Chin Med. 2018;46(4):835-852.

Hepatitis C virus (HCV) is recognized as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite rapid progress in the development of direct-acting antivirals (DAA) against HCV infection in recent years, cost-effective antiviral drugs with more affordable prices still need to be developed. In this study, we screened a library of natural compounds to identify natural HCV inhibitors. The library of the pure compounds extracted from Chinese herbs deposited in the chemical bank of National Research Institute of Chinese Medicine (NRICM), Taiwan was screened in the cell culture-derived HCV (HCVcc) system. We identified the Flavone or flavan-based compounds amentoFlavone, 7,4[Formula: see text]-dihydroxyflavanone, and orobol with the inhibition of viral entry, replication, and translation of the HCV life cycle. AmentoFlavone and orobol also showed inhibitory effects on resistant-associated variants to the NS5A inhibitor daclatasvir. The results of this study have the potential to benefit patients who are intolerant to the adverse effect of pegylated interferon or who harbor resistant strains refractory to treatment by current direct-acting antiviral agents.

Synthesis of New Glycosylated Flavonoids with Inhibitory Activity on Cell Growth.[Pubmed:29734739]

Molecules. 2018 May 5;23(5). pii: molecules23051093.

Natural flavonoids and xanthone glycosides display several biological activities, with the glycoside moiety playing an important role in the mechanism of action of these metabolites. Herein, to give further insights into the inhibitory activity on cell growth of these classes of compounds, the synthesis of four flavonoids (5, 6, 9, and 10) and one xanthone (7) containing one or more acetoglycoside moieties was carried out. Acetyl groups were introduced using acetic anhydride and microwave irradiation. The introduction of one or two acetoglycoside moieties in the framework of 3,7-dihydroxyFlavone (4) was performed using two synthetic methods: the Michael reaction and the Koenigs-Knorr reaction. The in vitro cell growth inhibitory activity of compounds 5, 6, 7, 9, and 10 was investigated in six human tumor cell lines: A375-C5 (malignant melanoma IL-1 insensitive), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), U251 (glioblastoma astrocytoma), U373 (glioblastoma astrocytoma), and U87MG (glioblastoma astrocytoma). The new flavonoid 3-hydroxy-7-(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl) Flavone (10) was the most potent compound in all tumor cell lines tested, with GI50 values < 8 μM and a notable degree of selectivity for cancer cells.

Fisetin inhibits the generation of inflammatory mediators in interleukin-1beta-induced human lung epithelial cells by suppressing the NF-kappaB and ERK1/2 pathways.[Pubmed:29758489]

Int Immunopharmacol. 2018 Jul;60:202-210.

Fisetin, a Flavone that can be isolated from fruits and vegetables, has anti-tumor and anti-oxidative properties and ameliorates airway hyperresponsiveness in asthmatic mice. This study investigated whether fisetin can suppress the expression of inflammatory mediators and intercellular adhesion molecule 1 (ICAM-1) in A549 human lung epithelial cells that were stimulated with interleukin-1beta (IL-1beta) to induce inflammatory responses. A549 cells were treated with fisetin (3-30muM) and then with IL-1beta. Fisetin significantly inhibited COX-2 expression and reduced prostaglandin E2 production, and it suppressed the levels of IL-8, CCL5, monocyte chemotactic protein 1, tumor necrosis factor alpha, and IL-6. Fisetin also significantly attenuated the expression of chemokine and inflammatory cytokine genes and decreased the expression of ICAM-1, which mediates THP-1 monocyte adhesion to inflammatory A549 cells. Fisetin decreased the translocation of nuclear transcription factor kappa-B (NF-kappaB) subunit p65 into the nucleus and inhibited the phosphorylation of proteins in the ERK1/2 pathway. Co-treatment of IL-1beta-stimulated A549 cells with ERK1/2 inhibitors plus fisetin reduced ICAM-1 expression. Furthermore, fisetin significantly increased the effects of the protective antioxidant pathway by promoting the expression of nuclear factor erythroid-2-related factor-2 and heme oxygenase 1. Taken together, these data suggest that fisetin has anti-inflammatory effects and that it suppresses the expression of chemokines, inflammatory cytokines, and ICAM-1 by suppressing the NF-kappaB and ERK1/2 signaling pathways in IL-1beta-stimulated human lung epithelial A549 cells.

New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of beta-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer's Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase.[Pubmed:29745222]

Mol Pharm. 2018 Jun 4;15(6):2206-2223.

In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of Flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 +/- 0.012 to 1.006 +/- 0.075 muM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Abeta aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.

The Chemistry and Biological Effects of Thioflavones.[Pubmed:29766803]

Mini Rev Med Chem. 2018;18(20):1714-1732.

ThioFlavone derivatives are the thio analogs of the core constituent of the natural product class of Flavones. Based on the position and oxidation level of sulfur, they can be divided into three major categories: 4-thioFlavones, 1-thioFlavones and 1-thioFlavones 1,1-dioxide. In recent years, great efforts have been made to develop an approach for the synthesis of thioFlavones, especially 1- thioFlavones with high functional group compatibility, high yields, low toxicity as well as proceeding under a mild condition, and a variety of synthetic protocols have been developed, the method of choice being dependent on the nature of substrates. As isosteric analogs of biologically active Flavones, thioFlavones also exhibit various pharmaceutical properties, such as antimicrobial, anticancer and neuroprotective activities. Replacement of the oxygen atom on Flavone skeleton by a sulfur atom resulted in modified biological effects due in most part to the change of the structural properties. However, these varying effects depend on the substituents present and the test species. To provide a comprehensive vision of this class of compounds, this review primarily focuses on the structure, synthetic methods, biological properties as well as structure-activity relationships of thioFlavones.

[Engineering of a flavonoid 3'-hydroxylase from tea plant (Camellia sinensis) for biosynthesis of B-3',4'-dihydroxylated flavones].[Pubmed:29756698]

Wei Sheng Wu Xue Bao. 2017 Mar 4;57(3):447-58.

Objective: A flavonoid 3'-hydroxylase from tea plant was engineered to synthesize B-3',4'-dihydroxylated Flavones such as eriodictyol, dihydroquercetin and quercetin. Methods: Four articifical P450 constructs harboring both flavonoid 3'-hydroxylase gene from Camellia sinensis (CsF3'H) and P450 reductase gene from Arabidopsis thaliana (ATR1 or ATR2) were introduced into Escherichia coli strains TOP10, DH5alpha and BL21, resultantly engineering strains S1 to S12. The plasmid pYES-Dest52-CsF3'H harboring CsF3'H gene was introduced into yeast Saccharomyces cerevisiae WAT11 designated as strain S13. The plasmid pES-HIS-CsF3H::AtFLS 9 AA was constructed through fusing flavanone 3-hydroxylase gene from Camellia sinensis (CsF3H) and flavonol synthase gene from Arabidopsis thaliana (AtFLS). Plasmid pES-URA-CsF3'H and pES-HIS-CsF3H::AtFLS 9 AA were then co-introduced into yeast S. cerevisiae WAT11 designated as strain S14. Results: Strain S6 generated highest bioconversion efficiency at 25 among all E. coli strains during 24 h fernentation. Supplemented with 1000 mumol/L naringenin, dihydrokaempferol and kaempferol, the maximum amounts of eriodictyol, dihydroquercetin and quercetin produced by strain S13 were 734.32 mumol/L, 446.07 mumol/L and 594.64 mumol/L respectively. Supplemented with 5 mmol/L naringenin, the maximum amounts of eriodictyol, kaempferol, quercetin, dihydroquercetin and dihydrokaempferol produced by strain S14 were 1412.16 mumol/L, 490.25 mumol/L, 445.75 mumol/L, 66.75 mumol/L and 73.50 mumol/L during 36-48 h fermentaion respectively. Conclusion: CsF3'H was engineered for biosynthesis of B-3',4'-dihydroxylated Flavone.

Flavones-bound in benzodiazepine site on GABAA receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin.[Pubmed:29738701]

Eur J Pharmacol. 2018 Jul 15;831:77-86.

Increasing evidence suggests that Flavones can modulate memory and anxiety-like behaviour. However, these therapeutic effects are inconsistent and induce of adverse effects, which have been associated with interactions at the Benzodiazepine (BZ)-binding site. To improve our understanding of Flavone effects on memory and anxiety, we employed a plus-maze discriminative avoidance task. Furthermore, we evaluated the potential of the compounds in modulating GABAA receptors via BZ-binding site using molecular modelling studies. Adult male Wistar rats were treated 30min before training session with Vicenin-2 (0.1 and 0.25mg/kg), Vitexin (0.1 and 0.25mg/kg), Isovitexin (0.1 and 0.25mg/kg) and 0.1mg/kg 6-C-glycoside-Diosmetin, vehicle and a GABAA receptor agonist. The analysis of the time spent in the non-aversive vs aversive enclosed arms during the test session and percentage of time in the open arms within the training session revealed that treatment with Isovitexin and 6-C-glycoside-Diosmetin had memory-enhancing and anxiolytic-like effects (P<0.001). In contrast, treatment with a higher dose of Diazepam impaired short-and long-term memory when it alleviated anxiety level. Docking studies revealed that Flavones docked in a very similar way to that observed to the Diazepam, except by a lack of interaction in residue alpha1His101 in the BZ-binding site on GABAA receptors, which may be related to memory-enhancing effect. The occurrence of the alpha1His101 interaction could justify the memory-impairing observed following Diazepam treatment. These findings provide the first evidence that Isovitexin and 6-C-glycoside-Diosmetin could exert their memory-enhancing and anxiolytic-like effects via GABAA receptor modulation, which likely occurs via their benzodiazepine-binding site.