apigenin and flavone

Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical achievement in hematological malignancies. However, the efficacy of HDACs inhibitors in treating solid tumors remains limited due to the complicated tumor microenvironment. In this study, we designed and synthesized a class of novel HDACs inhibitors based on the structure of flavones and isoflavones, followed by biological evaluation. To be specific, a lead compound 15a was discovered with strong anti-proliferative effects on a variety of solid tumor cells, especially for breast cancer cells with resistance to SAHA. Studies demonstrated that 15a could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class IIB), leading to a dose-dependent accumulation of acetylated histones and α-Tubulin, cell cycle arrest (G1/S phase) and apoptosis in breast cancer cells. Furthermore, the lead compound 15a could also antagonize the activation of STAT3 induced by HDACs inhibition in some breast cancer cells, which further reduced the level of pro-survive proteins in tumor cells and enhanced anti-tumor activity regulated by STAT3 signaling in vivo. Overall, our findings demonstrated that the novel compound 15a might be a HDACs inhibitor candidate, which could be used as promising chemotherapeutic agent for breast cancer.

Topics: Acetylation; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Drug Design; Flavones; G1 Phase Cell Cycle Checkpoints; Histone Deacetylase Inhibitors; Histones; Humans; S Phase Cell Cycle Checkpoints; Signal Transduction; STAT3 Transcription Factor; Tubulin

Many membrane-associated proteins are involved in various signaling pathways, including the phosphoinositide 3-kinase (PI3K) pathway, which has key roles in diverse cellular processes. Disruption of the activities of these proteins is involved in the development of disease in humans, making these proteins promising targets for drug development. In most cases, the catalytic domain is targeted; however, it is also possible to target membrane associations in order to regulate protein activity. In this study, we established a novel method to study protein-lipid interactions and screened for flavonoid-derived antagonists of PtdIns(3,4,5)P

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Binding Sites; Flavones; Flavonoids; Flavonols; Liposomes; Molecular Docking Simulation; Phosphatidylinositol Phosphates; Pleckstrin Homology Domains; Protein Binding; Quantitative Structure-Activity Relationship

Although several plant-derived flavones inhibit aurora B kinase (aurB), quantitative relationships between the structural properties of plant-derived flavones and their inhibitory effects on aurB remain unclear. In this report, these quantitative structure-activity relationships were obtained. For quercetagetin, found in the Eriocaulon species, showing the best IC50 value among the flavone derivatives tested in this report, further biological tests were performed using cell-based assays, including Western blot analysis, flow cytometry, and immunofluorescence microscopy. In vitro cellular experiments demonstrated that quercetagetin inhibits aurB. The molecular-binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB, aurA, and aurC and prevents the active phosphorylation of all three aurora kinases. In addition, quercetagetin triggers mitotic arrest and caspase-mediated apoptosis. These observations suggest that quercetagetin is an aurora kinase inhibitor. Induction of mitosis-associated tumor cell death by quercetagetin is a promising strategy for developing novel chemotherapeutic anticancer agents.

Topics: Apoptosis; Aurora Kinase A; Aurora Kinase B; Aurora Kinase C; Binding Sites; Chromones; Eriocaulaceae; Flavones; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; M Phase Cell Cycle Checkpoints; Microscopy, Fluorescence; Molecular Docking Simulation; Phosphorylation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship

Human protein kinase CK2 is one of the most intriguing enzymes, which functional role still remains unclear despite of decades of studying. At present there is abundant evidence pointing to the fact that inhibitors of CK2 could be used as pharmaceutical agents to treat cancer, viral infections and inflammatory diseases. Here we report novel synthetic flavone inhibitors, 4'-hydroxyflavones, possessing high activity towards CK2. These compounds were identified with receptor-based virtual screening and then chemically optimized on the base of rationale derived from biochemical screening and molecular modeling. It has been demonstrated that synthetic flavone derivatives are much more potent CK2 inhibitors than the natural ones, and we believe that their further examination will be helpful for studying biological role of CK2 as well as for development of new kinase-oriented drugs.

Topics: Binding Sites; Casein Kinase II; Drug Design; Drug Evaluation, Preclinical; Flavones; Humans; Kinetics; Molecular Docking Simulation; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Recombinant Proteins; Structure-Activity Relationship

Exploration for inhibitors against expression of IgE receptor (Fc epsilonRI) on human mast cell, a significant trigger to acute and chronic allergic symptoms, disclosed epigallocatechin gallate (EGCG), epicatechin gallate, and gallocatechin gallate as active principles. Additionally, the anthocyanidin, delphinidin, and the flavone, tricetinidin, possessing a pyrogallol function were also revealed to suppress expression of Fc epsilonRI. Structure-activity relationship analysis among catechins, anthocyanidins, and flavones revealed the pyrogallol moiety to be crucial for biological potency. Furthermore, EGCG was clarified to reduce generation of gamma-chain subunit to suppress expression of Fc epsilonRI on human mast cells.

Topics: Anthocyanins; Anti-Allergic Agents; Catechin; Cell Line; Flavones; Flavonoids; Gene Expression; Humans; Hypersensitivity; Mast Cells; Receptors, IgE

Some flavonoids are ligands of the aryl hydrocarbon receptor (AHR) and cause cell cycle arrest. The dependency of the cytostatic effects of five flavonoids (flavone, alpha-naphthoflavone, apigenin, 3'-methoxy-4'-nitroflavone and 2'-amino-3'-methoxyflavone) on a functional AHR was examined in AHR-containing rat hepatoma 5L cells and an AHR-deficient cell line (BP8) derived from the 5L line. The potent AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was cytostatic to the 5L line due to the induction of a G(1) arrest and dramatically elevated steady-state levels of CYP1A1 mRNA. TCDD affected neither the proliferation nor CYP1A1 mRNA contents of BP8 cells. With the exception of apigenin, the flavonoids under study induced G(1) arrest in both 5L and BP8 cells when used at concentrations at which they functioned as AHR agonists, but not antagonists. Apigenin-treated 5L and BP8 cultures primarily arrested in G(2)/M. The AHR-containing murine hepatoma cell line 1c1c7 arrested following exposure to AHR agonist concentrations of flavone and alpha-naphthoflavone, but not TCDD. Unlike the G(1) arrest observed in 5L cultures, the latter two flavonoids caused principally G(2)/M arrest in 1c1c7 cells. These studies demonstrate that the cytostatic activities of flavonoids do not require the AHR and the site of checkpoint arrest with a specific flavonoid can vary with cell type.

Topics: Animals; Benzoflavones; Cell Cycle; Cell Division; Chamomile; Cytochrome P-450 CYP1A1; Environmental Pollutants; Flavones; Flavonoids; G1 Phase; Oils, Volatile; Plants, Medicinal; Polychlorinated Dibenzodioxins; Rats; Receptors, Aryl Hydrocarbon; RNA, Messenger; Tumor Cells, Cultured

The effects of flavonoids on NADPH diaphorase activity were studied in vitro, and we found that the enzyme activity was markedly inhibited by quercetin. This inhibitory action was shown to be accompanied by an increase in the apparent Km value of the enzyme for the cofactor NADPH, with a decrease in the Vmax, and an increase in the apparent Km for the substrate nitro blue tetrazolium, without any significant change in the Vmax. These results indicate that quercetin may directly inhibit NADPH diaphorase, thus suggesting the possibility that this compound may be able to inhibit the production of nitric oxide in the brain.

Topics: Animals; Brain; Chamomile; Flavones; Flavonoids; Male; Mice; Mice, Inbred Strains; NADPH Dehydrogenase; Oils, Volatile; Plants, Medicinal; Quercetin

The effects of flavonoids on L-[14C]tyrosine uptake into cultured adrenal chromaffin cells were examined. Flavone markedly stimulated tyrosine uptake into these cells in a manner dependent on its concentration. Apigenin also caused a moderate stimulatory action, but quercetin had no significant effect on the uptake. Flavone also stimulated the uptake of histidine, but did not affect the uptake of serine, lysine, or glutamic acid. These results are considered to propose the possibility that flavonoids may be able to stimulate the precursor uptake into the cells, resulting in an enhancement of the biogenic amine production.

Topics: Adrenal Medulla; Animals; Biological Transport; Carbon Radioisotopes; Catecholamines; Cattle; Cells, Cultured; Chamomile; Flavones; Flavonoids; Glutamates; Glutamic Acid; Histidine; Lysine; Oils, Volatile; Plants, Medicinal; Quercetin; Serine; Tyrosine

Topics: Chamomile; Flavones; Glycosides; Humans; Matricaria; Plant Extracts