apigenin and chrysin

α-Glucosidase (AG) play crucial roles in the digestion of carbohydrates. Inhibitors of α-glucosidase (AGIs) are promising candidates for the development of anti-diabetic drugs. Here, five series of apigenin and chrysin nitric oxide (NO)-donating derivatives were synthesised and evaluated for their AG inhibitory activity and NO releasing capacity in vitro. Except for 9a-c, twelve compounds showed remarkable inhibitory activity against α-glucosidase, with potency being better than that of acarbose and 1-deoxynojirimycin. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure activity relationship studies indicated that 5-OH, hydrophobic coupling chain, and carbonyl groups of the coupling chain could enhance the inhibitory activity. Apigenin and chrysin derivatives therefore represents a new class of promising compounds that can inhibit α-glucosidase activity and supply moderate NO for preventing the development of diabetic complications.

Topics: alpha-Glucosidases; Apigenin; Diabetes Complications; Diabetes Mellitus; Flavonoids; Humans; Hypoglycemic Agents; Molecular Structure; Nitric Oxide; Structure-Activity Relationship

Luteolin (1), a natural product occurring in many vegetables and fruits, is known to have several biological activities. Cluster for differentiation (CD) families, such as CD11b, -14, and -36, are expressed during pathological processes of atherosclerosis and are used broadly as markers of monocytic differentiation into macrophages. Herein, it was investigated whether 1 and three other flavonoids [chrysin (2), apigenin (3), and tricetin (4)] blocked 12-O-tetradecanoylphorbol 13-acetate (TPA)-triggered induction of CD families, which were induced through the activation of protein kinase C (PKC), mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), and NADPH oxidase (NOX)-derived reactive oxygen species (ROS). When compared to flavonoids 2-4, 1 blocked TPA-triggered induction of CD families and cell adherence of monocytic THP-1 cells. Luteolin completely blocked intracellular ROS generation, whereas it did not inhibit MEK/ERK phosphorylation. Moreover, pretreatment with 1 suppressed TPA-triggered induction of NOX2 and membrane translocation of p47(phox). Overall, it is revealed that 1 suppresses TPA-triggered induction of CD families by the prevention of NOX2 activation.

Topics: Apigenin; Cell Differentiation; Chromones; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Humans; Luteolin; Membrane Glycoproteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Molecular Structure; Monocytes; NADPH Oxidase 2; NADPH Oxidases; Protein Kinase C; Reactive Oxygen Species; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemopreventive agents. In this study, we examined fully methylated flavones as promising improved agents. In the human oral SCC-9 cancer cells, 5,7-dimethoxyflavone and 5,7,4'-trimethoxyflavone were both 10 times more potent inhibitors of cell proliferation (IC(50) values 5-8 microM) than the corresponding unmethylated analogs chrysin and apigenin. Flow cytometry indicated that both methylated flavones arrested the SCC-9 cells in the G1 phase with a concomitant decrease in the S phase, dramatically different from the unmethylated analogs, which promoted G2/M phase arrest. Both methylated compounds inhibited the proliferation of two other cancer cell lines with very little effect on two immortalized normal cell lines. Examination of additional flavone structures indicated that methylated flavones in general have antiproliferative properties. Finally, we demonstrated that 5,7-dimethoxyflavone, in contrast to its unmethylated analog chrysin, was well absorbed and had high oral bioavailability as well as tissue accumulation in vivo in the rat. Thus, fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents, in particular in oral cancer.

Topics: Animals; Apigenin; Biological Availability; Cell Cycle; Cell Proliferation; Drug Screening Assays, Antitumor; Flavones; Flavonoids; Male; Methylation; Rats; Rats, Inbred F344; Toxicity Tests; Tumor Cells, Cultured

The list of activities of plant flavonoids did not include effects on the central nervous system (CNS) up to 1990, when our laboratory described the existence of natural anxiolytic flavonoids. The first of these was chrysin (5,7-dihydroxyflavone), followed by apigenin (5,7,4'-trihydroxyflavone) and flavone itself. Semisynthetic derivatives of flavone obtained by introducing halogens, nitro groups or both in its molecule, give rise to high affinity ligands for the benzodiazepine receptor, active in-vivo; 6,3'-dinitroflavone, for example, is an anxiolytic drug 30 times more potent than diazepam. The data collected in this paper make clear that some natural flavonoids are CNS-active molecules and that the chemical modification of the flavone nucleus dramatically increases their anxiolytic potency.

Topics: Anti-Anxiety Agents; Central Nervous System; Chamomile; Flavonoids; Humans; Oils, Volatile; Plants, Medicinal

Phytoestrogen effects on estrogen action and tyrosine kinase activity have been proposed to contribute to cancer prevention. To study these mechanisms, a number of phytoestrogens and related compounds were evaluated for their effects on DNA synthesis (estimated by thymidine incorporation analysis) in estrogen-dependent MCF-7 cells in the presence of estradiol (E2), tamoxifen, insulin, or epidermal growth factor. We observed that 1) at 0.01-10 microM, genistein and coumestrol enhanced E2-induced DNA synthesis, as did 10 microM enterolactone. Chrysin at 1.0-10 microM and 10 microM luteolin or apigenin inhibited E2-induced DNA synthesis, as did all compounds at > 10 microM, 2) tamoxifen enhanced genistein-induced DNA synthesis but inhibited DNA synthesis induced by all other compounds, and 3) genistein enhanced insulin- and epidermal growth factor-induced DNA synthesis at 0.1-1.0 and 0.1-10 microM, respectively. At higher concentrations, inhibition was observed. Similar effects were seen with coumestrol. In conclusion, the effects of phytoestrogens in the presence of E2 or growth factors are concentration dependent and variable. At low concentrations, genistein and coumestrol significantly enhanced E2-induced and tyrosine kinase-mediated DNA synthesis; at high concentrations, inhibition was observed. Differing effects were observed with the other compounds. The variable effects of phytoestrogens on DNA synthesis must be considered when their roles in cancer prevention or treatment are evaluated.

Topics: 4-Butyrolactone; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chamomile; Coumestrol; DNA, Neoplasm; Epidermal Growth Factor; Estradiol; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Humans; Insulin; Isoflavones; Lignans; Luteolin; Oils, Volatile; Phytoestrogens; Plant Preparations; Plants, Medicinal; Tamoxifen; Tumor Cells, Cultured

The identification of cellular factors that are required to complete various steps of the HIV-1 life cycle may lead to the development of new therapeutics. One key step, transcription from the integrated provirus, is inhibited by members of two distinct classes of compounds, the flavonoids and the benzothiophenes, via an unknown mechanism, possibly involving a cellular factor. A marked specificity toward inhibiting HIV-1 transcription is evidenced by the ability of drug-treated cells to retain their proliferative and differentiation capabilities. In addition, the compounds do not impede the activation and function of the transcriptional factor NF-kappaB. Here we report on the identification of several cellular proteins that mediate the HIV-1 transcriptional inhibitory property of the flavonoid chrysin. Chemical and immunologic analyses identified these cellular proteins as the individual subunits of casein kinase II (CKII). Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII. Both chrysin and the benzothiophenes inhibited human recombinant CKII enzymatic activity and showed competitive kinetics with respect to ATP, analogous to the classic CKII inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). Moreover, DRB potently inhibited HIV-1 expression in chronically infected cells. CKII may regulate HIV-1 transcription by phosphorylating cellular proteins involved in HIV-1 transactivation that contain multiple CKII phosphorylation consensus sequences.

Topics: Anti-HIV Agents; Carrier Proteins; Casein Kinase II; Catechin; Cell Line; Chamomile; Chromatography, Affinity; Flavonoids; Hesperidin; HIV-1; HL-60 Cells; Humans; Kinetics; NF-kappa B; Oils, Volatile; Plants, Medicinal; Protein Serine-Threonine Kinases; Recombinant Proteins; Thiophenes; Transcription, Genetic; Virus Integration; Virus Replication

The naturally occurring flavonoids, chrysin (5,7-dihydroxyflavone) and apigenin (5,7,4'-trihydroxyflavone), and the synthetic compound, 6,3'-dinitroflavone have been recently reported to selectively bind with high affinity to the central benzodiazepine receptor, and to exert powerful anxiolytic and other benzodiazepine-like effects in rats. Their chemical analog, quercetin, shares none of these effects. In the present article we find that, in contrast to diazepam, chrysin, apigenin, and 6,3'-dinitroflavone have no amnestic effect on acquisition or retention of three different learning tasks (inhibitory avoidance, shuttle avoidance, and habituation to an open field), even when given at doses higher than those previously reported to be anxiolytic. Apigenin had a slight enhancing effect on training session performance and, when given posttraining, on test session retention, of crossing responses in the open field and hindered retention of inhibitory avoidance, and showed no anxiolytic action in an elevated plus maze. Unlike diazepam, none of these drugs had any analgesic effect in the tail-flick test. The data suggest that chrysin, apigenin, and 6,3'-dinitroflavoine, three flavonoids derivatives possessing anxioselective effects acting on central benzodiazepine receptors, may deserve clinical trials as anxiolytic agents.

Topics: Animals; Anti-Anxiety Agents; Avoidance Learning; Chamomile; Diazepam; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Ligands; Male; Memory; Oils, Volatile; Plants, Medicinal; Psychomotor Performance; Quercetin; Rats; Rats, Wistar; Reaction Time; Receptors, GABA-A