lignans and hinokinin

Hinokinin is a lignan isolated from several plant species that has been recently investigated in order to establish its biological activities. So far, its cytotoxicity, its anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is its notable anti-trypanosomal activity.

Topics: 4-Butyrolactone; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antiparasitic Agents; Benzodioxoles; Dioxoles; Humans; Lignans; Plant Extracts

The diverse structures and profound biological activities of lignan natural products have enticed significant effort in the exploration of new methodologies for their total synthesis. We have prepared γ-butyrolactone oximes from readily available δ-nitro alcohols via Boc

Topics: 4-Butyrolactone; Biological Products; Lignans

Topics: Animals; Anthelmintics; Haemonchus; Larva; Lignans; Mammals; Molecular Docking Simulation; Nematoda; Phosphorylcholine; Piper

This work aimed to synthesize poly (D, L-lactic-co-glycolic acid) (PLGA) microparticles containing hinokinin (HNK) and to evaluate their cytotoxic activity against tumoral SiHa cells and non-tumoral HaCaT cells. Hinokinin was incorporated into PLGA (PLGA-HNK) with an encapsulation efficiency of 84.18 ± 2.32%. PLGA and PLGA-HNK were characterized by SEM microscopy and showed spherical morphology with an average size of ∼3.33. Encapsulation efficiency was determined by a calibration curve using UV-vis spectroscopy. PLGA-HNK more active inhibiting proliferation of SiHa cells (IC

Topics: 4-Butyrolactone; Antineoplastic Agents; Benzodioxoles; Lactic Acid; Lignans; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Type 2 diabetes, a global health concern has been considered as major risk factor for cardiovascular diseases. Hinokinin, an emerging bioactive lignin, is reported to show wide range of pharmacological activities. However, the protective role and mechanisms of Hinokinin against type 2 diabetes-mediated cardiotoxicity are still remains unknown. An experimental type 2 diabetic mice model was created by treating animals with high fat diet for four weeks and intraperitoneal injection of streptozotocin (35 mg/kg body weight). Post-type 2 diabetic induction, animals orally treated with Hinokinin (20 or 40 mg/kg body weight) for six weeks. The type 2 diabetic mice exhibited a rise in blood glucose level as well as glycated hemoglobin (HbA1c %), decrease in weekly body weights, decrease in food intake, reduction in absolute heart weight, fall in serum insulin level with altered lipid profile and cardiac functional damage. Diabetic mice treated with Hinokinin attenuated hyperglycemia, dyslipidemia and cardiac dysfunction. In addition, Hinokinin ameliorated histological alterations, fibrosis and glycated proteins in HFD/STZ-induced mice. Type 2 diabetic condition in mice exacerbated oxidative stress, inflammatory status and apoptosis. Hinokinin treatment significantly assuaged oxidative stress, inflammation and apoptosis and elevated antioxidant defenses in diabetic heart. The underlying mechanisms for such mitigation involved the modulation of Nrf2/Keap1/ARE pathway, MAPKs (JNK, p38 and ERK 1/2) and TLR4/MyD88/NF-κB mediated inflammatory pathways and mitochondrial-dependent (intrinsic) apoptosis pathway. In conclusion, the results of this study provided clear evidence that Hinokinin protects against HFD/STZ (type 2 diabetes)-induced cardiac injury by alleviating oxidative stress, inflammation and apoptosis.

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Benzodioxoles; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Dyslipidemias; Hyperglycemia; Lignans; Mice; Oxidative Stress; Signal Transduction; Streptozocin

The genus Absidia is widely used in the biotransformation of different classes of natural products. This study evaluates the ability of the Absidia coerulea 3A9 marine derived strain isolated from the ascidian Distaplia stilyfera to perform biotransformations by conducting assays with (-)-cubebin, as substrate. The experiment was optimized using the experimental design proposed by Plackett-Burman for seven factors and eight experiments, to establish the biotransformation conditions that would allow maximum production of biotransformed dibenzylbutyrolactone (-)-hinokinin. An analytical method based on Reverse-Phase-High Performance Liquid Chromatography (RP-HPLC) was developed to quantify the fungal biotransformation product. The factor that influenced the (-)-hinokinin peak area the most positively was the percentage of seawater (%seawater) given that its %relative standard deviation (%RSD) showed a 32.92% deviation from the real value.

Topics: 4-Butyrolactone; Absidia; Aquatic Organisms; Benzodioxoles; Biotransformation; Lignans; Seawater

Topics: 4-Butyrolactone; Analgesics; Animals; Aristolochia; Benzodioxoles; Chromatography, High Pressure Liquid; Diterpenes; Lignans; Magnetic Resonance Spectroscopy; Male; Mice; Pain; Pain Measurement; Plant Extracts

Encouraged by the anti-inflammatory activity of hinokinin in vivo, which is also observed for the analogues dinitrohinokinin and diidrocubebin, herein we used in vitro and in silico methods to assess their selectivity profiles and predict their binding modes with Cyclooxygenases (COX-1 and 2). The in vitro assays demonstrated dinitrohinokinin is about 13 times more selective for COX-2 than for COX-1, a similar profile observed for the drugs celecoxib (selective index ≈9) and meloxicam (selective index ≈11). Predictions of the binding modes suggested dinitrohinokinin interacts with COX-2 very similarly to rofecoxib, exploring residues at the hydrophilic pocket of the enzyme that accessible to ligands only in this isoform. This lignan also interacts with COX-1 in a similar mode to meloxicam, blocking the access of the substrate to the catalytic cleft. Therefore, dinitrohinokinin is a promising lead for the design of selective COX-2 inhibitors.

Topics: 4-Butyrolactone; Benzodioxoles; Binding Sites; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Lactones; Lignans; Meloxicam; Molecular Docking Simulation; Protein Binding; Quantitative Structure-Activity Relationship; Substrate Specificity; Sulfones

(-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK.

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Catalytic Domain; Computer Simulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyproheptadine; Dextrans; Dinoprostone; Dioxoles; Edema; Furans; Indomethacin; Ligands; Lignans; Male; Mice; Molecular Docking Simulation; Polysorbates; Rats, Wistar; Rutaceae

In this study, we evaluated the in vitro cytotoxicity of fractions and isolated constituents from Cinnamomum parthenoxylon woods against human leukemia HL-60 and U937 cells. The n-Hex, EtOAc, and MeOH-H2O fractions of the woods inhibited cell proliferation in both cell lines. Our phytochemical investigation of the n-Hex and EtOAc fractions led to the isolation of lignans and phenylpropanoids, whose chemical structures were confirmed by spectroscopic analyses. All isolated compounds were evaluated for their in vitro antileukemic activity; especially, hinokinin and cubebin exhibited strong inhibition toward U937 cell proliferation. Morphological observation indicated that these cytotoxic actions were mediated by apoptosis. Our findings suggested that an oxygenated functional group at the C-9 position in dibenzylfuran skeleton contributed their potency. In addition, these results enhanced the ethnopharmacological value of C. parthenoxylon.

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Proliferation; Cinnamomum; HL-60 Cells; Humans; Lignans; Plant Extracts; U937 Cells

Breast cancer incidence rises worldwide and new chemotherapeutical strategies have been investigated to overcome chemoresistance. (-)-Hinokinin is a dibenzylbutyrolactone lignan derived from the partial synthesis of (-)-cubebin extracted from Piper cubeba seeds. Biological effects of dibenzylbutyrolactone lignans include antiviral, antitumor, anti-inflammatory, and trypanocidal activities. In the present study, we evaluated the ability of (-)-hinokinin to modulate the antiproliferative effects of doxorubicin intumoral (MCF-7 and SKBR-3) and normal (MCF-10 A) breast cell lines. Treatment with (-)-hinokinin did not affect the cellular proliferation or contribute to the antitproliferative effects of doxorubicin in MCF-10 A cells. After 24 and 48 hours of treatment with (-)-hinokinin, MCF-7 and SKBR-3 were accumulated in G2/M and, when combined with doxorubicin, (-)-hinokinin contributed to the antiproliferative effects of this chemotherapic by modulation of the cyclin-dependent kinase inhibitor 1. Apoptotic cell death was observed in response to (-)-hinokinin alone in MCF-7, but not in SKBR-3 even 72 hours after treatment. In MCF-7, doxorubicin-induced apoptosis was not increased by (-)-hinokinin. The findings of the present study suggest (-)-hinokinin as an antiproliferative agent that contributes to the effects of doxorubicin. (-)-Hinokinin modulates apoptotic cell death via the molecular regulation of the cell cycle and apoptotic control genes, but the cellular genetic background directly affects the cell fate decision in response to treatment.

Topics: 4-Butyrolactone; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Lignans; M Phase Cell Cycle Checkpoints

We examined the effects of ambient, non-stressing ultraviolet (UV)-B (280-315nm) level combined with different intensities of photosynthetic active radiation (PAR, 400-700nm) on the accumulation of the lignan (-)-hinokinin, in leaves and stems of Hydrocotyle leucocephala. Plants were exposed in sun simulators under almost natural irradiance and climatic conditions to one of four light regimes, i.e. two PAR intensities (906 and 516μmolm(-2)s(-1)) including or excluding UV-B radiation (0 and 0.4Wm(-2)). Besides hinokinin, we identified three chlorogenic acid isomers, one other phenolic acid, 12 quercetin, and five kaempferol derivatives in the H. leucocephala extracts. Hinokinin was most abundant in the stems, and its accumulation was slightly enhanced under UV-B exposure. We therefore assume that hinokinin contributes to cell wall stabilization and consequently to a higher resistance of the plant to environmental factors. Quercetin derivatives increasingly accumulated under UV-B and high PAR exposure at the expense of kaempferols and chlorogenic acids, which was apparently related to its ability to scavenge reactive oxygen species. In general, the concentration of the constituents depended on the plant organ, the leaf age, the light regimes, and the duration of exposure. The distribution pattern of the compounds within the examined organs was not influenced by the treatments. Based on the chemical composition of the extracts a principal component analysis (PCA) enabled a clear separation of the plant organs and harvesting dates. Younger leaves mostly contained higher phenylpropanoid concentrations than older leaves. Nevertheless, more pronounced effects of the light regimes were detected in older leaves. As assessed, in many cases the individual compounds responded differently to the PAR/UV-B combinations, even within the same phenylpropanoid class. Since this is the first report on the influence of light conditions on the accumulation of lignans in herbaceous plants, it opens many perspectives for a more precise elucidation of all involved biochemical and molecular processes.

Topics: 4-Butyrolactone; Benzodioxoles; Centella; Chlorogenic Acid; Flavonols; Hydroxybenzoates; Kaempferols; Lignans; Oxidative Stress; Photosynthesis; Plant Leaves; Plant Stems; Propanols; Quercetin; Ultraviolet Rays

Astragalin was isolated for the first time along with (-)hinokinin, aristolactam I and aristolochic acids (I & II) from the extracts of Aristolochia indica L. using a new, efficient preparative HPLC method. A reversed-phase HPLC method of analysis was developed to analyse the isolated compounds. The crude extracts and the isolated compounds were tested for their anti-inflammatory potential. We report here for the first time the anti-inflammatory effects of (-)hinokinin and aristolactam I against IL-6 (IC50 = 20.5 ± 0.5 and 52 ± 8 μM) and TNFα (IC50 = 77.5 ± 27.5 and 116.8 ± 83.25 μM), respectively. (-)Hinokinin exerted its anti-inflammatory effects via NFκB-dependent mechanism whereas aristolactam I may be effective via a mechanism independent of NFκB.

Topics: 4-Butyrolactone; Anti-Inflammatory Agents; Aristolochia; Aristolochic Acids; Benzodioxoles; Chromatography, High Pressure Liquid; Dioxoles; Interleukin-6; Kaempferols; Lignans

(-)-Hinokinin (1) is a dibenzylbutyrolactone lignan obtained by the partial synthesis of (-)-cubebin. This study reports the antigenotoxic and anticarcinogenic potential of 1 by the comet and aberrant crypt focus assays in the peripheral blood and colon of 4-5-week-old Wistar rats, respectively. The rats were exposed to 1,2-dimethylhydrazine (40 mg/kg) and were treated by gavage with doses of 10, 20, and 40 mg/kg of 1. The results showed that the dose of 40 mg/kg was neither genotoxic nor carcinogenic. In the comet assay, all 1 doses displayed antigenotoxic effects. In addition, this compound (20 and 40 mg/kg) exhibited an anticarcinogenic effect in the aberrant crypt focus assay.

Topics: 1,2-Dimethylhydrazine; 4-Butyrolactone; Animals; Anticarcinogenic Agents; Benzodioxoles; Carcinogens; Colon; Comet Assay; Dimethylhydrazines; Dioxoles; DNA Damage; Lignans; Male; Molecular Structure; Piper; Rats; Rats, Wistar; Stereoisomerism

Silica gel column chromatography combined with high performance counter-current chromatography (HPCCC) was employed for the separation of potential anti-tumor compounds from a petroleum ether fraction of a crude extract of Zanthoxylum ailanthoides Sieb. & Zucc. This traditional Chinese medicine was recently found to display high inhibitory activity against A-549 human cancer cells in vitro and Lewis lung cancer in vivo. A 75% aqueous ethanol extract of the stem bark of Z. ailanthoides was fractionated with petroleum ether, ethyl acetate and n-butanol. In this paper, the petroleum ether fraction was pre-separated by silica gel column chromatography with a petroleum ether-ethyl acetate gradient. Two fractions were further separated and purified by HPCCC using n-hexane-ethyl acetate-methanol-water (3:1:2:1, v/v) and petroleum-ethyl acetate-methanol-water (8:6:7:7, v/v). Finally, coumarins and lignans including luvangetin, xanthyletin, hinokinin and asarinin were isolated and identified by MS, (1)H and (13)C NMR. In total, 56mg of xanthyletin (1), 140mg of hinokinin (2), 850mg of luvangetin (3) and 74mg of asarinin (4) were obtained from approximately 50g of petroleum ether extract, in 96.0%, 94.0%, 99.0% and 94.0% purity, respectively, as determined by HPLC. The separation method proved to be efficient, especially for those minor components.

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Line, Tumor; Cell Survival; Coumarins; Countercurrent Distribution; Dioxoles; Humans; Lignans; Plant Bark; Silica Gel; Zanthoxylum

The neurotransmitter transporters of the SLC6 family play critical roles in the regulation of neurotransmission and are the primary targets of therapeutic agents used to treat clinical disorders involving compromised neurotransmitter signaling. The dopamine and norepinephrine transporters have been implicated in clinical disorders such as attention deficit hyperactivity disorder (ADHD) and substance abuse. The GABA transporters (GATs) serve as a target for anxiolytic, antidepressant, and antiepileptic therapies. In this work, the interaction with neurotransmitter transporters was characterized for a derivative of the lignan (-)-cubebin (1), namely, (-)-hinokinin (2). Using in vitro pharmacological assays, 2 selectively inhibited the human dopamine and norepinephrine transporters, in a noncompetitive manner possibly mediated by binding to a novel site within the transporters, and displayed low affinity for the serotonin transporter. Compound 2 also specifically inhibited the GAT-1 GABA transporter subtype. Compound 2 is not a substrate of the carriers as it had no effect on the efflux of either of the neurotransmitters investigated. This compound is inactive toward glutamate and glycine transporters. These results suggest that 2 may serve as a tool to develop new therapeutic drugs for ADHD and anxiety that target the DAT, NET, and GAT-1 transporters.

Topics: 4-Butyrolactone; Attention Deficit Disorder with Hyperactivity; Benzodioxoles; Dioxoles; Dopamine; Dose-Response Relationship, Drug; GABA Plasma Membrane Transport Proteins; Humans; Lignans; Molecular Structure; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Stereoisomerism

Nifurtimox and benznidazole, medications currently used for the treatment of the Chagas disease, are not always successful. We determine whether (-)-cubebin and (-)-hinokinin could be used as alternative drugs for the treatment of parasitic infections by Trypanosoma cruzi. To this end, male BALB/c mice were treated with both drugs, and the nuclear parameters (largest diameter, smallest diameter, and perimeter) were determined from slides prepared from the spleen, liver, and heart. The cytotoxicity of the substances was determined after 24-h treatment. Results revealed increased cell nuclei in untreated infected animals as compared to uninfected mice. The values obtained for infected animals treated with (-)-cubebin and (-)-hinokinin were close to those observed for uninfected mice. For the spleen, perimeter values of 10.85 μm (p < 0.01) and 10.90 μm (p < 0.05) were obtained for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas untreated infected animals furnished a perimeter of 11.76 μm. As for the liver, perimeter values of 19.06 μm (p < 0.01) and 18.61 μm (p < 0.001) were achieved for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas a perimeter of 18.54 μm was obtained for untreated infected animals. The cytotoxicity assays demonstrated that (-)-cubebin and (-)-hinokinin does not display toxicity. Therefore, (-)-cubebin and (-)-hinokinin are promising therapeutic agents and could be used in future clinical studies concerning treatment of the Chagas disease. Even if the karyometry is not used frequently, it can complement other methods, such as PCR, and furthermore, it is a simple method which is easily possible to analyze the activity of substances in the tissues of treated infected animals compared to uninfected animals.

Topics: 4-Butyrolactone; Animals; Antiprotozoal Agents; Benzodioxoles; Biometry; Cell Line; Chagas Disease; Dioxoles; Disease Models, Animal; Fibroblasts; Karyotyping; Lignans; Liver; Macaca mulatta; Male; Mice; Mice, Inbred BALB C; Spleen; Trypanosoma cruzi

Even though the Chagas' disease, caused by the protozoan Trypanosoma cruzi, was described 100years ago by Carlos Chagas, it still represents a major public health concern and is found in 18 developing countries in South and Central America. In Brazil, Benznidazole (Rochagan) is the only drug with trypanocidal activity available in the market, despite its several side effects and limited efficacy in the chronic phase of the infection. In view of the need for new substances displaying biological activity against T. cruzi, there has been growing interest in research toward the attainment of compounds capable of acting on the parasite while being devoid of serious side effects. In this context, this study aims to evaluate the in vivo therapeutic activity of dibenzylbutyrolactone lignans (-)-cubebin and (-)-hinokinin during the acute phase of infection by T. cruzi. As a study criterion, animals with acute parasitemia were investigated by tissue morphometric analysis. There was significant parasitemia reduction in the groups of animals treated with (-)-cubebin or (-)-hinokin oral administration, compared to the negative control. Values close to those of the uninfected control were found in the groups treated with (-)-cubebin and (-)-hinokinin via kariometry, showing that there was positive cellular response compared to the infected control.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; Chagas Disease; Dioxoles; Lignans; Male; Mice; Mice, Inbred BALB C; Nitroimidazoles; Piper; Trypanocidal Agents; Trypanosoma cruzi

Seven lignans, previously isolated from Pycnanthus angolensis or obtained by derivatization, namely the dibenzylbutane-type lignans threo-4,4'-dihydroxy-3-methoxylignan (1), 4'-hydroxy-3,3',4-trimethoxylignan (2), (-)-dihydroguaiaretic acid (3), 3,3',4,4'-tetramethoxylignan (4), 4,4'-diacetyl-3,3'-dimethoxylignan (5), heliobuphthalmin (6) and the butyrolactone lignan hinokinin (7), were evaluted for their ability as apoptosis inducers in human hepatoma HuH-7 cells. Cell viability assays, morphological evaluation of apoptosis and enzymatic analyses of caspase activity in HuH-7 cells were carried out. Using the lactate dehydrogenase lactate dehydrogenase (LDH) assay, it was demonstrated that the lignans (1-7) tested significantly reduced viability of HuH-7 cells. Morphologic evaluation of HuH-7 cells using Hoechst staining and fluorescence microscopy revealed that lignans 1-7 were strong inducers of apoptosis. In fact, HuH-7 cells developed morphological changes of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. However, lignans 2 and 7 were the most promising compounds in this study, inducing 2.4- and 2.5-fold increases in apoptotic cells as compared to controls. Caspase-3-like activity assays confirmed the morphologic data.

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Benzodioxoles; Caspase 3; Cell Line, Tumor; Cell Survival; Dioxoles; Humans; L-Lactate Dehydrogenase; Lactones; Lignans; Myristicaceae; Plant Extracts; Plants, Medicinal

The dibenzylbutyrolactone lignan (-)-hinokinin (HK) was derived by partial synthesis from (-)-cubebin, isolated from the dry seeds of the pepper, Piper cubeba. Considering the good trypanosomicidal activity of HK and recalling that natural products are promising starting points for the discovery of novel potentially therapeutic agents, the aim of the present study was to investigate the (anti) mutagenic∕ genotoxic activities of HK.. The mutagenic∕ genotoxic activities were evaluated by the Ames test on Salmonella typhimurium strains TA98, TA97a, TA100 and TA102, and the comet assay, so as to assess the safe use of HK in the treatment of Chagas' disease. The antimutagenic ∕antigenotoxic potential of HK were also tested against the mutagenicity of a variety of direct and indirect acting mutagens, such as 4- nitro-o-phenylenediamine (NOPD), sodium azide (SA), mitomycin C (MMC), benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 2-aminoanthracene (2-AA) and 2-aminofluorene (2-AF), by the Ames test, and doxorubicin (DXR) by the comet assay.. The mutagenicity∕genotoxicity tests showed that HK did not induce any increase in the number of revertants or extent of DNA damage, demonstrating the absence of mutagenic and genotoxic activities. On the other hand, the results on the antimutagenic potential of HK showed a strong inhibitory effect against some direct and indirect-acting mutagens.. Regarding the use of HK as an antichagasic drug, the absence of mutagenic effects in animal cell and bacterial systems is encouraging. In addition, HK may be a new potential antigenotoxic ∕ antimutagenic agent from natural sources. However, the protective activity of HK is not general and varies with the type of DNA damage-inducing agent used.

Topics: 4-Butyrolactone; Animals; Antimutagenic Agents; Benzodioxoles; Cell Line; Chagas Disease; Comet Assay; Cricetinae; Dioxoles; DNA Damage; Humans; Lignans; Mutagens; Piper; Plant Extracts; Salmonella; Seeds; Trypanocidal Agents

The (-)-hinokinin display high activity against Trypanosoma cruzi in vitro and in vivo. (-)-Hinokinin-loaded poly(D,L-lactide-co-glycolide) microparticles were prepared and characterized in order to protect (-)-hinokinin of biological interactions and promote its sustained release for treatment of Chagas disease. The microparticles contain (-)-hinokinin were prepared by the classical method of the emulsion/solvent evaporation. The scanning electron microscopy, light-scattering analyzer were used to study the morphology and particle size, respectively. The encapsulation efficiency was determined, drug release studies were kinetically evaluated, and the trypanocidal effect was evaluated in vivo. (-)-Hinokinin-loaded microparticles obtained showed a mean diameter of 0.862 microm with smooth surface and spherical shape. The encapsulation efficiency was 72.46 +/- 2.92% and developed system maintained drug release with Higuchi kinetics. The preparation method showed to be suitable, since the morphological characteristics, encapsulation efficiency, and in vitro release profile were satisfactory. In vivo assays showed significant reduction of mice parasitaemia after administration of (-)-hinokinin-loaded microparticles. Thus, the developed microparticles seem to be a promising system for sustained release of (-)-hinokinin for treatment of Chagas disease.

Topics: 4-Butyrolactone; Animals; Antiprotozoal Agents; Benzodioxoles; Chagas Disease; Delayed-Action Preparations; Dioxanes; Dioxoles; Disease Models, Animal; Humans; Lactic Acid; Lignans; Mice; Microspheres; Parasitemia; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Treatment Outcome; Trypanosoma cruzi

The reduction of parasitism tissue upon treatment with two lignano lactones, namely (-)- cubebin (CUB) and (-)-hinokinin (HNK), was evaluated in the chronic phase of Chagas' disease by quantifying the enzyme beta-galactosidase expressed by the CL B5 clone strain of Trypanosoma cruzi. Tissue karyometry was also performed. Treatment with the assessed lignans led to a larger reduction in parasitism tissue in all evaluated organs, compared with benznidazole (BZN). Oral treatment with CUB or HNK was more effective. Karyometry results demonstrated that the infected control animals had increased nuclear area compared with uninfected controls, indicating cellular hypertrophy. Results also revealed that use of CUB or HNK was able to significantly prevent this increase, and a slight decrease in the nuclear area was observed, compared with mice treated with BZN. Taken together, these data demonstrate that CUB and HNK could be considered as potential compounds for the development of new drugs for treatment of Chagas' disease.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; beta-Galactosidase; Chagas Disease; Chronic Disease; Dioxoles; Heart; Karyometry; Lactones; Lignans; Liver; Mice; Mice, Inbred BALB C; Spleen; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

The dibenzylbutyrolactone lignan (-)-hinokinin (HK) was obtained by partial synthesis from (-)-cubebin, isolated from the dry seeds of the pepper, Piper cubeba. In view of the trypanocidal activity of HK and its potential as a lead compound for drug development, evaluation of its possible genotoxic activity is required. We have tested HK for possible genotoxicity and evaluated the compound's effect on the activity of the clastogens doxorubicin (DXR) and methyl methanesulfonate (MMS) in the micronucleus (MN) assay with Chinese hamster lung fibroblast V79 cells. HK alone did not induce MN, at concentrations up to 128microM. In combined treatments, HK reduced the frequency of MN induced by MMS. With respect to DXR, HK exerted a protective effect at lower concentrations, but at higher concentrations it potentiated DXR clastogenicity.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; Cell Line; Cricetinae; Cricetulus; Dioxoles; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Fibroblasts; Lignans; Lung; Methyl Methanesulfonate; Micronucleus Tests; Mutagens

Five new compounds, ailanthamide (1), N-(4-methoxyphenethyl)-N-methylbenzamide (2), (2E,4E)-N-isobutyl-6-oxohepta-2,4-dienamide (3), 4-(4'-hydroxy-3'-methylbutoxy)benzaldehyde (4), and (E)-methyl 4-[4-(3-hydroxypropyl)phenoxy]-2-methylbut-2-enoate (5), and 17 known compounds have been isolated from the stem bark of Zanthoxylum ailanthoides. The structures were determined through spectroscopic and MS analyses. Compounds 1, 3, xanthyletin, decarine, (+)-episesamin, (-)-hinokinin, and evofolin-B exhibited inhibition (IC(50) < or = 5.34 microg/mL) of superoxide anion generation by human neutrophils in response to formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (fMLP/CB). Compounds 1, xanthyletin, decarine, and (+)-episesamin also inhibited fMLP/CB-induced elastase release with IC(50) values < or = 5.53 microg/mL.

Topics: 4-Butyrolactone; Amides; Benzamides; Benzene Derivatives; Benzodioxoles; Coumarins; Dioxoles; Humans; Inhibitory Concentration 50; Lignans; Molecular Structure; Neutrophils; Pancreatic Elastase; Plant Bark; Plants, Medicinal; Superoxides; Taiwan; Zanthoxylum

To study the chemical constituents of Rhizome of Buddleia davidii.. The chemical constituents were isolated by repeated column chromatography (Toyopearl HW-40C and HPLC) and their structures were elucidated on the basis of physico-chemical properties and spectroscopic features.. From the petroleum ether extract of the material, eight compounds were isolated. Their structures were identified as: Buddlindeterpene B(1), Buddledin B(2), Buddledin C(3), deacetyldihydrobuddledin A(4), dihydrobuddledin C(5), Suberosol B(6), Gadain (7) and Hinokinin (8).. Compounds 1,4 - 8 are isolated from B. davidii for the first time.

Topics: 4-Butyrolactone; Benzodioxoles; Buddleja; Chromatography, High Pressure Liquid; Dioxoles; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Plant Roots; Plants, Medicinal; Sesquiterpenes; Steroids

Twenty constituents were isolated from the n-hexane and chloroform extracts of Aristolochia constricta, a plant whose aerial parts have been used empirically in folk medicine for various purposes. The inhibitory effects of these constituents on smooth muscle contraction in isolated guinea-pig ileum were studied in order to observe their antispasmodic effects. 3,4-Dibenzyldihydrofuran-type lignans [(-)-cubebin, (-)-hinokinin, and (-)-pluviatolide] and a kaurene-type diterpene [(-)-kaur-16-en-19-oic acid] were isolated as active principals. They inhibited electrically induced and acetylcholine-induced contraction in the isolated guinea-pig ileum. In addition, 9- O-[(-)-kaur-15-en-17-oxyl]cubebin was isolated as a new diterpeno-lignan hybrid, although this constituent did not exhibit antispasmodic activity.

Topics: 4-Butyrolactone; Animals; Aristolochia; Benzodioxoles; Dioxoles; Diterpenes; Ecuador; Guinea Pigs; Ileum; Lignans; Medicine, Traditional; Parasympatholytics; Plants, Medicinal; Stereoisomerism

Topics: 4-Butyrolactone; Animals; Antimutagenic Agents; Benzodioxoles; Chromosome Aberrations; Dioxoles; Lignans; Mutagens; Rats; Rats, Wistar

In the screening of biologically active constituents from woody plants, the methanol extract of leaves of Chamaecyparis obtusa showed potent neurite outgrowth-promoting activity in neuronal PC12 cells. The ethyl acetate-soluble fraction of the methanol extract showed potent activity and was separated by means of various chromatographic methods to give the two new compounds 1 and 2, as well as 11 known lignan and sesquiterpene derivatives. The structures of the new compounds were determined to be 9-O-acetyldihydrosesamin (1) and 9-O-(11-hydroxyeudesman-4-yl)dihydrosesamin (2), respectively, in NMR studies including 2D-NMR experiments. Of the 13 compounds, the known compound hinokinin (5) and the new compound 2 showed potent neurite outgrowth-promoting activity in PC 12 cells.

Topics: 4-Butyrolactone; Animals; Benzodioxoles; Chamaecyparis; Dioxoles; Lignans; Molecular Structure; Nerve Growth Factor; Neurites; PC12 Cells; Plant Leaves; Plants, Medicinal; Rats

Due to their peculiar stereochemistry and numerous biological activities, lignans are of widespread interest. As only a few biosynthetic steps have been clarified to date, we aimed to further resolve the molecular basis of lignan biosynthesis. To this end, we first established that the biologically active lignan (-)-hinokinin could be isolated from in vitro cultures of Linum corymbulosum. Two hypothetical pathways were outlined for the biosynthesis of (-)-hinokinin. In both pathways, (+)-pinoresinol serves as the primary substrate. In the first pathway, pinoresinol is reduced via lariciresinol to secoisolariciresinol by a pinoresinol-lariciresinol reductase, and methylenedioxy bridges are formed later. In the second pathway, pinoresinol itself is the substrate for formation of the methylenedioxy bridges, resulting in consecutive production of piperitol and sesamin. To determine which of the proposed hypothetical pathways acts in vivo, we first isolated several cDNAs encoding one pinoresinol-lariciresinol reductase (PLR-Lc1), two phenylcoumaran benzylic ether reductases (PCBER-Lc1 and PCBER-Lc2), and two PCBER-like proteins from a cDNA library of L. corymbulosum. PLR-Lc1 was found to be enantiospecific for the conversion of (+)-pinoresinol to (-)-secoisolariciresinol, which can be further converted to give (-)-hinokinin. Hairy root lines with significantly reduced expression levels of the plr-Lc1 gene were established using RNAi technology. Hinokinin accumulation was reduced to non-detectable levels in these lines. Our results strongly indicate that PLR-Lc1 participates in (-)-hinokinin biosynthesis in L. corymbulosum by the first of the two hypothetical pathways via (-)-secoisolariciresinol.

Topics: 4-Butyrolactone; Amino Acid Sequence; Benzodioxoles; Butylene Glycols; Cells, Cultured; Cloning, Molecular; Dioxoles; DNA, Complementary; Flax; Furans; Gene Expression; Gene Library; Genes, Plant; Lignans; Molecular Sequence Data; Oxidoreductases; Phylogeny; Plant Proteins; RNA, Plant; Sequence Alignment; Sequence Homology, Amino Acid

Heliopsis longipes (Compositae) is a Mexican plant used as analgesic in pain toothache. A solution of 10mug/ml of dichloromethane extract from this plant showed analgesic activity determined by means of GABA release in mice brain slices. Through a bioassay-directed separation, fractions G-1, G-2, G-4 and G-6 at the same concentration were active. Affinin was the unique and common active compound, and evoke the GABA release 0.5min after administration at 1x10(-4)M concentration. Inactive compound were undeca-2E-en-8,10-dyinoic acid isobutylamide, hinokinin, 2'-hydroxyhinokinin, 3beta-sn-glyceroyl-(1''-palmitoxy)urs-12-ene, 13(18)-ursen-3beta-ol, 13(18)-ursen-3beta-acetate, beta-sitosterol and stigmasterol. The analgesic activity of Heliopsis longipes could be associated to affinin.

Topics: 4-Butyrolactone; Alkenes; Amides; Analgesics; Animals; Asteraceae; Benzodioxoles; Brain; Dioxoles; Female; gamma-Aminobutyric Acid; In Vitro Techniques; Lignans; Medicine, Traditional; Methylene Chloride; Mexico; Mice; Pain; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides

(-)-Hinokinin, a dibenzylbutyrolactone lignan, exhibits significant trypanocidal activity both in vitro and in vivo, and was obtained by partial synthesis from (-)-cubebin isolated from the dry seeds of Piper cubeba. Considering the good trypanocidal activity of (-)-hinokinin, as well as its potential for the development of new drugs, it is extremely important to evaluate its possible mutagenic activity to allow its safe use in humans. In the present study, we evaluated the antimutagenic effect of (-)-hinokinin on the chromosome damage induced by the chemotherapeutic agent doxorubicin (DXR). The test system employed was the analysis of micronucleated polychromatic erythrocytes in peripheral blood of Wistar rats. Additionally, the antioxidant activity of (-)-hinokinin was evaluated in in vitro experiments by measuring the production of hydrogen peroxide and other peroxides. Our results showed that animals treated with different doses of (-)-hinokinin (10, 20, and 40mg/kgb.w.) exhibited micronucleated cell frequencies similar to that of the negative control. In addition, treatment with combinations of (-)-hinokinin and DXR resulted in lower micronucleated cell frequencies than those observed for animals treated with DXR alone. The present study shows that (-)-hinokinin not only has no genotoxic effect, but is also effective in reducing the chromosome damage induced by DXR. (-)-Hinokinin exerted a significant antioxidant effect on parasite mitochondria in the protocol used, which might be one possible mechanism by which this compound may exert a protective effect on the chromosome damage induced by the free radicals generated by DXR.

Topics: 4-Butyrolactone; Animals; Antimutagenic Agents; Benzodioxoles; Chromosome Aberrations; Dioxoles; Doxorubicin; Female; Lignans; Male; Micronucleus Tests; Rats; Rats, Wistar

The activities of the crude ethanol extract from Piper cubeba seeds, (-)-cubebin and its semi-synthetic derivatives were evaluated against oral pathogens. The crude ethanol extract was more active against Streptococcus salivarius (MIC value of 80 microg/mL). (-)-Cubebin displayed MIC values ranging from 0.20 mm for Streptococcus mitis to 0.35 mm for Enterococcus faecalis. The natural product (-)-cubebin and its semi-synthetic derivative (-)-hinokinin displayed bacteriostatic activity at all evaluated concentrations, as well as fungicidal activity against Candida albicans at 0.28 mm. The O-benzyl cubebin derivative showed fungistatic and fungicidal effects against C. albicans at 0.28 mm and 0.35 mm, respectively. Also, the other dibenzylbutyrolactone derivatives [(-)-6,6'-dinitrohinokinin and (-)-O-(N,N-dimethylaminoethyl)-cubebin] displayed bacteriostatic and fungistatic effects at the evaluated concentrations. Moreover, the semi-synthetic derivative (-)-6,6'-dinitrohinokinin was the most active compound against all the evaluated microorganisms. Therefore, it may be suggested that the presence of the carbonyl group at C-9 plus the introduction of polar groups in the aromatic rings improve the antimicrobial activity of dibenzylbutyrolactone compounds.

Topics: 4-Butyrolactone; Anti-Infective Agents; Benzodioxoles; Candida albicans; Dioxoles; Enterococcus faecalis; Lignans; Microbial Sensitivity Tests; Piper; Plant Extracts; Streptococcus

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.

Topics: 4-Butyrolactone; Benzodioxoles; Databases, Factual; Dioxoles; Lignans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Quantum Theory

The health-promoting effects of whole-grain consumption have been attributed in part to their unique phytochemical contents and profiles. Wheat is an important component of the human diet; however, little is known about the phytochemical profiles of different wheat varieties, especially of old wheats. The objective of this study was to investigate the distribution of lignans, a class of phytochemicals with proved health benefit effects, of four modern and six old Italian soft wheat (Triticum aestivum L.) cultivars. In this work, we describe the first analytical method involving CE coupled to MS (CE-MS) used to identify and quantify lignan compounds in grains of different cultivars of wheat. Total lignan content determined by CE-ESI-MS was 2.60+/-0.21 and 5.00+/-1.30 microg/g dry seed weight for modern and old cultivars, respectively. Secoisolariciresinol and pinoresinol were detected in all ten investigated soft wheat cultivars, whereas arctigenin, hinokinin, and syringaresinol were exclusively detected in old genotypes. Significant differences between modern and old cultivars were also observed for the number of glycosidic forms. Results highlighted the high content and unique composition in lignans of old cultivars suggesting their uses into a wide range of regular and specialty food products naturally enriched with health-promoting compounds.

Topics: 4-Butyrolactone; Benzodioxoles; Butylene Glycols; Dioxoles; Electrophoresis, Capillary; Furans; Italy; Lignans; Seeds; Tandem Mass Spectrometry; Triticum

In this paper we present a complete 1H and 13C NMR spectral analysis of three lignan lactones (methylpluviatolide, dimethylmatairesinol and hinokinin) by the use of techniques such as COSY, HMQC, HMBC and J-resolved. Complete assignment and all homonuclear hydrogen coupling constant measurements were performed, providing enough data also to the confirmation of the relative stereochemistry.

Topics: 4-Butyrolactone; Benzodioxoles; Carbon Isotopes; Dioxoles; Lactones; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Protons

[reaction: see text] Atom transfer carbonylation (ATC) of alkyl iodides leading to carboxylic acid esters is effectively accelerated by Pd(PPh(3))(4) and Mn(2)(CO)(10) under photoirradiation conditions. In the presence of amines, Pd(0) complexes affected double carbonylations leading to alpha-keto amides, whereas Mn(2)(CO)(10) accelerated only a single carbonylation reaction leading to the corresponding amides. The Pd(0)-accelerated ATC system was successfully applied to the synthesis of hinokinin and dihydrocapsaicin.

Topics: 4-Butyrolactone; Alkynes; Benzodioxoles; Capsaicin; Dioxoles; Iodides; Lignans; Manganese Compounds; Molecular Structure; Palladium

The arylbutyrolactone lignans (-)-hinokinin, 3,4 : 3',4'-bis(methylenedioxy)-lign-7( E)-en-9,9'-olide and 3,4 : 3',4'-bis(methylenedioxy)-lign-7( Z)-en-9,9'-olide, hitherto unknown for the genus LINUM, were isolated by HPLC from callus cultures of LINUM CORYMBULOSUM (Linaceae) and identified by spectroscopic methods.

Topics: 4-Butyrolactone; Benzodioxoles; Culture Techniques; Dioxoles; Flax; Lignans; Molecular Structure

Using an HBV-producing cell line and inhibition of the expression of the HBsAg and HBeAg as antiviral indicators, a study was conducted on 25 compounds isolated from four Phyllanthus (Euphorbiaceae) plants, including P. amarus Schum. & Thonn., P. multi florus Willd., P. tenellus Roxb. and P. virgatus Forst. f. It was found that niranthin (1), nirtetralin (3), hinokinin (5) and geraniin (13) at the non-cytotoxic concentration of 50 micro m, suppressed effectively both HBsAg and HBeAg expression, with the highest inhibition at 74.3%, 45.3%; 69.6%, 33.9%; 68.1%, 52.3%; 32.1%, 46.6%, respectively. Of these, niranthin (1) showed the best anti-HBsAg activity, while the most potent anti-HBeAg activity was observed with hinokinin (5).

Topics: 4-Butyrolactone; Anisoles; Benzodioxoles; Culture Techniques; Dioxoles; Enzyme-Linked Immunosorbent Assay; Glucosides; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Hydrolyzable Tannins; Lignans; Molecular Structure; Phyllanthus; Phytotherapy; Plant Extracts; Tannins