RESUMO
Novel flavanones that incorporate chromene motifs are synthesized via a one-step multicomponent reaction. The structures of the new chromenes are elucidated by using IR, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC, HMBC, and elemental analysis. The new compounds are screened for their in vitro antimicrobial and cytotoxic activities. The antimicrobial properties are investigated and established against seven human pathogens, employing the agar well diffusion method and the minimum inhibitory concentrations. A majority of the assessed derivatives are found to exhibit significant antimicrobial activities against most bacterial strains, in comparison to standard reference drugs. Moreover, their cytotoxicity is appraised against four different human carcinoma cell lines: human colon carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), human breast adenocarcinoma (MCF-7), and adenocarcinoma human alveolar basal epithelial cell (A-549). All the desired compounds are subjected to in-silico studies, forecasting their drug likeness, bioactivity, and the absorption, distribution, metabolism, and excretion (ADME) properties prior to their synthetic assembly. The in-silico molecular docking evaluation of all the targeted derivatives is undertaken on gyrase B and the cyclin-dependent kinase. The in-silico predicted outcomes were endorsed by the in vitro studies.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/química , Flavanonas/química , Flavanonas/farmacologia , Neoplasias/tratamento farmacológico , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The human bitter taste receptor hTAS2R39 can be activated by many dietary (iso)flavonoids. Furthermore, hTAS2R39 activity can be blocked by 6-methoxyflavanones, 4'-fluoro-6-methoxyflavanone in particular. A structure-based pharmacophore model of the hTAS2R39 binding pocket was built using Snooker software, which has been used successfully before for drug design of GPCRs of the rhodopsin subfamily. For the validation of the model, two sets of compounds, both of which contained actives and inactives, were used: (i) an (iso)flavonoid-dedicated set, and (ii) a more generic, structurally diverse set. Agonists were characterized by their linear binding geometry and the fact that they bound deeply in the hTAS2R39 pocket, mapping the hydrogen donor feature based on T5.45 and N3.36, analogues of which have been proposed to play a key role in activation of GPCRs. Blockers lack hydrogen-bond donors enabling contact to the receptor. Furthermore, they had a crooked geometry, which could sterically hinder movement of the TM domains upon receptor activation. Our results reveal characteristics of hTAS2R39 agonist and bitter blocker binding, which might facilitate the development of blockers suitable to counter the bitterness of dietary hTAS2R39 agonists in food applications.
Assuntos
Receptores de Superfície Celular/metabolismo , Software , Sítios de Ligação , Desenho de Fármacos , Flavanonas/química , Flavanonas/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidoresRESUMO
8-Prenylnaringenin (8-PN) and naringenin (Nar) are phytoestrogens found in food items and nutritional supplements, while 6-(1.1-dimethylallyl)naringenin (6-DMAN) is a component of an African plant. Besides their assumed beneficial effects they may promote mammary and endometrial cancer. We therefore assessed their proliferative and estrogenic potential on the mammary gland in vitro and in vivo. In competitive estrogen receptor (ER) ligand binding assays 8-PN displayed a high relative binding affinity for both ERs with a preference for ERα and had the strongest mitotic effect on MCF-7 cells among the test substances. In a three day exposure in young adult ovariectomized female rats 15 mg/kg 8-PN had the highest capacity to increase the number of terminal end buds (TEB) in the mammary gland and stimulated expression of proliferation markers in epithelial ductal cells, followed by 6-DMAN and Nar, but overall their capacity to stimulate proliferation was weak in comparison to 17ß-Estradiol (E2).
Assuntos
Flavanonas/farmacologia , Glândulas Mamárias Animais/citologia , Anfirregulina/metabolismo , Animais , Caseínas/metabolismo , Contagem de Células , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Flavanonas/administração & dosagem , Flavanonas/química , Flavanonas/metabolismo , Humanos , Concentração Inibidora 50 , Antígeno Ki-67/metabolismo , Células MCF-7 , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Endogâmicos Lew , Receptores de Progesterona/metabolismoRESUMO
Many (dietary) bitter compounds, e.g. flavonoids, activate bitter receptor hTAS2R39 in cell-based assays. Several flavonoids, amongst which some flavanones, are known not to activate this receptor. As certain flavanones are known to mask bitter taste sensorially, flavanones might act as bitter receptor antagonists. Fourteen flavanones were investigated for their potential to reduce activation of hTAS2R39 by epicatechin gallate (ECG), one of the main bitter compounds occurring in green tea. Three flavanones showed inhibitory behavior towards the activation of hTAS2R39 by ECG: 4'-fluoro-6-methoxyflavanone, 6,3'-dimethoxyflavanone, and 6-methoxyflavanone (in order of decreasing potency). The 6-methoxyflavanones also inhibited activation of hTAS2R14 (another bitter receptor activated by ECG), though to a lesser extent. Dose-response curves of ECG at various concentrations of the full antagonist 4'-fluoro-6-methoxyflavanone and wash-out experiments indicated reversible insurmountable antagonism. The same effect was observed for the structurally different agonist denatonium benzoate.
Assuntos
Catequina/análogos & derivados , Flavanonas/farmacologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Bioensaio , Cálcio/metabolismo , Sinalização do Cálcio , Catequina/antagonistas & inibidores , Catequina/química , Catequina/farmacologia , Flavanonas/química , Expressão Gênica , Células HEK293 , Humanos , Ligação Proteica , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade , Paladar/fisiologia , Chá/química , TransgenesRESUMO
Scutellaria baicalensis has been used as a traditional herbal medicine for bronchitis, hepatitis, and allergic diseases. The root of Scutellaria baicalensis contains active flavonoid components, including baicalin, baicalein, wogonoside, and wogonin, which have pharmaceutical properties. In the present study, the antiallergic properties of a standardized aqueous extract of S. baicalensis were evaluated, and the skin toxicity of its dermal application was also determined. The in vivo and in vitro assays were performed by using the ß-hexosaminidase assay in rat basophilic leukemia cells (RBL-2H3) and cutaneous skin reaction in BALB/c mice, respectively. In addition, the acute dermal irritation/corrosion test was carried out in New Zealand white rabbits, and the skin sensitization test was conducted by Buhler's method in Hartley guinea pigs to estimate the safety of the standardized aqueous extract of S. baicalensis for topical application. ß-Hexosaminidase release in RBL-2H3 was markedly decreased following treatment with the standardized aqueous extract of S. baicalensis. It also ameliorated antigen-induced ear swelling compared with the control group in BALB/c mice. In the toxicological studies, it did not induce any dermal irritation/corrosion in rabbits or skin sensitization in guinea pigs. Although still limited, these results concerning the toxicological effects of S. baicalensis could be an initial step toward the topical application of S. baicalensis extracts on hypersensitive skin.
Assuntos
Antialérgicos/farmacologia , Flavonoides/farmacologia , Hipersensibilidade , Extratos Vegetais/farmacologia , Administração Tópica , Animais , Antialérgicos/química , Antialérgicos/isolamento & purificação , Linhagem Celular Tumoral , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Raízes de Plantas/química , Plantas Medicinais , Coelhos , Ratos , Scutellaria baicalensis/química , Pele/efeitos dos fármacos , beta-N-Acetil-Hexosaminidases/análiseRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Pyungwi-san (PWS, Heii-san in Japanese) is a mixture of six herbs and is traditionally used in Northeast Asia (especially Korea and Japan) for the treatment of gastrointestinal disorder, such as dyspepsia and inappetance induced by gastric dilatation and gastrointestinal catarrh. AIM OF THE STUDY: Although PWS is a widely used herbal prescription in Korea and Japan, little information is available in the literature on the safety and toxicity of PWS. As part of a safety evaluation of PWS, the present study evaluated the potential genotoxicity of PWS using a standard battery of test. MATERIALS AND METHODS: We prepared PWS using a water extraction method and simultaneously extracted three compounds from PWS using high performance liquid chromatography. The PWS extract that was obtained was assayed for genotoxicity using the standard three tests recommended by the Korea Food and Drug Administration. These tests included the bacterial reverse mutation test (Ames test), the chromosomal aberration test using China hamster lung cells, and the micronucleus test using ICR mice. RESULTS: The Ames test showed that the PWS extract did not induce an increase in the number of revertant colonies compared with vehicle control at any dose in all of tester strains. In the micronucleus test, no significant increase was observed in micronucleated polychromatic erythrocytes (MNPCEs) at any dose of PWS extract compared with vehicle control. Conversely, chromosomal aberration test showed that the PWS extract at a dosage of 4500 µg/mL induced an increase in the number of chromosomal aberrations in the 6 h group with metabolic activation compared with the vehicle control. CONCLUSION: PWS extract exhibits genotoxicity, based on the results of the chromosomal aberration test. Thus, further detailed experiments will be needed to identify the ingredient responsible for inducing this genotoxicity and to determine its mechanism.
Assuntos
Fármacos Gastrointestinais/toxicidade , Mutagênicos/toxicidade , Preparações de Plantas/toxicidade , Animais , Linhagem Celular , Aberrações Cromossômicas/induzido quimicamente , Cricetinae , Cricetulus , Etnofarmacologia , Flavanonas/química , Flavanonas/toxicidade , Fármacos Gastrointestinais/química , Glucosídeos/química , Glucosídeos/toxicidade , Ácido Glicirrízico/química , Ácido Glicirrízico/toxicidade , Hesperidina/química , Hesperidina/toxicidade , Humanos , Masculino , Medicina Tradicional Coreana , Camundongos , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Testes de Mutagenicidade , Mutagênicos/química , Fitoterapia/efeitos adversos , Preparações de Plantas/química , República da CoreiaRESUMO
An efficient total synthesis of 7-O-beta-D-glucopyranosyl-4'-O-alpha-L-rhamnopyranosyl apigenin (1) was developed in only four steps from naringenin. Compared with our previously reported first total synthesis route (six steps and 19.6% overall yield), this new route contained two steps of highly regioselective glycosylation without any selective protection steps. 7,4'-di-O-beta-D-glucopyranosyl apigenin (2) was also prepared efficiently by this method. The method is environmentally friendly, economical, and provides a greener method for flavonoid synthesis starting from an inexpensive flavanone.
Assuntos
Apigenina/química , Apigenina/síntese química , Flavanonas/química , Química Verde/métodos , Glicosilação , Química Verde/economia , Estereoisomerismo , Especificidade por SubstratoRESUMO
The flavonoid content of several methanolic extract fractions of Navel orange peel (flavedo and albedo of Citrus sinensis) cultivated in Crete (Greece) was first analysed phytochemically and then assessed for its antioxidant activity in vitro. The chemical structures of the constituents fractionated were originally determined by comparing their retention times and the obtained UV spectral data with the available bibliographic data and further verified by detailed LC-DAD-MS (ESI+) analysis. The main flavonoid groups found within the fractions examined were polymethoxylated flavones, O-glycosylated flavones, C-glycosylated flavones, O-glycosylated flavonols, O-glycosylated flavanones and phenolic acids along with their ester derivatives. In addition, the quantitative HPLC analysis confirmed that hesperidin is the major flavonoid glycoside found in the orange peel. Interestingly enough, its quantity at 48 mg/g of dry peel permits the commercial use of orange peel as a source for the production of hesperidin. The antioxidant activity of the orange peel methanolic extract fractions was evaluated by applying two complementary methodologies, DPPH(*) assay and the Co(II)/EDTA-induced luminol chemiluminescence approach. Overall, the results have shown that orange peel methanolic extracts possess moderate antioxidant activity as compared with the activity seen in tests where the corresponding aglycones, diosmetin and hesperetin were assessed in different ratios.
Assuntos
Antioxidantes/metabolismo , Citrus sinensis/química , Hesperidina/metabolismo , Extratos Vegetais/metabolismo , Antioxidantes/análise , Antioxidantes/química , Compostos de Bifenilo/química , Cromatografia Líquida , Diosmina/análise , Diosmina/química , Diosmina/metabolismo , Flavanonas/análise , Flavanonas/química , Flavanonas/metabolismo , Grécia , Hesperidina/análise , Hesperidina/química , Medições Luminescentes , Luminol/química , Metanol/química , Modelos Químicos , Picratos/química , Extratos Vegetais/análise , Extratos Vegetais/química , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.
Assuntos
Flavanonas/química , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Flavanonas/isolamento & purificação , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Fenol/química , Software , Espectrofotometria Infravermelho/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , EstereoisomerismoRESUMO
The effect of (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CyD) on the solubility properties and spectroscopic features of hesperetin and its 7-rhamnoglucoside, hesperidin, was qualitatively and quantitatively investigated in water, by means of UV-vis absorption and fluorescence spectroscopy. The stoichiometric ratios and stability constants describing the extent of formation of the complexes have been determined by phase-solubility measurements; in both cases type-A(L) diagrams have been obtained (soluble 1:1 complexes). The higher degree of interaction showed by hesperetin may be attributed to the higher hydrophobicity and smaller size of the aglycone molecule, which therefore exhibits a greater affinity for the CyD and fits better into the cavity. The effect of molecular encapsulation on the two flavanones antioxidant activity was afterwards evaluated by means of different biological assays, concerned to the different mechanisms of in vivo action. The protection efficacy was in all cases higher for the complexed drugs, with respect to the free ones; these results are of great interest for their potential usefulness in pharmaceutics.