RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Glabridin, extracted from Glycyrrhiza glabra L., is widely used for the treatment of hyperpigmentation because of its anti-inflammatory and antioxidant activities and its ability to inhibit melanin synthesis. This led to the strict regulation of its quality and safety. However, traditional quality control methods used for plant extracts cannot reflect the product quality owing to multiple unknown impurities, which necessitates the further analysis of impurities. AIM OF THE STUDY: The study identified the toxic impurities of glabridin and their toxicological mechanism. MATERIALS AND METHODS: In total, 10 glabridin samples from different sources were quantified using high-performance liquid chromatography. Sample toxicities were evaluated using zebrafish and cell models. To identify impurities, samples with different toxicity were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry. The toxicity of related impurities was verified in the zebrafish model. Phalloidin stain was used to evaluate subtle changes in myofibril alignment. RESULTS: Although glabridin content in the samples was similar, there were significant differences in toxicity. The results were verified using four different mammalian cell lines. Higher contents of glabrone and glabrol were identified in the sample with the highest toxicity. In the zebrafish model, the addition of glabrol reduced the LC50 of glabridin to 9.224, 6.229, and 5.370 µM at 48, 72, and 96 h post-fertilization, respectively, whereas glabrone did not have any toxic effect. Phalloidin staining indicated that a glabrol impurity exacerbates the myotoxicity of glabridin in zebrafish embryos. CONCLUSION: Glabrol, but not glabrone, was identified as a key impurity that increased glabridin toxicity. This finding indicates that controlling glabrol content is necessary during glabridin product production.
Assuntos
Flavonoides/toxicidade , Glycyrrhiza/química , Isoflavonas/toxicidade , Miofibrilas/efeitos dos fármacos , Fenóis/toxicidade , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Embrião não Mamífero/efeitos dos fármacos , Feminino , Flavonoides/química , Humanos , Isoflavonas/química , Masculino , Espectrometria de Massas , Camundongos , Miofibrilas/patologia , Fenóis/química , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Controle de Qualidade , Peixe-ZebraRESUMO
Twenty-six alkaloids, including the new taberines A-I (1-9), were obtained from Tabernaemontana corymbosa. The structures and absolute configurations were elucidated via MS, NMR, and ECD spectroscopic data analyses. Alkaloids 1-4 are new vobasinyl-ibogan alkaloids, and 1 is characterized by an unusual 1,3-oxazinane moiety. Alkaloids 4 and 16 exhibited moderate cytotoxic potency against various human cancer cell lines, while 4, 10, 11, 13, 14, and 16 showed attenuation of lysosomal acidification activity (EC50: 12.9-29.8 µM), thereby inhibiting autophagic flux.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Tabernaemontana/química , Ácidos , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura MolecularRESUMO
Two new monoterpenoid indole alkaloids, tabervarines A (1) and B (2), along with seven known monoterpenoid indole alkaloids, were isolated from the methanol extract of the twigs and leaves of Tabernaemontana divaricata. The structures including the absolute configurations of the new alkaloids were elucidated based on MS, NMR, and ECD calculation. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines were also evaluated.
Assuntos
Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Tabernaemontana/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Folhas de Planta/química , Alcaloides de Triptamina e Secologanina/farmacologia , Análise Espectral/métodosRESUMO
Nineteen vobasinyl-ibogan-type bisindole alkaloids, including nine new compounds, taburnaemines A-I (1-9), were isolated from the twigs and leaves of Tabernaemontana corymbosa. The structures and absolute configurations of the new alkaloids were determined by a combination of MS, NMR, and ECD analyses. Alkaloids 1-5 contain a rare 1,3-oxazinane moiety in the vobasinyl unit, while 6 has an uncommon 1,3-oxazolidine moiety in the iboga unit. The absolute configurations of alkaloid 1 and the known alkaloid tabernaecorymbosine A (10) were confirmed by single-crystal X-ray diffraction analysis. All of the bisindole alkaloids, except 2 and 16'-decarbomethoxytabernaecorymbosine A (14), showed antiproliferative activity (IC50 2.6-9.8 µM) against several human cancer cell lines, including A-549, MDA-MB-231, MCF-7, KB, and P-glycoprotein-overexpressing multidrug-resistant KB cells. The preliminary structure-activity relationship correlations are also discussed.
Assuntos
Alcaloides Indólicos/química , Tabernaemontana/química , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Alcaloides Indólicos/farmacologia , Células KB , Células MCF-7 , Folhas de Planta/química , Relação Estrutura-AtividadeRESUMO
Two new indole alkaloids, winphyllines A (1) and B (4), along with four known alkaloids, Nb-demethylechitamine (2), 17-O-acetylnorechitamine (3), 12-methoxyechitamidine (5), and N(4)-demethylastogustine (6), were isolated from the methanol extract of the twigs of Alstonia rostrata. The structures of 1 and 4 were elucidated by means of HRMS and NMR spectroscopic methods. The in vitro cytotoxic activity of the isolated alkaloids against several human cancer cell lines was evaluated.
Assuntos
Alstonia/química , Antineoplásicos Fitogênicos/química , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Tabercorymines A (1) and B (2), two new vobasinyl-ibogan-type bisindole alkaloids with an unprecedented skeleton, were isolated from Tabernaemontana corymbosa. Their structures were established by a combination of spectroscopic data, chemical transformation, single-crystal X-ray diffraction, and ECD calculation. Compound 1 represents a novel bisindole alkaloid, characterized by a caged heteropentacyclic ring system incorporating an unprecedented C-7/C-20 bond in the vobasinyl unit. Alkaloids 1 and 2 showed potent antiproliferative activity against several human cancer cell lines, including vincristine-resistant KB.