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In this work, a benzofuranone-derived fluorescent probe BFSF was developed for imaging the sulphite level in living hypoxia pulmonary cells. Under the excitation of 510 nm, BFSF showed a strong fluorescence response at 570 nm when reacted with sulphite. In the solution system, the constructed hypercapnia and serious hypercapnia conditions did not affect the fluorescence response. In comparison with the recently reported probes, BFSF suggested the advantages including rapid response, steady signal reporting, high specificity and low cytotoxicity upon living lung cells. Under a normal incubation atmosphere, BFSF realized the imaging of both exogenous and endogenous sulphite in living pulmonary cells. In particular, BFSF achieved imaging the decrease of the sulphite level under severe hypoxia as well as the recovery of the sulphite level with urgent oxygen supplement. With the imaging capability for the sulphite level in living pulmonary cells under hypoxia conditions, BFSF together with the information herein was meaningful for investigating the anaesthesia-related biological indexes.
Assuntos
Benzofuranos , Corantes Fluorescentes , Pulmão , Sulfitos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Benzofuranos/química , Benzofuranos/síntese química , Sulfitos/análise , Sulfitos/química , Pulmão/diagnóstico por imagem , Pulmão/citologia , Humanos , Hipóxia Celular , Imagem Óptica , Estrutura MolecularRESUMO
The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse ß-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.
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Antivirais , Benzofuranos , Genótipo , Hepacivirus , Proteínas não Estruturais Virais , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/química , Benzofuranos/química , Benzofuranos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/genética , Antivirais/farmacologia , Antivirais/química , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Sítios de Ligação , Ligação Proteica , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , RNA Polimerase Dependente de RNARESUMO
Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1a) and of five benzofuran derivatives (2a, 2b, 2c, 2f and 2g) by single crystal X-Ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2b, 2e, and 2g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition > 60%). Compound 2e showed an IC50 of 0.2 µM and was selected for further analysis, results reinforce its anticancer potential.
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The minimum bactericidal concentration (MBC) of antibiotics is an important parameter for the potency of a drug in eradicating a bacterium as well as an important measure of the potential of a drug candidate in research and development. We have established a fluorescence-based microscopy method for the determination of MBCs against the non-tuberculous mycobacterium Mycobacterium abscessus (Mycobacteroides abscessus) to simplify and accelerate the performance of MBC determination compared to counting colony forming units on agar. Bacteria are labelled with the trehalose-coupled dye 3HC-2-Tre and analysed in a 96-well plate. The results of the new method are consistent with MBC determination by plating on agar. The method was used to evaluate the bactericidality of the antibiotics rifabutin, moxifloxacin, amikacin, clarithromycin and bedaquiline. Bactericidal effects against M. abscessus were observed, which are consistent with literature data.
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Antibacterianos , Testes de Sensibilidade Microbiana , Microscopia de Fluorescência , Mycobacterium abscessus , Mycobacterium abscessus/efeitos dos fármacos , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Microscopia de Fluorescência/métodos , Amicacina/farmacologia , Rifabutina/farmacologia , Diarilquinolinas/farmacologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Claritromicina/farmacologia , Moxifloxacina/farmacologiaRESUMO
Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-ß aggregates, which lead to oxidative stress and neuronal decay. Targeted α-therapy (TAT) has been shown to be efficacious against metastatic cancer. TAT takes advantage of tumor-localized α-particle emission to break disease-associated covalent bonds while minimizing radiation dose to healthy tissues due to the short, micrometer-level, distances traveled. We hypothesized that TAT could be used to break covalent bonds within amyloid-ß aggregates and facilitate natural plaque clearance mechanisms. Methods: We synthesized a 213Bi-chelate-linked benzofuran pyridyl derivative (BiBPy) and generated [213Bi]BiBPy, with a specific activity of 120.6 GBq/µg, dissociation constant of 11 ± 1.5 nM, and logP of 0.14 ± 0.03. Results: As the first step toward the validation of [213Bi]BiBPy as a TAT agent for the reduction of Alzheimer disease-associated amyloid-ß, we showed that brain homogenates from APP/PS1 double-transgenic male mice (6-9 mo old) incubated with [213Bi]BiBPy exhibited a marked reduction in amyloid-ß plaque concentration as measured using both enzyme-linked immunosorbent and Western blotting assays, with a half-maximal effective concentration of 3.72 kBq/pg. Conclusion: This [213Bi]BiBPy-concentration-dependent activity shows that TAT can reduce amyloid plaque concentration in vitro and supports the development of targeting systems for in vivo validations.
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Chemical investigation of the EtOAc extract of a deep-sea derived fungus Aspergillus sp. SCSIO41032 resulted in the isolation of ten known compounds, including eight aspochalasins. Their structures were elucidated by using extensive NMR spectroscopic, mass spectrometric and single crystal X-ray diffraction analysis. The detailed crystallographic data for structures 1, 2, and 4, along with the relative configurations of aspochalasin E (3) determined by its acetonide derivative were reported for the first time. The results of antitumor and antiviral activities showed that 3 displayed moderate antitumor activities against 22Rv1, PC-3, A549, and HCT-15 cell lines with IC50 values ranged from 5.9 ± 0.8 to 19.0 ± 7.7 µM, and 9 exhibited moderate antiviral activities against HSV-1/2 with EC50 values of 9.5 ± 0.5 and 5.4 ± 0.6 µM, respectively. Plate clone formation assays results indicated that 3 inhibited the 22Rv1, PC-3 cells growth in a dose-dependent manner.
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Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.
Assuntos
Benzofuranos , Privação do Sono , Animais , Masculino , Camundongos , Privação do Sono/tratamento farmacológico , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
The correlation between the CCL20/CCR6 axis and autoimmune and non-autoimmune disorders is widely recognized. Inhibition of the CCL20-dependent cell migration represents therefore a promising approach for the treatment of many diseases, such as inflammatory bowel diseases and colorectal cancer. We report herein our efforts to explore the biologically relevant chemical space around the benzofuran scaffold of MR120, a modulator of the CCL20/CCR6 axis previously discovered by our group. A functional screening allowed us to identify C4 and C5-substituted derivatives as the most effective inhibitors of the CCL20-induced chemotaxis of human peripheral blood mononuclear cells (PBMC). Moreover, selected compounds (16 e and 24 b) also proved to potently inhibit the growth of different colon cancer cell lines, with cytotoxic/cytostatic and antiproliferative activity.
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The fruit of Choerospondias axillaris (Anacardiaceae), known as south wild jujube in China, has been consumed widely in several regions of the world to produce fruit pastille and leathers, juice, jam, and candy. A comprehensive chemical study on the fresh fruits led to the isolation and identification of 18 compounds, including 7 new (1-7) and 11 known (8-18) comprised of 5 alkenyl (cyclohexenols and cyclohexenones) derivatives (1-5), 3 benzofuran derivatives (6-8), 6 flavonoids (9-14) and 4 lignans (15-18). Their structures were elucidated by extensive spectroscopic analysis. The known lignans 15-18 were isolated from the genus Choerospondias for the first time. Most of the isolates exhibited significant inhibitory activity on α-glucosidase with IC50 values from 2.26 ± 0.06 to 43.9 ± 0.96 µM. Molecular docking experiments strongly supported the potent α-glucosidase inhibitory activity. The results indicated that C. axillaris fruits could be an excellent source of functional foods that acquire potential hypoglycemic bioactive components.
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In this work, a triphenylamine-benzofuran-derived fluorescent probe TBSF was developed for monitoring the sulfite level in Chinese medicinal materials and imaging in living cells. In the testing system, under 445 nm excitation, TBSF responded to sulfite steadily with a 540 nm fluorescence reporting signal. The testing system showed advantages including high sensitivity, rapid response, and high selectivity. In particular, TBSF achieved the sulfite detection in the water decoction of Chinese medicinal materials from both addition and excessive fumigation. It also realized the intracellular imaging of both exogenous and endogenous sulfite in living HepG2 cells. The imaging in water decoction-treated cells inferred the potential for the interdisciplinary detection.
Assuntos
Benzofuranos , Corantes Fluorescentes , Espectrometria de Fluorescência , Sulfitos , Sulfitos/análise , Corantes Fluorescentes/química , Humanos , Benzofuranos/química , Benzofuranos/análise , Células Hep G2 , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Compostos de Anilina/química , Imagem ÓpticaRESUMO
We report an unprecedented iron-catalyzed C-H annulation using readily available 2-vinylbenzofurans as the reaction pattern. The redox-neutral strategy, based on cheap, non-toxic, and earth-abundant iron catalysts, exploits triazole assistance to promote a cascade C-H alkylation, benzofuran ring-opening and insertion into a Fe-N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis.
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Oxidative stress represents a hallmark for many degenerative pathologies of the Central Nervous System. Throughout life, the constant pressure of noxious stimuli and/or episodes of traumatic events may expose the brain to a microenvironment where the non-balanced reactive oxygen species inevitably lead to neuronal loss and cognitive decline. HO-1, a 32 kDa heat-shock protein catalyzing the degradation of heme into carbon monoxide (CO), iron and biliverdin/bilirubin is considered one of the main antioxidant defense mechanisms playing pivotal roles in neuroprotection. Restoring the redox homeostasis is the goal of many natural or synthetic antioxidant molecules pursuing beneficial effects on brain functions. Here, we investigated the antioxidant capacity of four selected benzofuran-2-one derivatives in a cellular model of neurodegeneration represented by differentiated SH-SY5Y cells exposed to catechol-induced oxidative stress. Our main results highlight how all the molecules have antioxidant properties, especially compound 9, showing great abilities in reducing intracellular ROS levels and protecting differentiated SH-SY5Y cells from catechol-induced death. This compound above all seems to boost HO-1 mRNA and perinuclear HO-1 protein isoform expression when cells are exposed to the oxidative insult. Our findings open the way to consider benzofuran-2-ones as a novel and promising adjuvant antioxidant strategy for many neurodegenerative disorders.
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An attractive approach for the preparation of spirocyclic benzofuran-furocoumarins has been developed through iodine-catalyzed cascade annulation of 4-hydroxycoumarins with aurones. The reaction involves Michael addition, iodination, and intramolecular nucleophilic substitution in a one-step process, and offers an efficient method for easy access to a series of valuable spirocyclic benzofuran-furocoumarins in good yields (up to 99%) with excellent stereoselectivity. Moreover, this unprecedented protocol provides several advantages, including readily available materials, an environmentally benign catalyst, a broad substrate scope, and a simple procedure.
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It is well known that anthracene is a persistent organic pollutant. Among the four natural polycyclic aromatic hydrocarbons (PAHs) degrading strains, Comamonas testosterone (CT1) was selected as the strain with the highest degradation efficiency. In the present study, prokaryotic transcriptome analysis of CT1 revealed an increase in a gene that encodes tryptophane-2,3-dioxygenase (T23D) in the anthracene and erythromycin groups compared to CK. Compared to the wild-type CT1 strain, anthracene degradation by the CtT23D knockout mutant (CT-M1) was significantly reduced. Compared to Escherichia coli (DH5α), CtT23D transformed DH5α (EC-M1) had a higher degradation efficiency for anthracene. The recombinant protein rT23D oxidized tryptophan at pH 7.0 and 37 °C with an enzyme activity of 2.42 ± 0.06 µmol min-1·mg-1 protein. In addition, gas chromatography-mass (GC-MS) analysis of anthracene degradation by EC-M1 and the purified rT23D revealed that 2-methyl-1-benzofuran-3-carbaldehyde is an anthracene metabolite, suggesting that it is a new pathway.
Assuntos
Comamonas testosteroni , Dioxigenases , Hidrocarbonetos Policíclicos Aromáticos , Comamonas testosteroni/genética , Dioxigenases/metabolismo , Triptofano , Antracenos , Hidrocarbonetos Policíclicos Aromáticos/metabolismoRESUMO
There are >350 species of the Ophiobolus genus, which is not yet very well-known and lacks research reports on secondary metabolites. Three new 3,4-benzofuran polyketides 1-3, a new 3,4-benzofuran polyketide racemate 4, two new pairs of polyketide enantiomers (±)-5 and (±)-7, two new acetophenone derivatives 6 and 8, and three novel 1,4-dioxane aromatic polyketides 9-11, were isolated from a fungus Ophiobolus cirsii LZU-1509 derived from an important medicinal and economic crop Anaphalis lactea. The isolation was guided by LC-MS/MS-based GNPS molecular networking analysis. The planar structures and relative configurations were mainly elucidated by NMR and HR-ESI-MS data. Their absolute configurations were determined by using X-ray diffraction analysis and via comparing computational and experimental ECD, NMR, and specific optical rotation data. 9 possesses an unreported 5/6/6/6/5 five-ring framework with a 1,4-dioxane, and 10 and 11 feature unprecedented 6/6/6/5 and 6/6/5/6 four-ring frames containing a 1,4-dioxane. The biosynthetic pathways of 9-11 were proposed. 1-11 were nontoxic in HT-1080 and HepG2 tumor cells at a concentration of 20 µM, whereas 3 and 5 exerted higher antioxidant properties in the hydrogen peroxide-stimulated model in the neuron-like PC12 cells. They could be potential antioxidant agents for neuroprotection.
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Antioxidantes , Ascomicetos , Policetídeos , Estrutura Molecular , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Policetídeos/química , Humanos , Ascomicetos/química , Linhagem Celular Tumoral , Animais , ChinaRESUMO
The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran-indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran-indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations.
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The development of synthetically accessible photoswitches showing an efficient performance in aqueous medium has recently become an urgent task due to the rapid progress of photopharmacology and novel biomedical applications. In response to this challenge, in this work, aurone derivatives are introduced as a novel class of efficient visible-light photoswitches for aqueous medium. In general, aurones exhibit superior performance in water, including significantly higher quantum yields, compared with other indigoid photoswitches (hemithioindigo and hemiindigo). Especially remarkable are the half-lives of the photoinduced E-isomers of aurones in water, reaching up to 7â years. Further modification of the aurone scaffold with substituents that increase water solubility does not affect most of the photoswitching characteristics and even improves some them. The highly advantageous property profile of the aurone photoswitches make them a perfect novel platform for the design of light-controllable systems in the areas requiring photoswitching in aqueous medium.
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In this paper, a novel cascade reaction of caesium carbonate-promoted Michael addition and lactonization for the one-pot synthesis of 3-alkyl-3-N-substituted aminobenzofuran-2(3H)-one derivatives has been established based on the screening of the alkaline reagents and optimization of reaction conditions, in which the N-substituted (ortho-hydroxy)aryl glycine esters were used as the Michael donors to react with different α, ß-unsaturated carbonyl compounds. In the case of using the asymmetric starting material, the epimers could be successfully separated by conventional chromatography. In addition, plausible mechanisms were suggested and the absolute configuration of the epimer was analysed. All the chemical structures of unreported benzofuran-2(3H)-one derivatives were characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, IR and high-resolution mass spectrometry (HRMS).
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The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.
Assuntos
Acetilcolinesterase , Benzofuranos , Butirilcolinesterase , Simulação de Acoplamento Molecular , Benzofuranos/farmacologia , Córtex CerebralRESUMO
Boxelder and sycamore maple contain hypoglycin A (HGA), the toxic metabolite of which, MCPA-CoA, inhibits fatty acid ß-oxidation, causing seasonal pasture myopathy (SPM) or atypical myopathy (AM), respectively. White snakeroot and rayless goldenrod contain multiple benzofuran ketones (BFKs). The identity/toxicity of BFKs appear variable, possibly involving interactions between toxins/toxic metabolites, but ultimately inhibit cellular energy metabolism. Unthrifty horses grazing sparse pastures during the fall appear predisposed to these plant-associated, frequently fatal, toxic myopathies. Toxidromes are characterized by varying degrees of rhabdomyolysis and cardiac myonecrosis, with plant toxins remaining toxic in hay and being excreted in milk.