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1.
J Agric Food Chem ; 67(42): 11769-11777, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31575115

RESUMO

The inhibitory effect of brazilin against α-synuclein (α-syn) fibrillogenesis, disruption effect against mature fibrils, and the following cytotoxicity were examined by systematical biochemical, biophysical, cellular biological, and molecular simulation experiments. It is found that brazilin inhibited α-syn fibrillogenesis and disrupted the performed fibrils with a concentration-dependent manner. Moreover, cellular experimental data showed that brazilin effectively reduced the cytotoxicity induced by α-syn aggregates. Finally, molecular dynamics simulations were performed to explore the interactions between brazilin and α-syn pentamer. It is found that brazilin directly interacts with α-syn pentamer, and the hydrophobic interactions are favorable for brazilin binding with the α-syn pentamer, while the electrostatic part provides adverse effects. Three binding regions were identified to inhibit α-syn fibrillogenesis or disrupt the preformed aggregates. Furthermore, six important residues (i.e., G51, V52, A53, E61, V66, and K80) of α-syn were also identified. We expected that brazilin is an effective agent against α-syn fibrillogenesis and associated cytotoxicity.


Assuntos
Amiloide/química , Benzopiranos/química , Substâncias Protetoras/química , alfa-Sinucleína/química , Motivos de Aminoácidos , Amiloide/metabolismo , Amiloide/toxicidade , Animais , Benzopiranos/metabolismo , Linhagem Celular , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Células PC12 , Agregados Proteicos , Ligação Proteica , Ratos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
2.
Phys Chem Chem Phys ; 21(32): 17971-17977, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384846

RESUMO

The electron-hole injection from a family of spiropyran photoswitches into A/T-duplex DNA has been investigated at the molecular level for the first time. Multiscale computations coupled with automatized quantitative wavefunction analysis reveal a pronounced directionality and regioselectivity towards the template strand of the duplex DNA. Our findings suggest that this directional and regioselective photoinduced electron-hole transfer could thus be exploited to tailor the charge transport processes in DNA in specific applications.


Assuntos
Benzopiranos/química , DNA/química , Indóis/química , Substâncias Intercalantes/química , Nitrocompostos/química , Transporte de Elétrons , Luz , Modelos Moleculares , Conformação de Ácido Nucleico , Oxirredução , Processos Fotoquímicos , Prótons , Termodinâmica
3.
Chemistry ; 25(55): 12795-12800, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376182

RESUMO

The controllable ion transport in the photoreceptors of rod cells is essentially important for the light detection and information transduction in visual systems. Herein, inspired by the photochromism-regulated ion transport in rod cells with stacking structure, layered ion channels have been developed with a visual photochromic function induced by the alternate irradiation with visible and UV light. The layered structure is formed by stacking spiropyran-modified montmorillonite 2D nanosheets on the surface of an alumina nanoporous membrane. The visual photochromism resulting from the photoisomerization of spiropyran chromophores reversibly regulates the ion transport through layered ion channels. Furthermore, the cooperation of photochromism and pH value achieves multiple switchable states of layered ion channels for the controllable ion transport mimicking the biological process of the visual cycle. The ion transport properties of these states are explained quantitatively by a theoretical calculation based on the Poisson and Nernst-Plank (PNP) equations.


Assuntos
Benzopiranos/química , Indóis/química , Canais Iônicos/química , Transporte de Íons/fisiologia , Nitrocompostos/química , Células Fotorreceptoras Retinianas Cones/química , Células Fotorreceptoras Retinianas Cones/metabolismo , Raios Ultravioleta
4.
Chemosphere ; 233: 896-904, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31340417

RESUMO

Understanding the distribution of PFOS isomers between the aqueous phase and goethite is crucial, since it is an abundant sorbent and thus may have a large influence on the mobility of PFOS. This study was conducted to understand the effects of pH, humic acid (HA), fulvic acid (FA) and sulfate on sorption of PFOS isomers. The results will increase the understanding about what parameters may control the fate and transport of PFOS in surface and ground water. The study was conducted by adding PFOS spiked water to a goethite slurry with different aqueous chemistry. Levels of total PFOS and PFOS isomers were quantified using an Ultra-Performance Liquid Chromatograph coupled to a triple quadrupole mass spectrometer. Results showed that sorption of PFOS was mainly dependent on pH; sorption decreased as pH increased. Presence of HA increased log Kd from 1.29 to 2.03, 1.76 to 1.92 and 1.51 to 1.96 at pH 5.50-7.50 for 3-/4-/4-PFOS, 6-/2-PFOS and L-PFOS, respectively. Changes in the aqueous chemistry also affected the behaviour of PFOS as the addition of Na2SO4 enhanced the sorption of PFOS. Results showed that L-PFOS was more readily sorbed to goethite at pH < 4.35 both in the presence and in the absence of humic or fulvic acids. At pH > 4.5 the 3-/4-/5-PFOS isomer group was more associated to goethite. Besides electrostatic interactions, which controlled the sorption of PFOS, this study indicate that the presence of dissolved humic substances in the aqueous phase enhances the sorption via hydrophobic mechanisms.


Assuntos
Ácidos Alcanossulfônicos/química , Benzopiranos/química , Fluorcarbonetos/química , Água Subterrânea/química , Substâncias Húmicas/análise , Compostos de Ferro/química , Minerais/química , Sulfatos/química , Poluentes Químicos da Água/química , Adsorção , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas
5.
Anal Chim Acta ; 1078: 135-141, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31358211

RESUMO

Hypochlorous acid (HOCl)/hypochlorite (OCl-), important reactive oxygen species, play essential roles in many physiological and pathological progresses. Accordingly, we developed a novel dicyanomethylene-4H-pyran (DCM)-based probe DCM-OCl for colorimetric and near-infrared fluorescent turn-on detection of OCl-. The probe exhibited excellent selectivity and sensitivity for OCl- over other bio-related analytes with a detection limit of 80 nM. The excellent selectivity of DCM-OCl for OCl- was ascribed to specific oxidative cleavage of the dimethylthiocarbamate (DMTC) recognition unit by OCl-. Moreover, DCM-OCl exhibited an ultrafast turn-on response (<3 s) to OCl-, potentially allowing real-time detection of OCl-. Furthermore, DCM-OCl was successfully used to image endogenous/exogenous OCl- in living cells.


Assuntos
Benzopiranos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Tiocarbamatos/química , Benzopiranos/síntese química , Benzopiranos/toxicidade , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Tiocarbamatos/síntese química , Tiocarbamatos/toxicidade
6.
Eur J Med Chem ; 179: 389-403, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260892

RESUMO

Highly diastereoselective synthesis of chromeno ß-lactam hybrids was achieved by an efficient one-pot three-component reaction. With this procedure, the desired ß-lactam products were obtained in good yields and with exclusive cis stereoselection, by combining a variety of benzaldehydes, malononitrile, and either 5,5-dimethylcyclohexane-1,3-dione or 4-hydroxycoumarin in the presence of 1,4-diazabicyclo [2.2.2]octane under reflux conditions. These adducts were structurally characterized on the basis of IR, 1D and 2D NMR spectra, X-ray analysis, H-H COSY and H-C HSQC two-dimensional NMR experiments, and elemental analysis. Each of the synthesized compounds was screened for anti-inflammatory and anticancer activities. ß-Lactams 5b and 8b showed a 53.4 and 19.8 anti-inflammatory ratio, respectively, and 5b appeared more active than the well-known dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation. ß-Lactams 5a, 5b, 5e, 5f, 5g, 8c, 8j and 8p also showed good antitumor activity against the SW1116 (colon cancer) cell line without notable cytotoxicity towards the HepG2 control cell line.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , beta-Lactamas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzopiranos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Camundongos , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade , Células Tumorais Cultivadas , beta-Lactamas/química
7.
Phys Chem Chem Phys ; 21(28): 15779-15786, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282523

RESUMO

Small-molecule fluorescent probes having optimized optical properties, such as high photostability and brightness, local microenvironment sensitivity and specific subcellular localizations, are increasingly available. Although the basis for designing efficient fluorophores for bioimaging applications is well established, implementing an improvement in a given photophysical characteristic always tends to compromise another optical property. This problem has enormous consequences for in vivo imaging, where ensuring a specific localization and precise control of the probe response is challenging. Herein we discuss a fluorescent probe, CC334, as a case study of the chromenylium-cyanine family that commonly exhibits highly complex photophysical schemes and highly interfered bioanalytical responses. By an exhaustive and concise analysis of the CC334 optical responses including detailed spectroscopic calibrations, steady-state microenvironment effects, ultrafast photophysics analysis and computational studies, we elucidate a new strategy to apply the probe in the singlet oxygen reactive oxygen species (1O2-ROS) monitoring using in vitro and in vivo models. The probe provides a new avenue for designing fluorescent probes to understand the dynamic behavior of subcellular environments.


Assuntos
Benzopiranos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Cobalto/química , Ferrocianetos/química , Quinolinas/química , Espécies Reativas de Oxigênio/química , Análise Espectral
8.
Anal Bioanal Chem ; 411(23): 5985-5992, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236651

RESUMO

In this study, a novel near-infrared fluorescent off-on probe for H2S based on seminaphthorhodafluor fluorophore is designed and constructed, which could be used in detection with 121-fold (23-fold) fluorescent (absorbance) enhancement at 630 nm (572 nm), fast responsiveness (completed within 5 min), high sensitivity, and lower cellular autofluorescence interference. Based on these excellent optical properties, the probe was employed to monitor H2S in red wine samples with satisfactory results. Moreover, the probe was successfully applied for monitoring and imaging H2S quantitatively in Hela cells and live athymic nude mice, indicating its potential application in biological science.


Assuntos
Benzopiranos/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Naftóis/química , Imagem Óptica/métodos , Rodaminas/química , Animais , Células HeLa , Humanos , Raios Infravermelhos , Camundongos Nus , Microscopia de Fluorescência/métodos
9.
Mar Pollut Bull ; 144: 129-133, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31179978

RESUMO

The effects of time, temperature, and salinity on the adsorption of Tonalide (AHTN), Musk Xylene (MX), Galaxolide (HHCB), and Musk Ketone (MK) by microplastics of polyethylene (PE) and polyvinyl chloride (PVC) are studied. Results indicate that the equilibrium sorption time was about 10 h and the adsorption kinetics model conformed to the first-order adsorption kinetic model and pseudo-second order kinetic model, this indicates that the main adsorption mechanism might be chemical adsorption and physical absorption. Adsorption reached a nadir at 15 °C and 14% salinity. The adsorption capacity gradually increases, and then decreases, finally increases with an increase in NaCl concentration. Due to the specific surface area and the pore volume of PVC was larger than PE, the adsorption capacity of PVC was higher than that of PE in the equal conditions.


Assuntos
Cosméticos/química , Modelos Teóricos , Polietileno/química , Cloreto de Polivinila/química , Poluentes Químicos da Água/química , Adsorção , Benzopiranos/análise , Benzopiranos/química , Cosméticos/análise , Cinética , Polietileno/análise , Cloreto de Polivinila/análise , Salinidade , Água do Mar/química , Tetra-Hidronaftalenos/análise , Tetra-Hidronaftalenos/química , Poluentes Químicos da Água/análise , Xilenos/análise , Xilenos/química
10.
Comput Biol Chem ; 80: 463-471, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31170562

RESUMO

A series of novel tacrine derivatives as multifunctional agents with potential inhibitory effects on both acetylcholinesterase(AChE) and butyrylcholinesterase (BuChE) enzymes for the treatment of Alzheimer's disease(AD), were applied to alignment independent 3D-QSAR methods using Pentacle software. In this studies, GRID-independent molecular descriptors (GRIND) analysis have been applied to characterize important interactions between enzymes and the studied compounds. Two H-bond acceptor groups as well as hydrophobic properties of tacrine rings for AChE and two H-bond acceptor on the carbonyl group of chromene and NH of amid group for BuChE, with positive effects on their inhibitory potency have been identified. The obtained 3D-QSAR models have been analyzed and validated. The statistical quality of the QSAR model for AChE, r2 = 0.87, q2 = 0.56 and for BuChE, r2 = 0.96, q2 = 0.70 was resulted. Using these models, novel structures have been designed and pIC50 of them were predicted. Molecular docking studies were also conducted on AChE (1ACJ) and BuChE (4BDS) and promising results in good agreement with 3D-QSAR studies were obtained.


Assuntos
Benzopiranos/metabolismo , Inibidores da Colinesterase/metabolismo , Nootrópicos/metabolismo , Tacrina/metabolismo , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Animais , Benzopiranos/química , Butirilcolinesterase/química , Domínio Catalítico , Inibidores da Colinesterase/química , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nootrópicos/química , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Tacrina/química , Torpedo
11.
Chemistry ; 25(46): 10954-10964, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31215691

RESUMO

Epicocconone 1 is a natural chromophore isolated from the fungus Epicoccum nigrum that has shown applications in proteomics and fluorescent microscopy thanks to its unique pro-fluorescence properties. The modification of the skeleton of the natural product by replacing the triene side chain by a fluorenyl scaffold can noticeably increase the fluorophore's absorption coefficient. The synthesis of the analogues of the natural product has been made possible by the use of a palladium-catalyzed carbonylation reaction, allowing the construction of the ß-keto-dioxinone key intermediate. Two-photon absorption cross-section measurements of the fluorenyl epicocconone analogues show a structure dependency with values ranging from 60 to 280 GM and live cell imaging show intense staining of intracellular vesicle-like structures around the nucleus.


Assuntos
Benzopiranos/química , Fluorenos/química , Corantes Fluorescentes/química , Furanos/química , Cetonas/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Animais , Benzopiranos/síntese química , Catálise , Fluorenos/síntese química , Corantes Fluorescentes/síntese química , Furanos/síntese química , Cetonas/síntese química , Imagem Óptica/métodos , Células PC12 , Paládio/química , Ratos
12.
Environ Sci Pollut Res Int ; 26(21): 21463-21474, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127516

RESUMO

Environmental behavior, bioavailability, and risks posed by Fe3O4, magnetic nanoparticles (Fe3O4 NPs) in surface waters are affected by complex geochemistry, including pH and inorganic and organic matter. This work provides a systematic analysis of adsorption of fulvic acid (FA) on surfaces of Fe3O4 NPs with adsorption kinetics, adsorption thermodynamic, and adsorption isotherm. Adsorption of FA on surfaces of Fe3O4 NPs is consistent with assumptions of Langmuir and Freundlich adsorption isotherm models. The adsorption amount of FA was inversely proportional to solution pH, and the maximum amount is 128.6 mg g-1. Adsorption of FA on surfaces of Fe3O4 NPs is a spontaneous endothermic process. FA plays an important role in aggregation and suspension/sedimentation behavior of Fe3O4 NPs in aquatic environmental. With continuous adsorption of FA, electrostatic repulsion between the particles and the steric hindrance of FA significantly decreased aggregation and increased suspension of Fe3O4 NPs. The results of FTIR and XPS indicated that FA was adsorbed on Fe3O4 NPs mainly through chemical reactions, and carbohydrates particularly play an important role in adsorption.


Assuntos
Benzopiranos/química , Nanopartículas de Magnetita/química , Adsorção , Cinética , Magnetismo , Modelos Químicos , Eletricidade Estática , Termodinâmica
13.
Molecules ; 24(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060338

RESUMO

A new series of coumarin derivatives, 7-hydroxy-7-(trifluoromethyl)-6a,12b-dihydro-6H,7H-chromeno[3,4-c]chromen-6-ones 3a-p, were synthesized via Michael addition, transesterification and nucleophilic addition from the reaction of 3-trifluoroacetyl coumarins and phenols in the presence of an organic base. The products were characterized by infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectroscopy (1H-NMR), carbon nuclear magnetic resonance spectroscopy (13C-NMR) and high-resolution mass spectrometer (HRMS). Single crystal X-ray analysis of compounds 3a and 3n clearly confirmed their assigned chemical structures and their twisted conformations. Compound 3a crystallized in the orthorhombic system, Pbca, in which a = 8.6244(2) Å, b = 17.4245(4) Å, c = 22.5188(6) Å, α = 90°, ß = 90°, γ = 90°, v = 3384.02(14) Å3, and z = 8. In addition, the mycelial growth rate method was used to examine the in vitro antifungal activities of the title compounds 3a-p against Fusarium graminearum and Fusarium monitiforme at 500 µg/mL. The results showed that compound 3l exhibited significant anti-Fusarium monitiforme activity with inhibitory index of 84.6%.


Assuntos
Antifúngicos/síntese química , Benzopiranos/síntese química , Cumarínicos/química , Fusarium/efeitos dos fármacos , Antifúngicos/química , Antifúngicos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade
14.
J Mass Spectrom ; 54(7): 634-642, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144377

RESUMO

Natural 2H-chromenes were isolated from the crude extract of Piper aduncum (Piperaceae) and analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) applying collision-induced dissociation. Density functional theory (DFT) calculations were used to explain the preferred protonation sites of the 2H-chromenes based on thermochemical parameters, including atomic charges, proton affinity, and gas-phase basicity. After identifying the nucleophilic sites, the pathways were proposed to justify the formation of the diagnostic ions under ESI-MS/MS conditions. The calculated relative energy for each pathway was in good agreement with the energy-resolved plot obtained from ESI-MS/MS data. Moreover, the 2H-chromene underwent proton attachment on the prenyl moiety via a six-membered transition state. This behavior resulted in the formation of a diagnostic ion due to 2-methylpropene loss. These studies provide novel insights into gas-phase dissociation for natural benzopyran compounds, indicating how reactivity is correlated to the intrinsic acid-base equilibrium and structural aspects, including the substitution pattern on the aromatic moiety. Therefore, these results can be applied in the identification of benzopyran derivatives in a variety of biological samples.


Assuntos
Benzopiranos/química , Modelos Químicos , Piper/química , Benzopiranos/isolamento & purificação , Íons , Estrutura Molecular , Prótons , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
15.
Mar Drugs ; 17(5)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035362

RESUMO

Three new azaphilone alkaloids containing glutamine residues, namely N-glutarylchaetoviridins A-C (1-3), together with two related compounds (4 and 5) were isolated from the extract of Chaetomium globosum HDN151398, a fungus isolated from a deep-sea sediment sample collected in South China Sea. Their structures were elucidated on the basis of extensive 1D and 2D NMR as well as HRESIMS spectroscopic data and chemical analysis. N-glutarylchaetoviridins A-C (1-3) represent the first class of chaetoviridins characterized by embedded glutamate residues. Amino acids incubation experiments produced five azaphilone laden different amino acids residues (6-10) which indicated that this method can enhanced the structural diversity of this strain by culturing with amino acids. Cytotoxicity of the isolated compounds were evaluated against a panel of human cancer cell lines.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Chaetomium/química , Sedimentos Geológicos/microbiologia , Pigmentos Biológicos/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Organismos Aquáticos/química , Benzopiranos/química , Benzopiranos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glutamina/química , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação
16.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035588

RESUMO

Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the instability of melanogenesis in melanoma by activating cellular autophagy. However, there is still a lack of knowledge about how autophagy is involved in the regulation of melanogenesis in melanoma cells. Here, we used rottlerin as an autophagy inducer to investigate the role of the cyclic adenosine monophosphate (cAMP)/cAMP response element binding (CREB) signaling pathway in melanogenesis. We found that rottlerin can inhibit melanin production by targeting cAMP, which is initially activated by alpha-melanocyte stimulating hormone (α-MSH). Our findings suggest that rottlerin has a pivotal role as an autophagy inducer in the regulation of melanogenesis by targeting the cAMP/CREB signaling pathway.


Assuntos
Acetofenonas/farmacologia , Autofagia/efeitos dos fármacos , Benzopiranos/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Melaninas/metabolismo , Acetofenonas/química , Animais , Benzopiranos/química , Linhagem Celular Tumoral , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanoma Experimental , Camundongos , Transdução de Sinais
17.
J Microbiol Biotechnol ; 29(6): 897-904, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31091861

RESUMO

Monascus purpureus recombinant mppC and mpp7 knockout strains were subjected to extractive fermentation in the context of azaphilone pigment production. Inclusion of Diaion HP-20 resin resulted in the selective production of unreduced azaphilone congeners, in addition to the early intermediate FK17-P2a, from ∆mppC and ∆mpp7 strains that would otherwise mainly produce reduced congeners. Structural determination of two novel unreduced azaphilones from the ∆mpp7 strain was accomplished. The unreduced azaphilone compound was converted into the cognate reduced congener in recombinant M. purpureus strains, demonstrating its intermediate role in azaphilone biosynthesis. This study demonstrates the possibility that extractive fermentation with Diaion HP-20 resin can be used to obtain cryptic azaphilone metabolites.


Assuntos
Benzopiranos/metabolismo , Microbiologia Industrial/métodos , Monascus/genética , Monascus/metabolismo , Pigmentos Biológicos/metabolismo , Poliestirenos/metabolismo , Benzopiranos/química , Vias Biossintéticas , Fermentação , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Deleção de Genes , Oxirredução , Pigmentos Biológicos/química
18.
Chem Biol Interact ; 308: 235-243, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145889

RESUMO

mHA11, a 2-amino-4-phenyl-4H-chromene-3-carboxylate analog, is a microtubule-targeting agent discovered by our group through the modification of the Bcl-2 inhibitor HA14-1. mHA11 exhibits cytotoxicities against tumor cells with nM IC50 values, whereas it has only a minimal effect on normal cells. We explored the plasma pharmacokinetics, tissue distribution, and excretion of mHA11 in rats using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Next, we identified the metabolites of mHA11 and assessed the influence of cytochrome P450 (CYP) isozymes on mHA11 metabolism. We also examined the in vitro stability in rat plasma and rat liver microsomes (RLMs), the blood-to plasma (B/P) ratio, and the inhibitory effect on CYP isozyme activities. After oral administration at 5, 15, and 45 mg/kg, mHA11 was absorbed and eliminated rapidly. There was a linear correlation between the area under the concentration-time curve (AUC0-∞) and the dose (R2 = 0.983). The bioavailability of mHA11 was 4.1% at the oral dose of 15 mg/kg mHA11 was extensively distributed in various tissues and exhibited a high penetration into the brain. No significant parent drug was detected in urine or bile, and only 0.74% was recovered in feces, whereas two demethylated metabolites, M1 and M2, were found in the urine and feces, and further studies showed that CYP2C19 primarily contributed to metabolites formation. mHA11 was stable in rat plasma but degraded significantly in RLMs; its B/P ratio was 1.05 in rat blood. In addition, mHA11 dose-dependently inhibited the activities of rat CYP isozymes, including CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1 and CYP3A2. The present study is the first report on the disposition of mHA11 in rats and provides important data for further research and development of this inhibitor.


Assuntos
Benzopiranos/farmacocinética , Moduladores de Tubulina/farmacocinética , Administração Oral , Animais , Benzopiranos/sangue , Benzopiranos/química , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Estabilidade de Medicamentos , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Espectrometria de Massas em Tandem , Distribuição Tecidual , Moduladores de Tubulina/sangue , Moduladores de Tubulina/química
19.
Soft Matter ; 15(18): 3740-3750, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31042253

RESUMO

A spiropyran-containing triazole-phosphatidylcholine (SPTPC) was synthesized through a copper-catalyzed azide alkyne cyclo-addition (CuAAC) reaction. In water, SPTPCs self-assembled and a spontaneous spiropyran-to-merocyanine (SP-to-MC) isomerization occurred, resulting in coexistence of liposomes and fibers, and switching from the spiropyran (SP) to the merocyanine (MC) isomeric structure induced a reversible transition between these molecular assemblies. Study of the self-assembly of SPTPCs and photo-induced liposome-fiber assembly-transition revealed that the presence of MC enabled additional inter-membrane interaction during self-assembly and that the MC-stacking effect was the driving force for the assembly-transition. Exposure to UV light induced switching from SP to MC, where the planar structure of MC and the confinement of MC led to enhanced MC-stacking. The effect of MC-stacking was both advantageous and disadvantageous: MC-stacking perturbed the hydrophobic phase in the bilayer membrane and facilitated the liposome-to-fiber transition, otherwise the MC-stacking retarded switching of MC to SP, and caused an incomplete recovery of MC to SP during fiber-to-liposome recovery, thus a fatigue of SP was induced by MC-stacking during the liposome-to-fiber transition cycle. To decrease the intermolecular interactions and suppress MC-stacking, photo-inert triazole-phosphatidylcholine (TPC) was incorporated to prepare two-component TPC/SPTPC-liposomes, which exhibited better recovery kinetics. The photo-adaptive behavior of TPC/SPTPC-liposomes confirmed the disturbance of bilayer membranes by inter-membrane MC-stacking and the formation of MCTPC-enriched phases in the bilayer membrane.


Assuntos
Benzopiranos/química , Indóis/química , Lipossomos/química , Nitrocompostos/química , Fosfatidilcolinas/química , Processos Fotoquímicos , Triazóis/química , Alquinos/química , Azidas/química , Catálise , Cobre/química , Bicamadas Lipídicas/química , Transição de Fase , Raios Ultravioleta
20.
Mar Drugs ; 17(5)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052279

RESUMO

Four new azaphilones, sclerotiorins A-D (1-4), as well as the dimeric sclerotiorin E (5) of which we first determined its absolute configuration, and 12 known analogues (5-16) were isolated from the fermentation broth of Penicillium sclerotiorum OUCMDZ-3839 associated with a marine sponge Paratetilla sp.. The new structures, including absolute configurations, were elucidated by spectroscopic analyses, optical rotation, ECD spectra, X-ray single-crystal diffraction, and chemical transformations. Compounds 11 and 14 displayed significant inhibitory activity against α-glycosidase, with IC50 values of 17.3 and 166.1 µM, respectively. In addition, compounds 5, 7, 10, 12-14, and 16 showed moderate bioactivity against H1N1 virus.


Assuntos
Benzopiranos/farmacologia , Penicillium/química , Pigmentos Biológicos/farmacologia , Animais , Benzopiranos/química , Benzopiranos/isolamento & purificação , Fungos , Glicosídeo Hidrolases/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Estrutura Molecular , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Poríferos
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