RESUMO
In this research, the magnetic solid acid nanocatalyst based on ferrierite has been prepared and used as catalyst for the green synthesis of some [1,3]-oxazine derivatives in water at room temperature. The synthesized compounds were obtained in high to excellent yields after short reaction times and the structure of synthesized products were investigated by spectroscopic methods such as: FT-IR, 1H NMR and 13C NMR. The prepared magnetic solid acid catalyst was characterized using XRD, FT-IR, FE-SEM, EDX, elemental mapping, TGA and VSM analysis methods. Magnetic catalyst has easy separation ability, which leads to better and easier recycling. The preparation and synthesis of [1,3]-oxazine derivatives were carried out at room temperature in the presence of M-FER/TEPA/SO3H. Easy workup, green solvent (water) and also short reaction times with high to excellent yield of products, are some of advantageous of presented method. Docking calculations on the structure of the synthesized compounds proved their medicinal properties against breast cancer cells.
Assuntos
Neoplasias da Mama , Simulação de Acoplamento Molecular , Oxazinas , Catálise , Neoplasias da Mama/tratamento farmacológico , Humanos , Oxazinas/química , Oxazinas/síntese química , Feminino , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Química Verde/métodosRESUMO
The development of a rapid and intuitive method for the detection of a specific small molecule biomarker is important for understanding the pathogenesis of relevant diseases. Described here is the design and evaluation of an HClO-specific triggered self-immolative fluorescent sensor (RESClO) based on the structure of an N-protected Resorufin dye. Due to the interrupted π-conjugated structure of the Resorufin dye, the free sensor showed very weak absorption and fluorescence. It can quickly complete the response to HClO (within 10 s) with high selectivity and sensitivity (LOD = 16.8 nM) in aqueous solution. The sensor can be made into test strips to quickly detect HClO in the environment by obvious changes in color and fluorescence. It was successfully used for bioimaging of exogenous and endogenous HClO in cells and zebra fish. More importantly, it can also be used for visual imaging of mouse arthritis models. Thus, sensor RESClO can provide a simple and promising visual analytical tool for the detection of HClO in the environment and the early diagnosis of HClO-mediated related diseases.
Assuntos
Artrite/diagnóstico por imagem , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Imagem Óptica , Oxazinas/química , Animais , Artrite/induzido quimicamente , Carragenina , Células Cultivadas , Corantes Fluorescentes/síntese química , Camundongos , Estrutura Molecular , Oxazinas/síntese química , Células RAW 264.7 , Peixe-ZebraRESUMO
After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aß levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.
Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Ribosomal S6 protein kinase 4 (RSK4) was identified to be a promising target for the treatment of esophageal squamous cell carcinoma (ESCC) in our previous research, whose current treatments are primarily chemotherapy and radiotherapy due to the lack of targeted therapy. However, few potent and specific RSK4 inhibitors are reported. In this study, a series of 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones derivatives were designed and synthesized as novel and potent RSK4 inhibitors. Compound 14f was identified with potent RSK4 inhibitory activity both in vitro and in vivo. 14f significantly inhibited the proliferation and invasion of ESCC cells in vitro with IC50 values of 0.57 and 0.98 µM, respectively. It dose dependently inhibited the phosphorylation of RSK4 downstream substrates while exerting little effect on the substrates of RSK1-3 in ESCC cells. The markedly suppressed tumor growth and no observed toxicity to main organs in the ESCC xenograft mouse model suggested 14f to be a promising RSK4-targeting agent for ESCC treatment.
Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Oxazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/metabolismo , Oxazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 90-kDa/química , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr2-promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-(N,N-dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr2 to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.
Assuntos
Brometos/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos de Magnésio/química , Oxazinas/química , Piperazinas/química , Piridonas/química , Ciclização , Compostos Heterocíclicos com 3 Anéis/síntese química , Hidrólise , Oxazinas/síntese química , Piperazinas/síntese química , Piridonas/síntese química , TemperaturaRESUMO
Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 µM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC50 values in low micromolar range, although accompanied by commensurate cytotoxicity.
Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Nucleosídeos/farmacologia , Oxazinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/toxicidade , Linhagem Celular Tumoral , Chlorocebus aethiops , Cães , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/toxicidade , Oxazinas/síntese química , Oxazinas/toxicidade , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Hypoxia is a pathological hallmark of solid tumors. Detection of hypoxia is therefore of great interest for tumor diagnosis and treatment. As a well-established biomarker of hypoxia, nitroreductase (NTR) has been widely exploited in the development of hypoxia-responsive fluorescent probes on the basis of its enzymatic activity to reduce nitroaryl groups. However, studies on the relationship between the nitroaryl structure and the probe performance for optimal probe design are still rare. Here we report a comparative investigation of nitroaryl groups and identification of the optimal nitroaryl structure for developing new fluorescent probes with extremely high efficiency in the detection of NTR and the imaging of hypoxic tumor cells. Specifically, we synthesized a series of resorufin-based fluorescent probes containing different nitroaryl groups, compared their fluorescence responses to NTR, and identified 2-nitro-N-methyl-imidazolyl as the optimal nitroaryl group that is much more efficient than the most widely used 4-nitrophenyl for NTR detection. The structure-performance relationship was then studied by theoretical molecular docking, revealing the unique features of 2-nitro-N-methyl-imidazolyl in binding and reaction with NTR. We further incorporated the 2-nitro-N-methyl-imidazolyl group into a near-infrared (NIR) hemicyanine fluorophore and developed a NIR fluorescent probe NFP-7 for the detection of NTR and hypoxic tumor cells. NFP-7 exhibits a strong fluorescence increase toward NTR in vitro with an ultrafast (within 40 seconds to fluorescence maximum) and ultrasensitive (0.2 ng mL-1 detection limit) response. NFP-7 has also been demonstrated for imaging the degree of hypoxia in live tumor cells and, more importantly, in a murine tumor model. Our study provides important insights into hypoxia probe development and new tools for hypoxia imaging.
Assuntos
Descoberta de Drogas , Corantes Fluorescentes/química , Nitrorredutases/análise , Imagem Óptica , Oxazinas/química , Animais , Corantes Fluorescentes/síntese química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Microscopia Confocal , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrorredutases/metabolismo , Oxazinas/síntese química , Células Tumorais CultivadasRESUMO
Despite almost 40 years having passed from the initial discovery of ubiquitin (Ub), fundamental questions related to its intracellular metabolism are still enigmatic. Here we utilized fluorescent tracking for monitoring ubiquitin turnover in mammalian cells, resulting in obtaining qualitatively new data. In the present study we report (1) short Ub half-life estimated as 4 h; (2) for a median of six Ub molecules per substrate as a dynamic equilibrium between Ub ligases and deubiquitinated enzymes (DUBs); (3) loss on average of one Ub molecule per four acts of engagement of polyubiquitinated substrate by the proteasome; (4) direct correlation between incorporation of Ub into the distinct type of chains and Ub half-life; and (5) critical influence of the single lysine residue K27 on the stability of the whole Ub molecule. Concluding, our data provide a comprehensive understanding of ubiquitin-proteasome system dynamics on the previously unreachable state of the art.
Assuntos
Fluorescência , Ubiquitina/metabolismo , Células Cultivadas , Citometria de Fluxo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Células HEK293 , Humanos , Oxazinas/síntese química , Oxazinas/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/análiseRESUMO
The high mortality rate and increasing prevalence of resistant Mtb are the major concerns for the Tuberculosis (TB) treatment in this century. To curtail the prevalence of resistant Mtb, we have prepared 1,3-oxazine-2-one based dual targeted molecules. Compound 67 and 68 were found to be equally active against replicating and non-replicatiing form of Mtb (MICMABA 3.48 and 2.97 µg/ml; MICLORA 2.94 and 2.15 µg/ml respectively). They had found to suppress the biosynthesis of alfa, methoxy and keto-mycolate completely, as well as inhibit enzymatic activity of MenG (IC50 = 9.11 and 6.25 µg/ml respectively for H37Ra; IC50 = 11.76 and 10.88 µg/ml respectively for M smegmatis).
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Ácidos Micólicos/metabolismo , Oxazinas/síntese química , Oxazinas/toxicidade , Relação Estrutura-AtividadeRESUMO
The steady increase in the prevalence of multidrug-resistant Staphylococcus aureus has made the search for novel antibiotics to combat this clinically important pathogen an urgent matter. In an effort to discover antibacterials with new chemical structures and mechanisms, we performed a growth inhibition screen of a synthetic library against S. aureus and discovered a promising scaffold with a 1,3,5-oxadiazin-2-one core. These compounds are potent against both methicillin-sensitive and methicillin-resistant S. aureus strains. Isolation of compound-resistant strains followed by whole genome sequencing revealed its cellular target as FabH, a key enzyme in bacterial fatty acid synthesis. Detailed mechanism of action studies suggested the compounds inhibit FabH activity by covalently modifying its active site cysteine residue with high selectivity. A crystal structure of FabH protein modified by a selected compound Oxa1 further confirmed covalency and suggested a possible mechanism for reaction. Moreover, the structural snapshot provided an explanation for compound selectivity. On the basis of the structure, we designed and synthesized Oxa1 derivatives and evaluated their antibacterial activity. The structure-activity relationship supports the hypothesis that noncovalent recognition between compounds and FabH is critical for the activity of these covalent inhibitors. We believe further optimization of the current scaffold could lead to an antibacterial with potential to treat drug-resistant bacteria in the clinic.
Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazinas/síntese química , Relação Estrutura-AtividadeRESUMO
Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives. A series of multisubstituted oxazolidinones, oxazinanones, and oxazepanones as well as their thio and sulfur derivatives are synthesized from readily available building blocks with mild conditions and high yields. Like a few other methods, MCR and cyclization allow for the collective transformation of a large chemical space into a related one with different properties.
Assuntos
Oxazepinas/síntese química , Oxazinas/síntese química , Oxazolidinonas/síntese química , Compostos de Sulfidrila/síntese química , Ciclização , Estrutura Molecular , Oxazepinas/química , Oxazinas/química , Oxazolidinonas/química , Compostos de Sulfidrila/químicaRESUMO
Three novel coordination compounds, [Cu(ca)2(Hbae)2] (1), [Cu(va)2(Hbae)2] (2) and [Cu4(va)4(bae)4]·H2O (3), have been prepared by self-assembly reactions of copper(ii) chloride (1 and 2) or tetrafluoroborate (3) and CH3OH (1 and 3) or CH3CN (2) solution of 2-benzylaminoethanol (Hbae) and cinnamic (Hca, 1) or valeric (Hva, 2 and 3) acid. Crystallographic analysis revealed that both 1 and 2 have mononuclear crystal structures, wherein the complex molecules are H-bonded forming extended supramolecular chains. The tetranuclear structure of 3 is based on the {Cu4(µ3-O)4} core, wherein the metal atoms are bound together by µ3 oxygen bridges from 2-benzylaminoethanol forming an overall cubane-like configuration. The strong hydrogen bonding in 1-3 leads to the joining of the neighbouring molecules into 1D chains. Concentration-dependent ESI-MS studies disclosed the equilibria between di-, tri- and tetranuclear species in solutions of 1-3. All three compounds act as catalysts for the aerobic oxidation of o-aminophenol to the phenoxazinone chromophore (phenoxazinone synthase-like activity), with the maximum reaction rates of 4.0 × 10-7, 2.5 × 10-7 and 2.1 × 10-7 M s-1 for 1, 2 and 3, respectively, supported by the quantitative yield of the product after 24 h. The dependence of the reaction rates on catalyst concentrations is evidence of reaction orders higher than one relative to the catalyst. Kinetic and ESI-MS data allowed us to assume that the tetranuclear species, originating from 1, 2 and 3 in solution, possess considerably higher activity than the species of lower nuclearity. Mechanistic and isotopic 18O-labelling experiments suggested that o-aminophenol coordinates to CuII species with the formation of reactive intermediates, while the oxygen from 18O2 is not incorporated into the phenoxazinone chromophore.
Assuntos
Aminofenóis/química , Complexos de Coordenação/química , Cobre/química , Etanolaminas/química , Oxazinas/síntese química , Catálise , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Oxazinas/química , OxirreduçãoRESUMO
Four new benzo[a]phenoxazinium chlorides with combinations of chloride, ethyl ester and methyl as terminals of the amino substituents were synthesized. These compounds were characterized and their optical properties were studied in absolute dry ethanol and water. Their antiproliferative activity was tested against Saccharomyces cerevisiae in a broth microdilution assay, along with an array of 36 other benzo[a]phenoxazinium chlorides. Minimum Inhibitory Concentration (MIC) values between 1.56 and >200 µM were observed. Fluorescence microscopy studies, used to assess the intracellular distribution of the dyes, showed that these benzo[a]phenoxazinium chlorides function as efficient and site specific probes for the detection of the vacuole membrane. The added advantage of some of the compounds, that displayed the lower MIC values, was the simultaneous staining of both the vacuole membrane and the perinuclear membrane of endoplasmic reticulum (ER). Molecular docking studies were performed on the human membrane protein oxidosqualene cyclase (OSC), using the crystal structure available on PDB (code 1W6K). The results showed that these most active compounds accommodated better in the active sites of ER enzyme OSC suggesting this enzyme as a potential target. As a whole, the results demonstrate that the benzo[a]phenoxazinium chlorides are interesting alternatives to the available commercial dyes. Changes in the substituents of these compounds can tailor both their staining specificity and antimicrobial activity.
Assuntos
Antifúngicos/farmacologia , Corantes Fluorescentes/farmacologia , Oxazinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Leveduras/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Células Cultivadas , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Testes de Sensibilidade Microbiana , Microscopia de Fluorescência , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The synthesis of a novel series of oxadiazine-4-thione biological molecules was executed through the incorporation of the ortho-, meta-, and para-benzoyl isocyanates to the tetrabromophthalimide nucleus. OBJECTIVES: A one-pot multicomponent methodology in a solvent-free microwave irradiation environment was employed to afford this series of oxadiazine-4-thione, deriving a comparison with the conventional method. Subsequently, the yielded derivatives were subjected to further biological assessment. MATERIALS AND METHODS: The acquired results denoted that the one-pot procedure, which delivered products in a 2-4 min. interval, was more efficient in evaluation against the classical method, which consumed a 1-2:30 hr. interval. RESULTS: The application of the antibacterial analyses was subjected to all the compounds, resulting in molecules 6a and 6c demonstrating the highest activity regarding Aspergillus Favus; molecules 5b and 5c exhibiting an equivalent level of activity towards E-coli and Fusarium Moniliform; and molecules 4b, 4c, 5b, and 5c presenting an identical level of activity to the aforementioned derivatives involving Staphylococcus. Concluison: Molecular modeling studies by the MOE, the preceding antibacterial behavior was conducted to advocate the newly prepared compounds. Moreover, the spectroscopic approaches were exploited to verify and establish the structures and mechanisms of the synthesized derivatives' reactions.
Assuntos
Antibacterianos/farmacologia , Oxazinas/farmacologia , Tionas/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antifúngicos/síntese química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Aspergillus flavus/efeitos dos fármacos , Cristalografia por Raios X , Fusarium/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxazinas/síntese química , Oxazinas/metabolismo , Pró-Proteína Convertase 9/metabolismo , Ligação Proteica , Staphylococcus aureus/efeitos dos fármacos , Tionas/síntese química , Tionas/metabolismoRESUMO
This work describes a straightforward diastereoselective synthetic access to azirino[2,1-b]benzo[e][1,3]oxazines containing phosphorus substituents such as phosphonate or phosphine oxide, by means of nucleophilic addition of functionalized phenols to the C-N double bond of 2H-azirine derivatives. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. Some azirino[2,1-b]benzo[e][1,3]oxazines 4 and 6 exhibited very good activity against the A549â¯cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been detected.
Assuntos
Antineoplásicos/farmacologia , Oxazinas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Fosforilação , Relação Estrutura-AtividadeRESUMO
GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).
Assuntos
Hipoglicemiantes/farmacologia , Oxazinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A novel hypochlorous-acid-selective signaling probe based on the carbonodithioate derivative of resorufin (RT-1) was developed. Probe RT-1 showed prominent colorimetric and turn-on type fluorescence signaling behavior exclusively toward hypochlorous acid, induced by oxidative hydrolysis, to regenerate resorufin dye. Hypochlorous acid signaling was not affected by the presence of common metal ions and anions as background, except for the redox active bromide and iodide anions. The detection limit of RT-1 for hypochlorous acid was found to be 2.18 × 10-9 M (0.11 ppb), and the signaling was completed within 3 min. It was also confirmed that hypochlorous acid signaling by the carbonodithioate-based probe RT-1 was superior to that of the closely related carbonothioate derivative RT-2. This was rationalized by density functional theory calculations, which demonstrated that the C[double bond, length as m-dash]S sulfur atom of the former is more negatively charged than that of the latter. Finally, as a biological application of the probe, visualization of hypochlorous acid in RAW 264.7 murine macrophages and HeLa cells was successfully conducted to detect the cellular response to hypochlorous acid.
Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Oxazinas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Oxazinas/síntese química , Oxazinas/toxicidade , Células RAW 264.7RESUMO
Development of next-generation fluorescent probes is a key element in the quest for a greater understanding of complex biological environments (e.g., membranes) by bioimaging. Such fluorescence-based techniques rely on specialized small molecules that possess excellent fluorescent properties but also do not perturb the native biological environment in which they reside. Herein we present a theoretical/computational strategy for the design of novel optical probes for sensing in membranes based on the parent chromophore Nile Red. Using a combination of time-dependent density functional theory (TD-DFT) and molecular dynamics (MD), we have studied the optical properties and accommodation in a model membrane of Nile Red and eight analogs. Special attention has been given to the design of probes with improved solvatochromism and two-photon absorption (2PA) without altering the membrane properties. Of the eight studied analogs, two probes were found to possess attractive probe features and are hence suggested to be taken forward to chemical synthesis and experimental exploration.
Assuntos
Teoria da Densidade Funcional , Corantes Fluorescentes/química , Lipídeos de Membrana/química , Simulação de Dinâmica Molecular , Oxazinas/química , Corantes Fluorescentes/síntese química , Oxazinas/síntese química , Fatores de TempoRESUMO
A phenoxazine-based fluorescence chemosensor 4PB [(4-(tert-butyl)-N-(4-((4-((5-oxo-5H-benzo[a]phenoxazin-6-yl)amino)phenyl)sulfonyl)phenyl)benzamide)] was designed and synthesized by a simple synthetic methods. The 4PB fluorescence chemosensor selectively detects Ba2+ in the existence of other alkaline metal ions. In addition, 4PB showed high selectivity and sensitivity for Ba2+ detection. The detection limit of 4PB was 0.282 µM and the binding constant was 1.0 × 106 M-1 in CH3CN/H2O (97.5:2.5 v/v, HEPES = 1.25 mM, pH 7.3) medium. This chemosensor functioned through the intramolecular charge transfer (ICT) mechanism, which was further confirmed by DFT studies. Live cell imaging in MCF-7 cells confirmed the cell permeability of 4PB and its capability for specific detection of Ba2+ in living cells.
Assuntos
Bário/análise , Corantes Fluorescentes/química , Microscopia Confocal , Oxazinas/química , Bário/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Corantes Fluorescentes/farmacologia , Humanos , Íons/química , Células MCF-7 , Oxazinas/síntese química , Oxazinas/farmacologiaRESUMO
In this article, a novel fluorescent probe (NRBE) for detecting H2O2 was developed using benzyl boronic ester as the H2O2-recognized group and Nile red as the matrix. The probe has several advantages, such as good selectivity, high sensitivity (LODâ¯=â¯75â¯nM), good water solubility and emission in the near-infrared region (ex/em:585/670â¯nm). With the NRBE probe, the endogenous H2O2 in human hepatocellular carcinoma cells BEL-7402, was detected, and the H2O2 generated during the ischemia-reperfusion of the cells was imaged. These results show that NRBE can be applied for real-time detection of H2O2 in biological systems.