Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 553
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
J Enzyme Inhib Med Chem ; 35(1): 50-58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31656107

RESUMO

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-Atividade
2.
Eur J Med Chem ; 185: 111771, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31671309

RESUMO

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 A549 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-Atividade
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 223: 117284, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31229902

RESUMO

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 (LOD = 75 nM), good water solubility and emission in the near-infrared region (ex/em:585/670 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.


Assuntos
Corantes Fluorescentes/química , Peróxido de Hidrogênio/análise , Oxazinas/química , Espectroscopia de Luz Próxima ao Infravermelho , Sobrevivência Celular , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Oxazinas/síntese química , Espectrometria de Fluorescência , Eletricidade Estática
4.
Talanta ; 201: 111-118, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122400

RESUMO

Thiophenols as high toxic environmental pollutants are poisonous for animals and aquatic organisms. Therefore, it is indispensable to monitor thiophenols in the environment. Herein, a novel near-infrared fluorescent probe was developed for the detection of thiophenols, which was easily prepared by one-step coupling of 2,4-dinitrobenzenesulfonyl chloride with Nile blue. The probe showed a significant near infrared (∼675 nm) fluorescence "turn-on" response to thiophenols with some good features including chromogenic reaction, high sensitivity and selectivity, fast response, near-infrared emission along with low detection limit (1.8 nM). The probe was employed to rapidly and visually determine thiophenols in several industrial wastewaters with good recoveries (90-110%). Moreover, this probe has been demonstrated good capability for imaging thiophenol in HeLa cells.


Assuntos
Corantes Fluorescentes/química , Oxazinas/química , Fenóis/análise , Compostos de Sulfidrila/análise , Sulfonamidas/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Limite de Detecção , Microscopia Confocal/métodos , Modelos Químicos , Oxazinas/síntese química , Oxazinas/efeitos da radiação , Oxazinas/toxicidade , Espectrometria de Fluorescência/métodos , Sulfonamidas/síntese química , Sulfonamidas/efeitos da radiação , Sulfonamidas/toxicidade
5.
Analyst ; 144(11): 3676-3684, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31086902

RESUMO

Biothiols, including cysteine (Cys), homocysteine (Hcy), glutathione (GSH) and H2S, play important roles in human physiological processes. However, it is a great difficulty to distinguish biothiols from each other because of their similar chemical properties. Based on Nile red, we have designed and synthesized a near-infrared fluorescent probe for discriminating Cys/Hcy from GSH/H2S by a dual-channel detection method. Using an ether bond, near-infrared Nile red was attached to 7-nitrobenzofurazan to construct the probe. Due to the photo-induced electron transfer, the probe showed almost no fluorescence from the green to red emission band. But upon the addition of Cys (0-150 µM) or Hcy (0-200 µM), the probe exhibited a noteworthy fluorescence "turn-on" signal in two unique emission bands (Green and Red) with a fast response (within 30 min). In contrast, the probe displayed an increase in fluorescence only in the red channel when encountering GSH (0-70 µM) or H2S (0-50 µM), and GSH/H2S could be tested respectively by different response time. The limit of detection was calculated to be 0.09 µM (Cys), 0.30 µM (Hcy), 0.24 µM (GSH), and 0.04 µM (H2S), respectively (based on S/N = 3). The desirable dual-channel detection could be achieved in serum samples and living cells. Moreover, the probe could be applied for bioimaging in mice, which indicated its potential application in the clinic.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Glutationa/análise , Homocisteína/análise , Sulfeto de Hidrogênio/análise , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/síntese química , 4-Cloro-7-nitrobenzofurazano/toxicidade , Animais , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Camundongos Nus , Imagem Óptica/métodos , Oxazinas/síntese química , Oxazinas/química , Oxazinas/toxicidade , Espectrometria de Fluorescência
6.
Analyst ; 144(10): 3221-3225, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31011728

RESUMO

As the oxidative metabolites of the endogenous gasotransmitter H2S, H2Sn have attracted ever-increasing attention in the field of biomedical research due to their vital functions in biological systems. Herein, we report a resorufin-based "turn-on" probe for H2Sn sensing. An SNAr substitution-intramolecular cyclization cascade reaction was used in this probe for detecting exogenous and endogenous H2Sn. The detection process could be monitored using UV-Vis and fluorescence spectroscopy and the naked eye. The emission response of the probe towards H2Sn presented a good linear relationship in the 0-50 µM concentration range, and the LOD of this probe was 24 nM. The probe was used successfully to visualize endogenous H2Sn generated in the RAW 246.7 cells under external stimulation.


Assuntos
Corantes Fluorescentes/química , Nitrobenzoatos/química , Oxazinas/química , Sulfetos/análise , Animais , Cor , Colorimetria/métodos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Concentração de Íons de Hidrogênio , Limite de Detecção , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nitrobenzoatos/síntese química , Nitrobenzoatos/toxicidade , Oxazinas/síntese química , Oxazinas/toxicidade , Células RAW 264.7 , Espectrometria de Fluorescência/métodos , Sulfetos/química
7.
ChemMedChem ; 14(6): 645-662, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30702807

RESUMO

Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure-activity relationships.


Assuntos
Inibidores Enzimáticos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas , Timidilato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Oxazinas/síntese química , Oxazinas/química , Oxazinas/farmacologia , Relação Estrutura-Atividade
8.
Mol Divers ; 23(1): 123-135, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30062671

RESUMO

The acid-promoted three-component reaction of o-aminophenol or 2-aminoethanol with dialkyl acetylenedicarboxylate and 3-phenacylideneoxindolines in refluxing acetonitrile afforded functionalized oxindolinyl-substituted benzo[b]pyrrolo[1,2-d][1,4]oxazine or pyrrolo-[2,1-c][1,4]oxazine derivatives in good yields. However, using o-phenylenediamine only resulted in oxindolinyl-substituted 3,4-dihydroquinoxaline derivatives.


Assuntos
Alquinos/química , Aminofenóis/química , Indóis/química , Oxazinas/síntese química
9.
J Enzyme Inhib Med Chem ; 34(1): 55-74, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30362381

RESUMO

The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC50s of 0.53 and 2.90 µM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV/efeitos dos fármacos , Oxazinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Relação Dose-Resposta a Droga , HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
10.
Chem Pharm Bull (Tokyo) ; 66(12): 1196-1198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504633

RESUMO

Herein we describe a short total synthesis of (+)-spinoxazine B, which inhibits nitric oxide (NO) production in BV-2 microgrial cells. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus, and it is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.


Assuntos
Oxazinas/síntese química , Animais , Linhagem Celular Transformada , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Oxazinas/química , Oxazinas/farmacologia , Estereoisomerismo
11.
ACS Chem Biol ; 13(12): 3354-3360, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30451487

RESUMO

Hypoxia, a condition of reduced oxygen, occurs in a wide variety of biological contexts, including solid tumors and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated, small-molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-ß-d-galactopyranoside. As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia. Our system has the potential to be extended to regulate the production of any given protein of choice.


Assuntos
Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Isopropiltiogalactosídeo/análogos & derivados , Isopropiltiogalactosídeo/farmacologia , Pró-Fármacos/farmacologia , Anaerobiose/fisiologia , Linhagem Celular Tumoral , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Isopropiltiogalactosídeo/síntese química , Isopropiltiogalactosídeo/metabolismo , Nitrofuranos/síntese química , Nitrofuranos/metabolismo , Oxazinas/síntese química , Oxazinas/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo
12.
Drug Dev Res ; 79(7): 352-361, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30302774

RESUMO

Hit, Lead & Candidate Discovery A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, 1 H NMR, 13 C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II. Results for in vitro assay revealed that compound 3b having 4-methoxy phenyl moiety was the most potent inhibitor with IC50 value of 0.144 ± 0.008 µM. It exhibited higher enzyme inhibitory activity as compared to the standard acetazolamide (IC50 = 0.997 ± 0.061 µM). The compounds 3c, 3h, and 3n also displayed superior inhibitory activities compared to the rest of the synthesized oxazine derivatives. The radical scavenging activity of oxazine derivatives was also performed and it was found that compounds showed moderate antioxidant activity. Lipinski rule confirmed the therapeutic potential of the synthesized compounds. Molecular docking studies were also performed to further understand the binding affinity of these compounds with PDBID 1V9E which confirmed that the synthesized derivatives bind in the active binding site of the target protein. Based upon our results, it is proposed that compound 3b may serve as a lead structure to design more potent carbonic anhydrase inhibitors.


Assuntos
Antioxidantes/síntese química , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Oxazinas/síntese química , Antioxidantes/farmacologia , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/farmacologia , Simulação de Acoplamento Molecular/métodos , Oxazinas/farmacologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
13.
J Fluoresc ; 28(6): 1347-1355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30242629

RESUMO

Derivatives of oxazine dyes were synthesized on mulitigram scales via efficient synthetic strategies. One practical route was selected to prepare compounds 6, 9 and 10, especially water-soluble compound 6 was obtained in better yield than reported, and compound 10 was insoluble in aqueous media in absence of phenolic-OH. Compounds 3 and 9 were found to be clear pH-dependent between pH = 4.0 and 10.0, and could be used as acid-base indicators to measure intracellular pH. Compounds 6, 9, 10 all have carboxylic acid functionalities, which could be activated and used to conjugate the dyes to biomolecules. In addition, compounds 6 and 9 with good solubility in aqueous media were used to develop a simple, quick, safe, highly sensitive staining method to detect PHAs-producing bacteria on heat-fixed smears, which was confirmed by fluorescence images of PHAs granules of bacteria.


Assuntos
Bactérias/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Oxazinas/química , Oxazinas/síntese química , Polímeros/metabolismo , Água/química , Bactérias/isolamento & purificação , Corantes Fluorescentes/metabolismo , Microscopia de Fluorescência , Oxazinas/metabolismo , Solubilidade
14.
Eur J Med Chem ; 157: 310-319, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30099253

RESUMO

1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Naftalenos/farmacologia , Oxazinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Transcriptase Reversa do HIV/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Oxazinas/síntese química , Oxazinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
15.
Cell Biochem Biophys ; 76(3): 377-389, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30062659

RESUMO

Twenty-two 2-thiophen-naphtho(benzo)oxazinone derivatives are prepared using 3-amino-2-naphthoic and 5-nitroanthranilic acids as building blocks. The target compounds (1-22) were evaluated quantitatively for their cytotoxic effects in vitro against three cancer cell lines, including the lung A549, the hepatocyte HepG2, and the breast MCF-7 carcinoma cells. Compounds 1, 12, 14, and 21 were found to exhibit remarkable cytotoxicity against the tested cancer cell lines. Compound 21 has shown the highest activity against A549 and MCF-7 (IC50: 9.8 & 3.6 µg mL-1) whereas 1 (IC50: 5.9 µg mL-1) and 5 (3.6 µg mL-1) were the most active against HepG2. To elucidate the structure-cytotoxicity relationships of the synthesized compounds, a number of their chemical descriptors are determined including electronic, steric and hydrophobicity descriptors. The electronic properties were calculated through density functional theory (DFT) calculations at the B3LYP/6-31 + G(d,p). The impact of the chosen descriptors is evaluated statistically through simple and multiple linear regression analyses (SLR and MLR). SLR analyses reveal that the impact of each descriptor on the cell lines are relatively weak except for MCF-7, where hardness and softness show moderate correlations with correlation coefficients higher than 60%. The correlations were improved by considering MLR analyses (R2 ≥ 90%), which showed that the cytotoxicity of synthesized compounds is correlated with their combined descriptors hardness, softness, electrophiliciy and hydrophobicity (LogP).


Assuntos
Antineoplásicos/química , Oxazinas/química , Teoria Quântica , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Modelos Lineares , Células MCF-7 , Oxazinas/síntese química , Oxazinas/farmacologia , Relação Estrutura-Atividade
16.
ACS Comb Sci ; 20(9): 529-543, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30040392

RESUMO

In this review, we summarize synthetic approaches to preparing single or fused oxazine and thiazine derivatives using solid-phase synthesis (SPS). The literature survey revealed that diverse compounds bearing variously functionalized 1,2-oxazine, 1,3-oxazine, or 1,4-oxazine scaffolds and the corresponding thiazines are accessible by SPS. The latest contributions involving the stereoselective polymer-supported syntheses of morpholines indicate that the field is continuing to expand.


Assuntos
Oxazinas/síntese química , Polímeros/química , Técnicas de Síntese em Fase Sólida/métodos , Tiazinas/síntese química , Reação de Cicloadição , Estrutura Molecular , Morfolinas/química , Oxirredução , Pirazóis/química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
17.
Bioorg Med Chem ; 26(14): 3982-3991, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29937355

RESUMO

The abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Drogas , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Molecules ; 23(6)2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899273

RESUMO

The use of photodynamic therapy (PDT) and development of novel photosensitizers (PSs) for cancer treatment have received more and more attention nowadays. In the present work, five benzo[a]phenoxazinium derivatives have been prepared and evaluated for their in vitro anticancer photodynamic activity for the first time. They are red light absorbers and show low fluorescence quantum yield. Of these compounds, PS4 exhibited a higher quantum yield for reactive oxygen species (ROS) generation. The assays with cells in vitro showed that PS1 and PS4 were not significantly toxic in the dark, but was robustly toxic against the murine breast adenocarcinoma cells 4T1 and normal murine fibroblast cells NIH-3T3 upon photoactivation. More interestingly, PS5 was particularly selective towards 4T1 cancer cells and nearly non-phototoxic to non-cancerous NIH-3T3 cells. The results described in this report suggest that these new benzo[a]phenoxazinium derivatives are potential candidates as PSs for anticancer PDT. Further investigation of benzo[a]phenoxaziniums for anticancer PDT is warranted.


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/metabolismo , Oxazinas/síntese química , Fármacos Fotossensibilizantes/síntese química , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Estrutura Molecular , Células NIH 3T3 , Oxazinas/química , Oxazinas/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia
19.
Lipids Health Dis ; 17(1): 120, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789011

RESUMO

BACKGROUND: The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. METHODS: The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD50 of the most active derivatives were determined using mice. RESULTS: The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD50 showed that the novel compounds have improved toxicity profile. CONCLUSION: The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.


Assuntos
Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/síntese química , Fígado/efeitos dos fármacos , Simulação de Acoplamento Molecular , Oxazinas/síntese química , PPAR alfa/antagonistas & inibidores , Animais , Domínio Catalítico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Desenho de Drogas , Expressão Gênica , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipolipemiantes/farmacologia , Testes de Função Renal , Fígado/metabolismo , Testes de Função Hepática , Masculino , Camundongos , Oxazinas/farmacologia , PPAR alfa/química , PPAR alfa/genética , PPAR alfa/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Termodinâmica , Triglicerídeos/sangue
20.
Bioorg Med Chem Lett ; 28(12): 2195-2200, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29764741

RESUMO

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aß levels in mice in an acute treatment regimen.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Molecular , Oxazinas/síntese química , Oxazinas/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA