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1.
Food Chem ; 308: 125612, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31670192

RESUMO

A mixture of glucosamine (GlcN, 15% w/v) and different amino acids in 1:1 M ratio was incubated at 70 °C for 12 h. The resulting GlcN-amino acid caramels were analysed for α-dicarbonyl compounds, polyhydroxyalkyl pyrazines, heterocyclic compound and alkylimidazoles. All the analyses were performed by using HPLC-MS/MS followed by pooling the variables with principal component analysis (PCA). GlcN-Gly caramels generated the greatest amount of butterscotch aromatic compound diacetyl and polyhydroxyalkyl pyrazines (fructosazine and deoxyfructosazine). The potentially toxic heterocyclic compound, 5-hydroxymethylfurfural (HMF) was generated in greater amounts with the GlcN-Arg caramels. However, the toxic alkylimidazoles (4-MEI and THI) were not present in any of the GlcN-amino acid caramels. The results suggest that caramel with butterscotch aroma and bioactivity can be produced with GlcN-amino acid at 70 °C. The PCA performed discriminated the majority of the GlcN-amino acid combinations; GlcN-Gly and GlcN-Ser were best discriminated.


Assuntos
Aminoácidos/química , Glucosamina/química , Pirazinas/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem
2.
Eur J Med Chem ; 183: 111695, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541868

RESUMO

As for complex brain diseases involved with multiple pathogenic factors, it is extremely difficult to achieve curative effect by acting on a single target. Multi-approach drugs provide a promising prospect in the treatment of complex brain diseases and have been attracting more and more interest. Enlightened by synergetic effect of combination in traditional herb medicines, forty-two novel cinnamic acid derivatives were designed and synthesized by introducing capsaicin and/or ligustrazine moieties to enhance biological activities in both neurological function and neurovascular protection. Elevated levels of cell viability on human brain microvascular endothelium cell line (HBMEC-2) and human neuroblastoma cell line (SH-SY5Y) against free radical injury were observed in most of compounds. Among them, compound 14a exhibited the most potent activities with a significant EC50 value of 3.26 ±â€¯0.16 µM (HBMEC-2) and 2.41 ±â€¯0.10 µM (SH-SY5Y). Subsequently, the results of morphological staining and flow cytometry analysis experiments on both cell lines showed that 14a had the potential to block apoptosis, maintain cell morphological integrity and protect physiological function of mitochondria. Moreover, 14a displayed specific angiogenesis effect in the chick chorioallantoic membrane (CAM) assay; and the results of RT-PCR suggested that the mechanism for angiogenesis effect was associated with the enhancement of the expressions of VEGFR2 mRNA in chick embryo. Preliminary structure-activity relationship was analyzed. The above evidences suggested that conjunctures gained by combining active ingredients in traditional herb medicines deserved further study and might provide references in discovering dual-effective lead compounds for brain diseases.


Assuntos
Indutores da Angiogênese/farmacologia , Cinamatos/farmacologia , Desenho de Drogas , Fármacos Neuroprotetores/farmacologia , Indutores da Angiogênese/síntese química , Indutores da Angiogênese/química , Apoptose/efeitos dos fármacos , Capsaicina/química , Capsaicina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
J Chromatogr Sci ; 57(9): 784-789, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31504275

RESUMO

Various pyrazines have been synthesized via reaction of selected cellulosic-derived sugars, ammonium hydroxide and amino acids at 110°C for 2 hours. Different methods of sample cleanup such as liquid-liquid extraction (LLE), liquid-solid extraction, column chromatography and distillation were employed to isolate pyrazines from the reaction mixture. Effective LLE of pyrazines from aqueous solution using either hexane, methyl-t-butyl ether (MTBE) or ethyl acetate required multiple extraction steps with fresh solvent each time. When hexane was used as the extraction solvent, no imidazole derivatives were extracted with the pyrazines. However, when MTBE or ethyl acetate was employed, 4-methyl imidazole was co-extracted and further cleanup was required. Passing the organic solvent extracts through a column of silica revealed that the silica retained the undesirable imidazoles, such as 4-methyl imidazole. A mixture of 90/10 hexane/ethyl acetate as eluting solvent provided the desirable pyrazines, but it also provided a desirable separation of pyrazines as a function of total alkyl substituent content. Distillation of the aqueous reaction mixture was also used to isolate the pyrazines, leaving the undesirable imidazoles in the undistilled portion of the reaction. Additional chromatographic methods were used to isolate pyrazines from the aqueous distillate including a column packed with C18-bonded silica.


Assuntos
Aminoácidos/química , Hidróxido de Amônia/química , Pirazinas/análise , Pirazinas/isolamento & purificação , Açúcares/química , Celulose/química , Cromatografia Gasosa-Espectrometria de Massas , Imidazóis , Pirazinas/síntese química , Pirazinas/química , Dióxido de Silício/química
4.
Eur J Med Chem ; 183: 111683, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514060

RESUMO

While photodynamic therapy is known for significant advantages over conventional cancer therapies, its dependence on light has limited it to treating tumors on or just under the skin or on the outer lining of organs/cavities. Herein, we have developed a single-molecule photosensitizer capable of intracellular self-activation and with potential tumor-selectivity due to a chemiluminescent reaction involving only a cancer marker. Thus, the photosensitizer is directly chemiexcited to a triplet excited state capable of generating singlet oxygen, without requiring either a light source or any catalyst/co-factor. Cytotoxicity assays involving the photosensitizer show significant toxicity toward tumor cells, even better than reference drugs, while not inducing toxicity toward normal cells. This work provides a proof-of-concept for a novel type of photosensitizer that eliminates the current restrictions that photodynamic therapy presents regarding tumor size and localization.


Assuntos
Imidazóis/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Pirazinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Luz , Fármacos Fotossensibilizantes/farmacologia , Estudo de Prova de Conceito , Pirazinas/farmacologia , Oxigênio Singlete/metabolismo , Termodinâmica
5.
Phys Chem Chem Phys ; 21(36): 20095-20106, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31482894

RESUMO

Rational modification of biomolecules especially DNA base pairs for the theoretical design of molecular magnets has attracted extensive interest. In this work, we report a modification strategy for adenine/thymine-based magnets through introducing a N,N-dioxidized pyrazine ring to either adenine or thymine to form ring-expanded bases (noA/noT) based on their experimentally synthesized derivatives. Further functionalization is conducted by double protonation and pairing with a normal complementary base (nohA-T/nohT-A), respectively. The diversity of protonation sites in noA generates totally six nohA-Ts, together with nohT-A forming seven two-step modified topic base pairs. DFT calculations are performed to characterize the magnetic properties and the diradical character, which indicate three diamagnetic (DM) nohA-Ts and three antiferromagnetic (AFM) nohA-Ts with extremely large magnetic coupling constants J ranging from -1279.7 to -2807.4 cm-1, while a relatively mild AFM nohT-A with a J of -194.6 cm-1. The electron separation effect induced by attraction of positive charges originating from protonation is proposed to explain the diradicalization, which is different from the traditional radical-coupler-radical coupling mode. In addition, atomic natural charges and spin densities, and H-bond and molecular orbital analyses are further discussed for verification and deep understanding of the observed unique phenomena. It should be noted that our designed seven topic base pairs have excellent characters including a good synthetic basis, a large scope of the |J| values, and the AFM-DM magnetic conversion or AFM strength modulation controlled by protonation/deprotonation, prototropic tautomerization, base pairing/dissociation, single proton transfer, and even the applied electric field. All these indicate the promising applications in the field of magnetic information storage or switch control. This work highlights the magnetic modification schemes and possible modulation methods of double positive charge doped DNA base pairs by utilizing their potential spin coupling modes.


Assuntos
Pareamento de Bases , DNA/química , Magnetismo , Pirazinas/química , Timina/química , Prótons
6.
Molecules ; 24(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487829

RESUMO

4,8-Dihydrodifurazano[3,4-b,e]pyrazine (DFP) is one kind of parent compound for the synthesis of various promising difurazanopyrazine derivatives. In this paper, eleven series of energetic salts composed of 4,8-dihydrodifurazano[3,4-b,e]pyrazine-based anions and ammonium-based cations were designed. Their densities, heats of formation, energetic properties, impact sensitivity, and thermodynamics of formation were studied and compared based on density functional theory and volume-based thermodynamics method. Results show that ammonium and hydroxylammonium salts exhibit higher densities and more excellent detonation performance than guanidinium and triaminoguanidinium salts. Therein, the substitution with electron-withdrawing groups (-NO2, -CH2NF2, -CH2ONO2, -C(NO2)3, -CH2N3) contributes to enhancing the densities, heats of formation, and detonation properties of the title salts, and the substitution of -C(NO2)3 features the best performance. Incorporating N-O oxidation bond to difurazano[3,4-b,e]pyrazine anion gives a rise to the detonation performance of the title salts, while increasing their impact sensitivity meanwhile. Importantly, triaminoguanidinium 4,8-dihydrodifurazano[3,4-b,e]pyrazine (J4) has been successfully synthesized. The experimentally determined density and H50 value of J4 are 1.602 g/cm3 and higher than 112 cm, which are consistent with theoretical values, supporting the reliability of calculation methods. J4 proves to be a thermally stable and energetic explosive with decomposition peak temperature of 216.7 °C, detonation velocity 7732 m/s, and detonation pressure 25.42 GPa, respectively. These results confirm that the derivative work in furazanopyrazine compounds is an effective strategy to design and screen out potential candidates for high-performance energetic salts.


Assuntos
Compostos de Amônio/química , Ânions/química , Cátions/química , Modelos Teóricos , Pirazinas/química , Sais/química , Algoritmos , Estrutura Molecular , Sensibilidade e Especificidade , Termodinâmica
7.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434286

RESUMO

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.


Assuntos
Neovascularização Patológica/tratamento farmacológico , Pirazinas/química , Pirazinas/uso terapêutico , Triterpenos/química , Triterpenos/uso terapêutico , Animais , Caenorhabditis elegans/efeitos dos fármacos , Membrana Corioalantoide/efeitos dos fármacos , Descoberta de Drogas , Células Endoteliais da Veia Umbilical Humana , Humanos , Metabolômica/métodos
8.
J Agric Food Chem ; 67(36): 10137-10144, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31423769

RESUMO

Volatile extractive compounds from high-quality oak wood (Quercus sp.) are responsible for important pleasant olfactory notes, such as coconut, wood, vanilla, caramel, and spice. Recently, a new off-flavor reminiscent of rancid butter has been detected in oak wood. Using gas chromatography-olfactometry (GC-O) coupled to several detection modes, such as nitrogen-phosphorus detection (GC-O-NPD) or mass spectrometry (GC-O-MS) and multidimensional GC-O coupled to time-of-flight mass spectrometry, six compounds containing nitrogen atoms were identified. The volatiles were suggested to belong to 2,5-disubstituted pyrazines family, which was confirmed by comparison with synthetic reference compounds. For this purpose, symmetric and dissymmetric 2,5-dialkylpyrazines were prepared from methyl esters of corresponding aliphatic amino acids (Val, Leu, and Ile) by a three-step, one-pot reaction under mild reducing conditions. Organoleptic descriptors and odor detection thresholds were also determined, whereas a bacterial origin explaining these off-flavors was hypothesized.


Assuntos
Aromatizantes/química , Pirazinas/química , Quercus/química , Madeira/química , Cromatografia Gasosa-Espectrometria de Massas , Odorantes/análise , Olfatometria
9.
Chem Asian J ; 14(22): 3962-3968, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31389664

RESUMO

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity.


Assuntos
Adenina/análogos & derivados , Antivirais/química , Guanina/análogos & derivados , Febres Hemorrágicas Virais/tratamento farmacológico , Adenina/farmacologia , Adenina/uso terapêutico , Amidas/química , Amidas/metabolismo , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Pareamento de Bases , Ebolavirus/efeitos dos fármacos , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Nucleotídeos/química , Nucleotídeos/uso terapêutico , Ácidos Fosfóricos/química , Ácidos Fosfóricos/uso terapêutico , Pirazinas/química , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Triazinas/química , Triazinas/uso terapêutico
10.
Eur J Med Chem ; 180: 546-561, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344614

RESUMO

A novel series of 6-substituted-8-(1-cyclohexyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine and 6-substituted-8-(1-benzyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine is first time synthesized and screen in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Derivatives 10 and 36 show antitumor activity for all tested cell lines, display comparable full panel mean-graph midpoint growth inhibition (MG_MID GI50) values of 2.10 and 2.23 µM, respectively. Furthermore, these derivatives show strong binding interactions with DNA and bovine serum albumin (BSA), studied through absorption, emission, and circular dichroism techniques. These spectroscopic studies reveal that imidazo[1,2-a]pyrazine-benzimidazoles 10 and 36, intercalate with ct-DNA as a leading interaction for fundamental biologically significant effects, with monobenzimidazole show better activity than bisbenzimidazole. These experiments have confirmed that the imidazo[1,2-a]pyrazine and benzimidazole moieties are efficient pharmacophores to trigger binding to DNA. These compounds have also interacted with bovine serum albumin protein that demonstrating high values of binding constant.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Animais , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Relação Estrutura-Atividade
11.
Eur J Pharm Biopharm ; 142: 435-448, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306750

RESUMO

Acalabrutinib (Calquence®) 100 mg (bid) has received accelerated approval by FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Acalabrutinib is a substrate of PgP and CYP3A4, with a significant fraction of drug metabolized by first pass gut extraction and 25% absolute bioavailability. The absorption of acalabrutinib is affected by stomach pH, with lower pharmacokinetic exposure observed following co-administration with proton pump inhibitors. During dissolution at pH values below its highest basic pKa, the two basic moieties of acalabrutinib react with protons from the aqueous solution, leading to a higher pH at the drug surface than in the bulk solution. A batch-specific product particle size distribution (P-PSD), was derived from dissolution data using a mechanistic model that was based on the understanding of surface pH and the contribution of micelles to the dissolution rate. P-PSD values obtained for various batches of acalabrutinib products in simple buffers, or in complex fluids such as fruit juices, were successfully integrated into a physiologically based pharmacokinetic (PBPK) model developed using GastroPlus v9.0™. The integrated model allowed the prediction of clinical pharmacokinetics under normal physiological stomach pH conditions as well as following treatment with proton pump inhibitors. The model also accounted for lower pharmacokinetic exposure that was observed when acalabrutinib was co-administered with the acidic beverages, grapefruit juice, (which contains CYP3A inhibitors), and orange drink (which does not contain CYP3A inhibitors), relative to administration with water. The integration of dissolution data in the PBPK model enables mechanistic understanding and the establishment of more robust in vitro-in vivo correlations (IVIVC) under a variety of conditions. The model can then distinguish the interplay between dissolution and first pass extraction and how in vivo stomach pH, saturation of gut PgP, and saturation or inhibition of gut CYP3A4, will impact the pharmacokinetics of acalabrutinib.


Assuntos
Benzamidas/química , Benzamidas/farmacocinética , Interações de Medicamentos/fisiologia , Sucos de Frutas e Vegetais/efeitos adversos , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Solubilidade/efeitos dos fármacos , Disponibilidade Biológica , Química Farmacêutica/métodos , Humanos , Modelos Biológicos
12.
Eur J Pharm Biopharm ; 142: 421-434, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306753

RESUMO

Drug product dissolution for four batches of acalabrutinib 100 mg capsules were analyzed with in vitro dissolution in various pH conditions and in media containing synthetic surfactant micelles or biorelevant micelles. Non-sink conditions, where the drug is unionized, were used to derive a batch specific drug product particle size distribution (P-PSD). The purpose of this P-PSD is to serve as an input in physiological based pharmacokinetic (PBPK) models to calculate in vivo dissolution in various administration conditions. The P-PSD was used to predict dissolution in all other conditions tested, introducing a different Unstirred Water Layer (UWL) thickness for free- and micelle-bound drug and the calculation of surface solubility using a theoretical model. With the proposed P-PSD approach and proposed model inputs, percent dissolved at all time points and for all conditions and batches were adequately anticipated with an 11% overprediction. In contrast, the use of drug substance laser diffraction particle size data with equivalent inputs to the models led to an underprediction of observed percent dissolved by 31% overall. Finally, the use of bulk solubility instead of surface solubility led to an overall 48% overprediction of the dissolution data. Batch specific P-PSD were used to predict in vivo dissolution of acalabrutinib drug products with PBPK models. The current limitations of PBPK models for integration of in vitro dissolution are also discussed and improvements are suggested to improve future predictions.


Assuntos
Benzamidas/química , Liberação Controlada de Fármacos/efeitos dos fármacos , Pirazinas/química , Solubilidade/efeitos dos fármacos , Cápsulas/química , Micelas , Modelos Biológicos , Tamanho da Partícula
13.
Eur J Med Chem ; 179: 470-482, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271959

RESUMO

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor trkB/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Receptor trkB/metabolismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
14.
J Food Sci ; 84(8): 2031-2041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31276204

RESUMO

Yeast extract was analyzed through headspace solid-phase microextraction (HS-SPME) in combination with (GC-MS) for its pyrazine compounds. Four different types of SPME fibers with various polarities were selected for preoptimization. The three coated fiber 50/30 µm DVB/CAR/PDMS showed the maximum volatile extraction efficiency and was selected for further analysis. Twenty-eight volatile compounds were tentatively identified through GC-MS including eight pyrazines and were categorically characterized as major volatile compounds responsible for the flavor enhancing notes in YE. Response surface methodology encoded with face centered central composite design was employed to optimize the experimental design. Average peak area of selected pyrazines; methylpyrazine, 2,3-dimethylpyrazine, 2,6-dimethylpyrazine, 2-ethyl-5-methylpyrazine, trimethylpyrazine, 3-ethyl-2,5-dimethylpyrazine, tetramethylpyrazine, 3,5-diethyl-2-methylpyrazine, and 2,3,5-trimethyl-6-ethylpyrazine were optimized through RSM-CCD to get the best conditions for HS-SPME. The HS-SPME variables X1 (equilibrium time), X2 (extraction time), and X3 (extraction temperature) were programed into the run sheets to opt an optimistic statistical approach. Among these, the variable X2 and X3 showed the most significant results with the response variable R and could be concluded as the most tantalize variables while practicing pyrazines extraction through HS-SPME method. Resultantly, the optimization methodology was successfully applied for the extraction of pyrazines from yeast extract. PRACTICAL APPLICATION: The selection of optimal conditions to conduct a HS-SPME experiment can dramatically affect the sensitivity and accuracy of aroma extraction process. Optimizing the SPME conditions is the best way to identify the role of all the possible factors that can fluctuate the volatile profile of any sample. This type of statistical approach to optimize the HS-SPME conditions for pyrazines in yeast extract was practiced for the very first time and could be considered as a prerequisite strategy to proliferate future projects related to some novel studies in terms of pyrazines flavor perception.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Pirazinas/química , Pirazinas/isolamento & purificação , Microextração em Fase Sólida/métodos , Leveduras/química , Odorantes/análise , Temperatura Ambiente
15.
J Enzyme Inhib Med Chem ; 34(1): 1368-1372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347930

RESUMO

To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/química , Pirazinas/química , Relação Estrutura-Atividade
16.
Pestic Biochem Physiol ; 157: 122-137, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153459

RESUMO

Novel phospho guanidine and phospho pyrazine derivatives were synthesized and characterized by 31P, 13C, 1HNMR and IR spectroscopy to obtain novel and human-safe insecticides. Compound 35 [(C4H4N2NH)2P(O)(C6H6)] was investigated by X-ray crystallography. The inhibitory effects of synthesized compounds were evaluated on human and insect acetylcholinesterase (AChE) using in vitro Ellman method. A few of these compounds, which had low human toxicity, were selected for assessing the killing effects (in vivo) on the elm leaf beetle (X.luteola). The in vitro and in vivo results indicated that compounds bearing both phosphoryl groups and aromatic systems were found to possess a good selectivity for the inhibition of insect AChE over human AChE; up to 550-fold selectivity was achieved for compound 19. Docking studies were performed to explain reasons for the selective behavior of AChE inhibitors. Additionally, the quantitative structure-activity relationship (QSAR) and density functional theory (DFT) results of AChEs demonstrated that the size, shape, dipole moment, and ability to form hydrogen bond played the main role in both models. In addition, the aromatic π - π interactions and charge of the amide nitrogen had a major effect on insecticidal activity of the compounds. The present research can be helpful to gain a better understanding of the interactions between the insect AChE and its inhibitors and introduces compounds which are capable of becoming human-safe insecticides.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Guanidinas/química , Pirazinas/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Besouros/efeitos dos fármacos , Humanos , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-Atividade
17.
Chem Pharm Bull (Tokyo) ; 67(6): 556-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155561

RESUMO

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).


Assuntos
Aldeído Redutase/metabolismo , Inibidores Enzimáticos/síntese química , Pirazinas/química , Aldeído Redutase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Pirazinas/síntese química , Pirazinas/metabolismo
18.
Int J Mol Med ; 44(2): 503-512, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173163

RESUMO

Glaucoma is the leading cause of irreversible blindness worldwide; the apoptosis of the retinal ganglion cells (RGCs) is a hallmark of glaucoma. Tetramethylpyrazine (TMP) is the main active component of Ligusticum wallichii Franchat, and has been demonstrated to improve a variety of injuries through its antioxidative and antiapoptotic properties. However, these effects of TMP on glaucoma have not been studied. The present study aimed to investigate the potential role of TMP in glaucoma and to elucidate its possible mechanisms responsible for these effects. An in vitro model was generated, in which primary RGCs (PRGCs) were treated with H2O2. Our study revealed that TMP protected against H2O2­induced injury to PRGCs, as evidenced by enhanced cell viability, reduced caspase 3 activity and decreased cell apoptosis. We also reported that TMP treatment inhibited reactive oxygen species (ROS) production and malondialdehyde levels, but upregulated the antioxidative enzyme superoxide dismutase. In particular, TMP significantly increased the expression of microRNA­182­5p (miR­182) in H2O2­treated PRGCs, which was selected as the target miRNA for further research. In addition, our findings suggested that the protective effects of TMP on H2O2­induced injury were attenuated by knockdown of miR­182. The results of a luciferase reporter assay demonstrated that Bcl­2 interacting protein 3 (BNIP3), an effector of mitochondria­mediated apoptosis, was a direct target of miR­182. In addition, TMP treatment significantly decreased the expression of BNIP3, Bax, cleaved­caspase­3 and cleaved­poly(ADP­ribose)polymerase, but increased that of Bcl­2. Also, TMP treatment decreased the release of cytochrome c from mitochondria and improved mitochondrial membrane potential in H2O2­treated RGCs. Of note, the inhibitory effects of TMP on the mitochondrial apoptotic pathway were suggested to be reversed by knockdown of miR­182. Collectively, our findings provide novel evidence that TMP protects PRGCs against H2O2­induced damage through suppressing apoptosis and oxidative stress via the miR­182/mitochondrial apoptotic pathway.


Assuntos
Antioxidantes/farmacologia , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Pirazinas/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Células Cultivadas , Peróxido de Hidrogênio/metabolismo , Ligusticum/química , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Pirazinas/química , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Analyst ; 144(10): 3250-3259, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31049499

RESUMO

The trend for improved more precise diagnostics and management of disease heavily relies on the measurement of panels of biomarkers in physiological samples of patients. Ideally, the ultimate goal would be to detect as many clinically relevant biomarkers as possible in a single drop of blood, achieving quick, sensitive, reproducible, and affordable detection in small volume physiological samples. Bioluminescent (BL) proteins provide many of the desired characteristics required for such labels, including detection at extremely low concentrations, no interference from physiological fluids leading to excellent detection limits, and compatibility with many miniaturized systems. However, to date the use of BL proteins has been restricted by their limited multiplexing capabilities. BL proteins typically exhibit a single emission profile and decay kinetics making the simultaneous detection of multiple analytes difficult. Recent progresses in this area include the use of two different engineered luminescent proteins to achieve resolved signals via one-dimensional time resolution. This approach, however, to date only lead to a dual analyte detection. Herein, we have demonstrated that using a two-dimensional approach that combines both temporal and spatial resolution, we can expand the multiplexing capabilities of bioluminescent proteins. To that end, the photoprotein aequorin (AEQ) has been employed for the simultaneous detection of three separate analytes in a single well, differentiated through the use of three discrete time/wavelength windows. Through a combination of site-specific mutations and synthetic coelenterazines "semi-synthetic" AEQ variants have been developed with altered emission profiles and decay kinetics. In this study, two AEQ mutant proteins were genetically conjugated to three pro-inflammatory cytokines (tumor necrosis factor alpha, interleukins 6 and 8) resulting in AEQ-labeled cytokines. These fusion proteins were combined with synthetic coelenterazines resulting in proteins with differing emission maxima and half-lives to allow for the simultaneous detection of all three cytokines in a single sample. The validity of the assay was demonstrated in serum by employing human physiological samples and comparing our results with commercially available individual tests for each of the three cytokines.


Assuntos
Equorina/química , Interleucina-6/sangue , Interleucina-9/sangue , Fator de Necrose Tumoral alfa/sangue , Equorina/genética , Animais , Cabras , Humanos , Hidrozoários/química , Imidazóis/química , Imunoensaio/métodos , Imunoglobulina G/imunologia , Interleucina-6/imunologia , Interleucina-9/imunologia , Limite de Detecção , Luminescência , Medições Luminescentes/métodos , Camundongos , Mutação , Pirazinas/química , Reprodutibilidade dos Testes , Fator de Necrose Tumoral alfa/imunologia
20.
Sensors (Basel) ; 19(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052519

RESUMO

A small extent of endogenous labile zinc is involved in many vital physiological roles in living systems. However, its detailed functions have not been fully elucidated. In this study, we developed a novel biheteroaryl-based low molecular weight fluorescent sensor, 3-(phenylsulfonyl)-pyrazine-pyridone (5b), and applied it for the detection of endogenous labile zinc ions from lung cancer cells during apoptosis. The electron-withdrawing property of the sulfonyl group between the phenyl ring as an electron donor and the pyridone ring as a fluorophore inhibited the intramolecular charge transfer state, and the background fluorescence of the sensor was decreased in aqueous media. From the structure-fluorescence relationship analysis of the substituent effects with/without Zn2+, compound 5b acting as a sensor possessed favorable properties, including a longer emission wavelength, a large Stokes shift (over 100 nm), a large fluorescence enhancement in response to Zn2+ under physical conditions, and good cell membrane permeability in living cells. Fluorescence imaging studies of human lung adenocarcinoma cells (A549) undergoing apoptosis revealed that compound 5b could detect endogenous labile zinc ions. These experiments suggested that the low molecular weight compound 5b is a potential fluorescence sensor for Zn2+ toward understanding its functions in living systems.


Assuntos
Técnicas Biossensoriais , Íons/isolamento & purificação , Neoplasias Pulmonares/química , Zinco/isolamento & purificação , Humanos , Íons/química , Neoplasias Pulmonares/diagnóstico , Imagem Óptica , Pirazinas/síntese química , Pirazinas/química , Piridonas/síntese química , Piridonas/química , Água/química , Zinco/química
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