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1.
J Photochem Photobiol B ; 204: 111804, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007677

RESUMO

The ubiquitous influence of double stranded RNAs in biological events makes them imperative to gather data based on specific binding procedure of small molecules to various RNA conformations. Particular interest may be attributed to situations wherein small molecules target RNAs altering their structures and causing functional modifications. The main focus of this study is to delve into the interactive pattern of two small molecule phenothiazinium dyes, methylene blue and new methylene blue, with three duplex RNA polynucleotides-poly(A).poly(U), poly(C).poly(G) and poly(I).poly(C) by spectroscopic and molecular modeling techniques. Analysis of data as per Scatchard and Benesi-Hildebrand methodologies revealed highest affinity of these dyes to poly(A).poly(U) and least to poly(I).poly(C). In addition to fluorescence quenching, viscometric studies also substantiated that the dyes follow different modes of binding to different RNA polynucleotides. Distortion in the RNA structures with induced optical activity in the otherwise optically inactive dye molecules was evidenced from circular dichroism results. Dye-induced RNA structural modification occurred from extended conformation to compact particles visualized by atomic force microscopy. Molecular docking results revealed different binding patterns of the dye molecules within the RNA duplexes. The novelty of the present work lies towards a new contribution of the phenothiazinium dyes in dysfunctioning double stranded RNAs, advancing our knowledge to their potential use as RNA targeted small molecules.


Assuntos
Azul de Metileno/análogos & derivados , Azul de Metileno/química , RNA de Cadeia Dupla/química , Sítios de Ligação , Corantes/química , Azul de Metileno/metabolismo , Microscopia de Força Atômica , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Fenotiazinas/química , Poli C/química , Poli C/metabolismo , Poli G/química , Poli G/metabolismo , RNA de Cadeia Dupla/metabolismo , Espectrometria de Fluorescência , Espectrofotometria , Viscosidade
2.
Chemistry ; 26(2): 534-542, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31638287

RESUMO

The interlocking of ring and axle molecular components in rotaxanes provides a way to combine chromophoric, electron-donor and electron-acceptor moieties in the same molecular entity, in order to reproduce the features of photosynthetic reaction centers. To this aim, the photoinduced electron transfer processes involving a 1,8-naphthalimide chromophore, embedded in several rotaxane-based dyads, were investigated by steady-state and time-resolved absorption and luminescence spectroscopic experiments in the 300 fs-10 ns time window. Different rotaxanes built around the dialkylammonium/ dibenzo[24]crown-8 ether supramolecular motif were designed and synthesized to decipher the relevance of key structural factors, such as the chemical deactivation of the ammonium-crown ether recognition, the presence of a secondary site for the ring along the axle, and the covalent functionalization of the macrocycle with a phenothiazine electron donor. Indeed, the conformational freedom of these compounds gives rise to a rich dynamic behavior induced by light and may provide opportunities for investigating and understanding phenomena that take place in complex (bio)molecular architectures.


Assuntos
Naftalimidas/química , Rotaxanos/química , Éteres de Coroa/química , Transporte de Elétrons , Luz , Fenotiazinas/química , Teoria Quântica , Rotaxanos/síntese química , Espectrometria de Fluorescência
3.
J Photochem Photobiol B ; 202: 111686, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731078

RESUMO

In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from λmax = 521 nm in solution to λmax = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state (3CMZ*), monitored at λ = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 µs vs. 0.7 µs); besides, photochemical ionization leading to the radical cation CMZ+• was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel.


Assuntos
Antipsicóticos/química , Hidrogéis/química , Fenotiazinas/química , Lasers , Oxirredução , Fotólise/efeitos da radiação , Espectrometria de Fluorescência
4.
Chem Biol Interact ; 314: 108845, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593690

RESUMO

Phenazines, naturally produced by bacteria and archaeal Methanosarcina species are nitrogen-containing tricyclic molecules with antibiotic, antitumoral, and antiparasitic activities. Phenazines are used as electron acceptors-donors in wide range of fields including environmental biosensors. In this study, the inhibitory effects of a synthetic phenazine dye, methylene violet 3RAX (also known as diethyl safranine) on human erythrocyte AChE and human plasma BChE were tested and also its inhibitory mechanisms for both enzymes were studied in detail. Kinetic analyses showed that methylene violet 3RAX acts as a hyperbolic noncompetitive inhibitor of AChE with Ki value of 1.58 ±â€¯0.36 µM; α = 1; ß = 0.12 ±â€¯0.0003. On the other hand, it caused linear competitive inhibition of BChE with Ki value of 0.51 ±â€¯0.006 µM; α = ∞. In conclusion, methylene violet 3RAX which is a highly effective inhibitor of both human AChE and human BChE with Ki values in low micromolar range may be a promising candidate for the treatment of Alzheimer's disease.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Fenotiazinas/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/metabolismo , Humanos , Cinética , Fenotiazinas/metabolismo
5.
Mikrochim Acta ; 186(10): 677, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511998

RESUMO

A Pb(II)-DNAzyme is used in an amperometric method for the determination of Pb(II). The method is based on two feedback processes. In the first, the Pb(II)-DNAzyme initiates a reaction in presence of Pb(II) in a micro-tube to release a linear DNA (S1). In the second, the S1 triggers the recycling amplification between two types of hairpin-shaped DNA templates (H1 and H2) which consist of a primer sequence and a Pb(II)-DNAzyme substrate sequence. The Pb(II)-DNAzyme has excellent cleavage specificity toward the substrate sequence in S1 that combined firstly with H1 and then is linked to H2. This process will connect H1 and H2. After hybridization with H1 and H2 to form two DNA complexes, S1 is released and initiates the next recycling process. This results in efficient amplification. A glassy carbon electrode (GCE) was immersed into solution of HAuCl4 to electrodeposit a layer of gold nanoparticles. This is followed by the assembly of the hairpin probe H1 on the GCE. In addition, a nanohybrid consisting of 3, 4, 9, 10-Perylenetetracarboxylic acid (PTCA) and nitrogen-doped graphene (NG) was loaded with electroactive thionine (Thi) and gold to form nanoparticles of type NG-PTCA-Thi-Au. This is responsible for generating the amperometric signal (best measured at around -0.30 V vs. SCE) and also acts as the reducing agent for synthesizing the NG-PTCA-Thi-Au nanohybrid. H2 is immobilized on NG-PTCA-Thi-Au to form a new tracer label. The concentration of Pb(II) in a solution can be quantified by determination of the amount of cleaved S1. The method has high sensitivity and selectivity for Pb(II). The detection limit is 0.42 pM (S/N = 3), and the detection range extends from 1 pM to 1000 nM. Graphical abstract Schematic representation of electrodes for the determination of the lead ions (Pb2+). The sensor is using Pb2+-DNAzyme assisted recycling amplification based on hairpin assembly on a composite prepared from nitrogen doped graphene, perylenetetracarboxylic anhydride, thionine and gold nanoparticles (NG-PTCA-Thi-Au). This versatile platform expands studies on the detection of heavy metal ions.


Assuntos
DNA Catalítico/química , Técnicas Eletroquímicas , Chumbo/análise , Nanocompostos/química , Técnicas de Amplificação de Ácido Nucleico , Técnicas Biossensoriais , Ouro/química , Grafite/química , Nanopartículas Metálicas/química , Nitrogênio/química , Hibridização de Ácido Nucleico , Perileno/química , Fenotiazinas/química
6.
Eur J Med Chem ; 183: 111692, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541872

RESUMO

A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the treatment of breast cancer. Phenothiazine derivatives (l) did not noticeably inhibit the growth of SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, whereas phenothiazine derivatives (ll) containing the NO donor were more potent or had comparable inhibitory activity to trifluoperazine (TFP) and thioridazine against SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells. Compounds 20a-c and 21a-c showed the strongest activity in SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, and more potent inhibitory activity than TFP against KG1a cells (IC50 = 1.63, 2.93, 1.14, 1.78, 2.20, and 1.20 vs. 4.58 µM). Compounds 20a and 21a had lower toxicity than compounds 20b-c and 21b-c, and inhibited colony formation in MCF-7 cells, decreased the formation of mammospheres in SUM159 cells, and inhibited the migration of MDA-MB-231 cells. Compounds 20a and 21a could inhibited pNF-κB-p65 as shown by dual-luciferase reporter assays and western blotting in MDA-MB-231 cells.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade
7.
Bioelectrochemistry ; 130: 107344, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31404808

RESUMO

In this work, a novel electrochemical sensing platform was designed and fabricated by the modification of boronic acid functionalized carbon nanodots (B-CNDs) and poly(thionine) (pTHI) on an electrode surface. B-CNDs can not only accelerate electron transfer but also covalently interact with cis-diol groups of dihydronicotinamide adenine dinucleotide (NADH) through functionalized boronic acid groups. Meanwhile, pTHI served as an inner reference element to provide a built-in correction, which enabled the sensor to detect NADH with high accuracy and reliability based on a ratiometric signal (∆INADH/∆ITHI). The electrochemical experimental results demonstrated that the ratiometric strategy-based sensor possessed good selectivity and high sensitivity. A linear range of 5.0 × 10-7 - 2.0 × 10-4 mol/L for NADH detection was obtained with a limit of detection of 1.5 × 10-7 mol/L. The sensor has been applied to analyze NADH in human serum samples with satisfactory results. The simple and effective ratiometric strategy reported here can be further used to prepare electrochemical sensors for selective, sensitive, and reliable detection of other cis-diol compounds.


Assuntos
Ácidos Borônicos/química , Carbono/química , NADP/sangue , Nanoestruturas/química , Fenotiazinas/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos , Humanos , Limite de Detecção , Polímeros/química , Reprodutibilidade dos Testes
8.
Eur J Med Chem ; 181: 111585, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404860

RESUMO

Brain amyloid deposits have been identified as the main neuropathological hallmarks of Alzheimer's diseases (AD) and intensive efforts have been devoted to develop aggregation inhibitors preventing the formation of toxic oligomeric Aß for therapeutic. In addition, evidence indicates that the formation and accumulation of ß-amyloid plaques probably precede clinical symptoms by around 20 years and imaging of such plaques would be beneficial for early-stage AD detection. In this study, we investigated phenothiazine-based compounds as novel promising theranostic agents for AD. These multifunctional agents exhibited BBB permeability, low neurotoxicity, good bio-stability as well as strong turn-on fluorescence with a Stokes shift upon binding to Aß aggregates. They had metal-chelating property which could delay Aß aggregation and displayed high binding affinity for ß-amyloid aggregates. Moreover, they have been simultaneously applied to perform in vivo near-infrared fluorescence imaging of ß-amyloid plaques in double transgenic AD mouse model, to prevent self-aggregation of Aß monomer from forming toxic oligomers and to protect human neuroblastoma SH-SY5Y cells against Aß-induced toxicity and oxidative stress.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/análise , Fármacos Neuroprotetores/uso terapêutico , Fenotiazinas/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Imagem Óptica , Fenotiazinas/química , Fenotiazinas/farmacocinética , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/tratamento farmacológico , Agregação Patológica de Proteínas/diagnóstico por imagem , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Nanomedicina Teranóstica
9.
J Enzyme Inhib Med Chem ; 34(1): 1298-1306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307242

RESUMO

10H-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced 1H and 13C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and N, N-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).


Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Biomed Chromatogr ; 33(10): e4627, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31222787

RESUMO

The aim of this study was to develop an analytical method to determine mequitazine in rat plasma and urine. Mequitazine was separated by UPLC-MS/MS equipped with a Kinetex core-shell C18 column (50 × 2.1 mm, 1.7 µm) using 0.1% (v/v) aqueous formic acid and acetonitrile containing 0.1% (v/v) formic acid as a mobile phase by gradient elution at a flow rate of 0.3 mL/min. Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operating in multiple reaction monitoring positive ion mode. Mass transitions were m/z 323.3 → 83.1 for mequitazine and 281.3 → 86.3 for imipramine as internal standard. Liquid-liquid extraction with ethyl acetate and protein precipitation with methanol were used for sample extraction. Chromatograms showed that the method had high resolution, sensitivity and selectivity without interference from plasma constituents. Calibration curves for mequitazine in rat plasma and urine were 0.02-200 ng/mL, showing excellent linearity with correlation coefficients (r2 ) >0.99. Both intra- and inter-day precisions (CV%) were within 4.08% for rat plasma and urine. The accuracies were 99.58-102.03%. The developed analytical method satisfied the criteria of international guidance. It could be successfully applied to pharmacokinetic studies of mequitazine after oral and intravenous administration to rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fenotiazinas/sangue , Fenotiazinas/urina , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Fenotiazinas/química , Fenotiazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
11.
Chem Asian J ; 14(22): 4035-4041, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31251464

RESUMO

Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure-activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.


Assuntos
Mitocôndrias/metabolismo , Oligopeptídeos/metabolismo , Fenotiazinas/química , Survivina/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Citocromos c/metabolismo , Humanos , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Fenotiazinas/metabolismo , Fenotiazinas/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade , Survivina/química
12.
Chem Biol Interact ; 308: 224-234, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100279

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multitarget studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the NMDA subtype of the glutamate receptor was conducted as an additional indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and calcium-induced swelling as indicators of mitochondrial permeability transition. Antioxidant potential was measured to evaluate the tendency to prevent oxidative stress. Potential for disease modification was gauged by the ability to stimulate microtubule assembly. Finally, binding modes of conjugates to AChE and BChE were studied using quantum mechanical-assisted molecular docking. We found selective BChE inhibitors (conjugates of γ-carbolines and phenothiazine I, γ-carbolines and carbazoles II, and aminoadamantanes and carbazoles III) as well as inhibitors of both cholinesterases (conjugates of γ-carbolines and methylene blue IV and bis-γ-carbolines with ditriazole-containing spacers V). These compounds combined potentials for cognition enhancement, neuroprotection, and disease modification. None of the conjugates exhibited high potency against CaE, thereby precluding potential drug-drug interactions from CaE inhibition. Thus, the studied compounds exhibited positive characteristics of multitarget drugs, indicating their potential for the next generation of AD therapeutics.


Assuntos
Adamantano/química , Carbazóis/química , Carbolinas/química , Inibidores da Colinesterase/química , Fenotiazinas/química , Adamantano/metabolismo , Adamantano/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Carbazóis/metabolismo , Carbazóis/uso terapêutico , Carbolinas/metabolismo , Carbolinas/uso terapêutico , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Colinesterases/química , Colinesterases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Fenotiazinas/metabolismo , Fenotiazinas/uso terapêutico
13.
Photochem Photobiol Sci ; 18(6): 1576-1586, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31066390

RESUMO

We report herein the physicochemical properties and antimicrobial activity of a new monobrominated derivative of Azure B and its parent compound. These dyes are used as photosensitizers for photodynamic therapy and photodynamic antimicrobial chemotherapy. Relevant pharmaceutical properties (pKa, chemical and photochemical stability, and in vitro antimicrobial activity) were determined. A UV-visible spectrophotometry method was developed and validated according to the International Conference on Harmonization (ICH) guidelines for use in stability indicating studies and determination of the acid dissociation constant of Azure B and its monobrominated derivative. The results showed that both dyes were chemically stable. In addition, bromination of the phenothiazine dye decreased its photochemical stability and pKa value without affecting the ionization rate at physiological pH. The analytical parameters for validation of the method were linearity (r2 > 0.9981), limit of detection (LOD) (0.2-0.9 µM), limit of quantification (LOQ) (0.6-2.7 µM), and intra-day precision (0.76-1.40%) expressed as relative standard deviation (RSD). Recoveries ranging from 99.5 to 100.9% were obtained for the two dyes. Thus, this method provides a simple, sensitive, accurate, and precise assay for the determination of all compounds. The effect of photosensitizer concentration and visible irradiation time on lethal photosensitization against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was investigated. Both photosensitizers were active against the evaluated bacteria. However, the new monobrominated derivative was more effective than its predecessor and managed to eradicate these microorganisms by using different doses of the dye and light. In other words, a lower concentration of AzBBr and irradiation time were required to cause bacterial death equal to or greater than its precursor. The photodynamic efficacy of the two photosensitizers presented the following order: S. aureus > E. coli > P. aeruginosa. These studies indicated that the tested dyes satisfy the conditions of potential photosensitizers in terms of physicochemical and antimicrobial properties.


Assuntos
Antibacterianos/farmacologia , Fenotiazinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antibacterianos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenotiazinas/química , Fármacos Fotossensibilizantes/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Biosens Bioelectron ; 135: 224-230, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31030030

RESUMO

Dopamine (DA), as one of the central neurotransmitters, plays an important role in many physiological and pathological processes. Detection of DA is critical to diagnose and monitor some neurological diseases. In this work, a novel on-off ratiometric electrochemical sensor with molecularly imprinted polymers (MIPs) as target molecule recognizer has been developed for selective and accurate detection of DA. Nanoporous gold (NPG) was electrodeposited on bare gold electrode, which not only benefited the output signal amplification, but also provided enlarged surface for immobilization of polythionine (pThi) and MIPs. Oxidation of DA and pThi served as response signal and internal reference signal, respectively. The oxidation peak currents of DA at +0.12 V increased with increasing the concentration of DA, while the peak currents of pThi at -0.2 V decreased simultaneously. Due to the specificity from MIPs and the built-in correction from pThi, the fabricated sensor showed excellent performance in view of selectivity and reproducibility. It's worth to mention that even if the surface area and morphology of working electrode underwent huge variation deliberately, the assay deviation among these ratiometric sensors was largely reduced around 10 times. The proposed sensor demonstrated a broad dynamic range of 0.3-100 µM, as well as a low detection limit of 0.1 µM (S/N = 3). Moreover, superior anti-interfering ability toward DA detection was obtained despite the presence of interferents at high concentration in artificial cerebrospinal fluid (aCSF). Therefore, this work is expected to provide an alternative pathway for constructing ratiometric electrochemical sensor and offer reliable determination of small molecules with high selectivity and stability.


Assuntos
Técnicas Biossensoriais , Dopamina/análise , Impressão Molecular , Polímeros/química , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Dopamina/líquido cefalorraquidiano , Técnicas Eletroquímicas/métodos , Eletrodos , Desenho de Equipamento , Ouro/química , Humanos , Limite de Detecção , Impressão Molecular/métodos , Fenotiazinas/química
15.
Mikrochim Acta ; 186(4): 264, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30929090

RESUMO

The presented voltammetric mercury(II) sensor is based on the specific interaction between Hg(II) ion and thymine-thymine base pairs. Reduced graphene oxide is functionalized with gold nanorods and then loaded with thionine and streptavidin (RGO@AuNR-TH-SA). A T-rich thiolated DNA (S1) is firstly immobilized on a gold electrode. In the presence of Hg (II), the T-rich biotin-DNA (biotin-S2) binds to S1 via T-Hg(II)-T interaction. Then, the RGO@AuNR-TH-SA is linked to the gold electrode by specific binding between SA and biotin-S2. This produces an electrochemical signal (at -0.208 V vs. Ag/AgCl) of TH that depends on the concentration of Hg (II). The peak current increases linearly in the 1 to 200 nM Hg (II) concentration range, and the detection limit is 0.24 nM. The sensor is highly selective for Hg (II) over other environmentally relevant metal ions, even at concentration ratios of >1000. Graphical abstract Schematic representation of a voltammetric biosensor for mercury(II) using reduced graphene oxide@gold nanorods (RGO@AuNRs) and thymine-Hg(II)-thymine interaction. It is based on the fact that RGO@AuNR can strongly adsorb thionine (TH) and streptavidin to realize the signal amplification.


Assuntos
Técnicas Biossensoriais/métodos , DNA/química , Grafite/química , Mercúrio/análise , Nanotubos/química , Timina/química , Pareamento de Bases , DNA/genética , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Ouro/química , Ácidos Nucleicos Imobilizados/química , Limite de Detecção , Fenotiazinas/química , Reprodutibilidade dos Testes , Estreptavidina/química , Poluentes Químicos da Água/análise
16.
Anal Sci ; 35(7): 815-819, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30956261

RESUMO

This study attempted to determine the phenothiazine antipsychotics concentration in serum and whole blood samples using various diatomaceous earth-based solid-phase columns and elution solvents and subsequently evaluate their efficiency. Phenothiazine antipsychotics concentrations of 5 - 2000 ng/mL were extracted from serum and whole blood using each column. All compounds were analyzed using liquid chromatography-tandem mass spectrometry. Phenothiazine antipsychotics extraction in serum and whole blood using diatomaceous earth-based solid-phase columns seemed to have an affinity with the elution solvent.


Assuntos
Antipsicóticos/sangue , Análise Química do Sangue/métodos , Terra de Diatomáceas/química , Fenotiazinas/sangue , Antipsicóticos/química , Humanos , Fenotiazinas/química , Solventes/química
17.
Biosens Bioelectron ; 135: 1-7, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981027

RESUMO

A paper-based electrochemical immunosensor was developed for the detection of cancer antigen 125 (CA125) by screen-printing technique. The reduced graphene oxide/thionine/gold nanoparticles (rGO/Thi/AuNPs) nanocomposites were compounded and coated onto the working electrode of immunosensor for CA125 antibody (anti-CA125) immobilization and detection signal amplification. The detection principle was based on the fact that the immunocomplex formed by specify binding of CA125 antibody and antigen could reduce the current response of thionine, which was proportional to the corresponding concentration of CA125 antigen. The immunoassay results showed that the linear range of CA125 was from 0.1 U mL-1 to 200 U mL-1 with the limit of detection (LOD) of 0.01 U mL-1 at signal to noise of 3. Quality control serum samples measured by our proposed immunosensor showed acceptable agreement with traditional ELISA method with the relative error less than 8.05%. The immunosensor exhibited good electrochemical performance with high reproducibility, reliability, stability and accuracy. The proposed immunosensor could be used for the determination of CA125 and had the potential for point-of-care testing (POCT) of other tumor marker.


Assuntos
Técnicas Biossensoriais/instrumentação , Antígeno Ca-125/sangue , Grafite/química , Nanocompostos/química , Anticorpos Imobilizados/química , Técnicas Eletroquímicas/instrumentação , Desenho de Equipamento , Ouro/química , Humanos , Imunoensaio/instrumentação , Limite de Detecção , Nanopartículas Metálicas/química , Papel , Fenotiazinas/química , Sistemas Automatizados de Assistência Junto ao Leito
18.
Artigo em Inglês | MEDLINE | ID: mdl-30870786

RESUMO

Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or ß-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of ß-sheet-rich fibrils from α-helix-rich fibrils of PLL.


Assuntos
Amiloide/metabolismo , Antipsicóticos/efeitos adversos , Doença de Parkinson Secundária/etiologia , Fenotiazinas/efeitos adversos , Polilisina/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Estrutura Secundária de Proteína/efeitos dos fármacos , Amiloide/química , Amiloide/ultraestrutura , Antipsicóticos/química , Dicroísmo Circular , Humanos , Modelos Moleculares , Doença de Parkinson Secundária/metabolismo , Fenotiazinas/química , Polilisina/química , Agregação Patológica de Proteínas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Mikrochim Acta ; 186(4): 242, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877385

RESUMO

Graphene quantum dots (GQDs) were prepared via pyrolysis of citric acid and glutamic acid, then reacted with chlorauric acid to form a gold/graphene quantum dot hybrid (Au/GQD), and finally connected with hairpin DNA probe 1 (H1) and thionine (Thi). The H1-Au/GQD-Thi composite is found to be a viable redox probe for electrochemical and aptamer-based determination of vascular endothelial growth factor VEGF165. A dual amplification strategy is employed based on the use of molecular machine and the Au/GQD. Each single VEGF165 molecule can bind two DNA probes via specific aptamer-target recognition to produce a molecular machine. Surface-tethered hairpin DNA 2 (H2) hybridizes with the molecular machine through proximity effect, and the prelocked toehold domain of H2 becomes exposed. This part binds to H1-Au/GQD-Thi to release the molecular machine which then moves to the neighboring H2 upon which a surface programmatic chain reaction is initiated. By continuous molecular machine travel, many H1-Au/GQD-Thi probes are present on the gold electrode surface. This implies an efficient signal amplification capability. The Au/GQD based redox probes in-situ catalyzes the redox activity of thionine and further enhances the detection signal. The aptasensor exhibits ultrahigh sensitivity and selectivity for VEGF165. The square wave voltammetric signal, best measured at -0.18 V vs. Ag/AgCl, increases linearly in the 1.0 fM to 120 pM VEGF165 concentration range, and the detection limit is 0.3 fM. Conceivably, the method may be applied to other target proteins if the corresponding high-affinity aptamers are available. Graphical abstract This study report one dual amplification strategy for ultrasensitive electrochemical detection of VEGF165 based on gold-graphene quantum dot hybrid (Au/GQD) and bipedal molecular machine (BMM) powered surface programmatic chain reaction (SPCR).


Assuntos
Técnicas Eletroquímicas/métodos , Ouro/química , Grafite/química , Pontos Quânticos/química , Fator A de Crescimento do Endotélio Vascular/sangue , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Técnicas Biossensoriais/métodos , DNA/química , DNA/genética , Sondas de DNA/química , Sondas de DNA/genética , Técnicas Eletroquímicas/instrumentação , Eletrodos , Limite de Detecção , Hibridização de Ácido Nucleico , Oxirredução , Fenotiazinas/química
20.
Eur J Med Chem ; 168: 263-282, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822714

RESUMO

The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 µg/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Fenotiazinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Triazóis/farmacologia , Adsorção , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenotiazinas/química , Fenotiazinas/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo , Células Vero
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