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1.
J Oleo Sci ; 69(10): 1331-1337, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32908098

RESUMO

The development of actuators for power sources is essential for the efficient manipulation of fluids in microfluidics systems. In this work, a capacitor-type three-layer paper actuator was fabricated by sandwiching a polyelectrolyte layer between two films of poly(3,4-ethylenedioxythiophene) doped with poly(4-styrenesulfonate) (PEDOT/PSS). The paper actuator exhibited stable large electromechanical deformations in bilateral symmetry under alternating square-wave electric field. The actuation properties were examined in a function of voltage (±0.5, ±1, ±1.5, ±2, and ±2.5 V) and frequency (1, 0.5, 0.2, and 0.05 Hz). In addition, the PEDOT/PSS electrode films with different thicknesses were prepared, and the effects of actuator thickness on actuation properties were examined. As a result, it was found that the actuator displacement increased considerably with reducing actuator thickness. In addition, the actuator with a thickness of 48 µm demonstrated a maximum displacement of 5.8 mm at a voltage of 1.5 V and a frequency of 0.05 Hz. The proposed actuator can be potentially used in the development of power sources for micropumps and check valves of microfluidic devices.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Eletrodos , Dispositivos Lab-On-A-Chip , Microfluídica , Papel , Polímeros/química , Poliestirenos/química , Tiofenos/química , Compostos Bicíclicos Heterocíclicos com Pontes/classificação , Eletricidade , Polímeros/classificação
2.
Anesthesiology ; 133(4): 740-749, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773684

RESUMO

The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.


Assuntos
Comitês Consultivos/normas , Analgésicos Opioides/química , Analgésicos/química , Anestésicos/química , Aprovação de Drogas/métodos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anestésicos/efeitos adversos , Congressos como Assunto/normas , Tomada de Decisões , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Humanos , Oximorfona/efeitos adversos , Oximorfona/química , Compostos de Espiro/efeitos adversos , Compostos de Espiro/química , Tiofenos/efeitos adversos , Tiofenos/química , Estados Unidos
3.
J Oleo Sci ; 69(7): 743-750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612024

RESUMO

In this study, two new mixed-ligand coordination polymers {[Co(bbi)(tdc)]·5H2O}n (1, bbi = 1,4-bis(imidazolyl)butane) and {[Cu2(bimb)(H2O)(µ3-tdc)2(DMF)2]·H2O}n (2, bimb = 4-bis(1H-imidazol-1-yl-methyl)benzene) were synthesized under the solvothermal conditions via reaction of 2,5-thiophenedicarboxylic acid (H2tdc) with the corresponding metal salts in the existence of different flexible bis-imidazole ligands (bbi for 1 and bimb for 2). The as-prepared two structures were detected via the single crystal X-ray diffraction (SXRD) and then characterized via the analysis of element, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) as well as infrared (IR) spectroscopy. Furthermore, the protective activity of the compound on the mice with ischemic stroke was evaluated. Firstly, the real time reverse transcription-polymerase chain raction (RT-PCR) was carried out to determine the effect of compounds 1 and 2 against the relative expression level of the glucagon-like peptide 1 receptors (glp1r) on the cerebrovascular endothelial cells. Next, the Morris Water Maze Experiment was also used to detect the improvement function of compounds 1 and 2 on the nice mice cognitive function.


Assuntos
Encéfalo/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Expressão Gênica/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Metais/química , Polímeros/síntese química , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Tiofenos/química , Animais , Encéfalo/citologia , Fenômenos Químicos , Cognição/efeitos dos fármacos , Complexos de Coordenação/uso terapêutico , Cristalização , Células Endoteliais/metabolismo , Imidazóis/química , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Molecular , Polímeros/química , Relação Estrutura-Atividade , Difração de Raios X
4.
Nucleic Acids Res ; 48(14): 7914-7923, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32652039

RESUMO

Bacterial RNA polymerase is a potent target for antibiotics, which utilize a plethora of different modes of action, some of which are still not fully understood. Ureidothiophene (Urd) was found in a screen of a library of chemical compounds for ability to inhibit bacterial transcription. The mechanism of Urd action is not known. Here, we show that Urd inhibits transcription at the early stage of closed complex formation by blocking interaction of RNA polymerase with the promoter -10 element, while not affecting interactions with -35 element or steps of transcription after promoter closed complex formation. We show that mutation in the region 1.2 of initiation factor σ decreases sensitivity to Urd. The results suggest that Urd may directly target σ region 1.2, which allosterically controls the recognition of -10 element by σ region 2. Alternatively, Urd may block conformational changes of the holoenzyme required for engagement with -10 promoter element, although by a mechanism distinct from that of antibiotic fidaxomycin (lipiarmycin). The results suggest a new mode of transcription inhibition involving the regulatory domain of σ subunit, and potentially pinpoint a novel target for development of new antibacterials.


Assuntos
Antibacterianos/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Regiões Promotoras Genéticas , Tiofenos/farmacologia , Iniciação da Transcrição Genética/efeitos dos fármacos , Antibacterianos/química , Bactérias/enzimologia , RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fator sigma/antagonistas & inibidores , Fator sigma/química , Tiofenos/química
5.
Mol Pharmacol ; 98(4): 475-486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32680919

RESUMO

Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classic opioids-in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of ß-arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classic opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes are unknown. Here, we report the results of submillisecond adaptive sampling molecular dynamics simulations of a predicted methadone-bound MOR complex and compare them with analogous data obtained for the classic opioid morphine and the G protein-biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov state models and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR. SIGNIFICANCE STATEMENT: Opioid addiction has reached epidemic proportions in both industrialized and developing countries. Although methadone maintenance treatment represents an effective therapeutic approach for opioid addiction, it is not as widely used as needed. In this study, we contribute an atomic-level understanding of how methadone exerts its unique function in pursuit of more accessible treatments for opioid addiction. In particular, we present details of a methadone-specific active conformation of the µ-opioid receptor that has thus far eluded experimental structural characterization.


Assuntos
Analgésicos Opioides/farmacologia , Metadona/farmacologia , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Analgésicos Opioides/química , Animais , Sítios de Ligação , Entropia , Humanos , Cadeias de Markov , Metadona/química , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Compostos de Espiro/química , Tiofenos/química
6.
PLoS One ; 15(6): e0234115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544157

RESUMO

The variation of the HOMO-LUMO band gap is explored for varying packing arrangements of the 4mod BT-4TIC donor-acceptor molecule pair, by means of a high-throughput ab-initio random structure search of packing possibilities. 350 arrangements of the dimer have been relaxed from initial random dispositions, using non-local density-functional theory. We find that the electronic band gap varies within 0.3 eV, and that this magnitude, the binding energy, and the geometry are not significantly correlated. A clearly favoured structure is found with a binding energy of 1.75±0.07 eV, with all but three other arrangements displaying values of less than one third of this highest binding one, which involves the aliphatic chain of 4TIC.


Assuntos
Compostos Orgânicos/química , Energia Solar , Teoria da Densidade Funcional , Tiadiazóis/química , Tiofenos/química
7.
Chem Biol Interact ; 320: 109028, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119865

RESUMO

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 µg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 µg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.


Assuntos
Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Antifúngicos/química , Humanos , Estrutura Molecular , Tiofenos/química , Tiossemicarbazonas/química
8.
J Med Chem ; 63(6): 3215-3226, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32142284

RESUMO

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.


Assuntos
Inibidores Enzimáticos/química , Indóis/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Tiofenos/química , Sítio Alostérico , Cristalografia por Raios X , Descoberta de Drogas , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Guanina/análogos & derivados , Guanina/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Indóis/síntese química , Indóis/metabolismo , Estrutura Molecular , NAD/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Espermidina/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismo
9.
Biochem J ; 477(6): 1149-1158, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32150261

RESUMO

Searching for compounds that inhibit the growth of photosynthetic organisms highlighted a prominent effect at micromolar concentrations of the nitroheteroaromatic thioether, 2-nitrothiophene, applied in the light. Since similar effects were reminiscent to those obtained also by radicals produced under excessive illumination or by herbicides, and in light of its redox potential, we suspected that 2-nitrothiophene was reduced by ferredoxin, a major reducing compound in the light. In silico examination using docking and tunneling computing algorithms of the putative interaction between 2-nitrothiophene and cyanobacterial ferredoxin has suggested a site of interaction enabling robust electron transfer from the iron-sulfur cluster of ferredoxin to the nitro group of 2-nitrothiophene. ESR and oximetry analyses of cyanobacterial cells (Anabaena PCC7120) treated with 50 µM 2-nitrothiophene under illumination revealed accumulation of oxygen radicals and peroxides. Gas chromatography mass spectrometry analysis of 2-nitrothiophene-treated cells identified cytotoxic nitroso and non-toxic amino derivatives. These products of the degradation pathway of 2-nitrohiophene, which initializes with a single electron transfer that forms a short-live anion radical, are then decomposed to nitrate and thiophene, and may be further reduced to a nitroso hydroxylamine and amino derivatives. This mechanism of toxicity is similar to that of nitroimidazoles (e.g. ornidazole and metronidazole) reduced by ferredoxin in anaerobic bacteria and protozoa, but differs from that of ornidazole in planta.


Assuntos
Anabaena/metabolismo , Ferredoxinas/metabolismo , Herbicidas/metabolismo , Fotossíntese/fisiologia , Tiofenos/metabolismo , Anabaena/efeitos dos fármacos , Ferredoxinas/farmacologia , Herbicidas/farmacologia , Fotossíntese/efeitos dos fármacos , Estrutura Terciária de Proteína , Tiofenos/química
10.
J Agric Food Chem ; 68(14): 4144-4154, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32191457

RESUMO

In the current work, we synthesized two series of dehydroabietyl amide derivatives from natural product rosin and evaluated their antifungal effects on Valsa mali, Phytophthora capsici, Botrytis cinerea, Sclerotinia sclerotiorum, and Fusarium oxysporum. In vitro and in vivo antifungal activities results indicated that rosin-based amide compounds containing thiophene heterocycles had better inhibitory effects on B. cinerea. In particular, compound 5b (5-fluoro-2-thiophene dehydroabietyl amide) exhibited the excellent antifungal properties against B. cinerea with an EC50 of 0.490 mg/L, which was lower compared to the positive control penthiopyrad (0.562 mg/L). Physiological and biochemical studies showed that the primary action mechanism of compound 5b on B. cinerea changes mycelial morphology, increases cell membrane permeability, and inhibits the TCA pathway in respiratory metabolism. Furthermore, QSAR and SAR studies revealed that charge distribution of rosin-based amides derivatives have a key role in the antifungal activity through the hydrogen bonding, conjugation, and electrostatic interaction between the compounds and the receptors of the target. To sum up, this study contributes to the development of rosin-based antifungal agents with a novel structure and preferable biological activity.


Assuntos
Amidas/síntese química , Antifúngicos/química , Produtos Biológicos/química , Proteção de Cultivos/métodos , Resinas Vegetais/química , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Descoberta de Drogas , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fungos Mitospóricos/efeitos dos fármacos , Estrutura Molecular , Phytophthora/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Resinas Vegetais/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
11.
Biochem J ; 477(2): 461-475, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003437

RESUMO

Mitochondrial turnover is required for proper cellular function. Both mitochondrial biogenesis and mitophagy are impaired in several degenerative and age-related diseases. The search for mitophagy activators recently emerged as a new therapeutical approach; however, there is a lack in suitable tools to follow mitochondrial turnover in a high-throughput manner. We demonstrate that the fluorescent protein, MitoTimer, is a reliable and robust probe to follow mitochondrial turnover. The screening of 15 000 small molecules led us to two chemically-related benzothiophenes that stimulate basal mitophagy in the beta-cell line, INS1. Enhancing basal mitophagy was associated with improved mitochondrial function, higher Complex I activity and Complex II and III expressions in INS1 cells, as well as better insulin secretion performance in mouse islets. The possibility of further enhancing mitophagy in the absence of mitochondrial stressors points to the existence of a 'basal mitophagy spare capacity'. To this end, we found two small molecules that can be used as models to better understand the physiological regulation of mitophagy.


Assuntos
Envelhecimento/genética , Secreção de Insulina/genética , Mitocôndrias/genética , Mitofagia/genética , Envelhecimento/patologia , Animais , Autofagia/genética , Linhagem Celular , Citometria de Fluxo , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Renovação Mitocondrial , Mitofagia/efeitos dos fármacos , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tiofenos/química , Tiofenos/farmacologia
12.
Chemistry ; 26(33): 7425-7432, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32022335

RESUMO

Protein deposits are associated with many devastating diseases and fluorescent ligands able to visualize these pathological entities are essential. Here, we report the synthesis of thiophene-based donor-acceptor-donor heptameric ligands that can be utilized for spectral assignment of distinct amyloid-ß (Aß) aggregates, one of the pathological hallmarks in Alzheimer's disease. The ability of the ligands to selectively distinguish Aß deposits was abolished when the chemical composition of the ligands was altered. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of the same peptide or protein. In addition, such ligands might aid in interpreting the potential role of polymorphic Aß deposits in the pathogenesis of Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Encéfalo/patologia , Tiofenos/síntese química , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Humanos , Ligantes , Tiofenos/química
13.
Eur J Med Chem ; 189: 112088, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007666

RESUMO

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 µM, and 0.29-12.2 µM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tiadiazóis/química , Tiofenos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pancreáticas/patologia , Tiofenos/química , Células Tumorais Cultivadas
14.
Molecules ; 25(4)2020 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-32102204

RESUMO

The four compounds, namely: 5-nitro-2-furaldehyde thiosemicarbazone (1); 5-nitro-2-thiophene thiosemicarbazone (2); 5-nitro-2-furaldehyde semicarbazone (3); and 5-nitro-2-thiophene semicarbazone (4) were synthesized and crystallized. The three new crystal structures of 1, 2, and 4 were determined and compared to three already known crystal structures of 3. Additionally, two new polymorphic forms of 1 solvate were synthesized and studied. The influence of the exchange of 2-thiophene to 2-furaldehyde as well as thiosemicarbazone and semicarbazone on the self-assembly of supramolecular nets was elucidated and discussed in terms of the formed synthons and assemblies accompanied by Full Interaction Maps analysis. Changes in the strength of IR oscillators caused by the molecular and crystal packing effects are described and explained in terms of changes of electron density.


Assuntos
Tiossemicarbazonas/química , Cristalografia , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Espectrofotometria Infravermelho , Tiofenos/química , Tiossemicarbazonas/síntese química
15.
Molecules ; 25(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936766

RESUMO

The mechanism for the walk rearrangement in Dewar thiophenes has been clarified theoretically by studying the evolution of chemical bonds along the intrinsic reaction coordinates. Substituent effects on the overall mechanism are assessed by using combinations of the ring (R = H, CF3) and traveling (X = S, S = O, and CH2) groups. The origins of fluxionality in the S-oxide of perfluorotetramethyl Dewar thiophene are uncovered in this work. Dewar rearrangements are chemical processes that occur with a high degree of synchronicity. These changes are directly related to the activation energy.


Assuntos
Modelos Moleculares , Tiofenos/química , Estrutura Molecular
16.
Talanta ; 209: 120581, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31892020

RESUMO

Conjugated polyelectrolytes (CPEs) have been widely used as reporters in colorimetric assays targeting nucleic acids. CPEs provide naked eye detection possibility by their superior optical properties however, as concentration of target analytes decrease, trace amounts of nucleic acid typically yield colorimetric responses that are not readily perceivable by naked eye. Herein, we report a pixelated analysis approach for correlating colorimetric responses of CPE with nucleic acid concentrations down to 1 nM, in plasma samples, utilizing a smart phone with an algorithm that can perform analytical testing and data processing. The detection strategy employed relies on conformational transitions between single stranded nucleic acid-cationic CPE duplexes and double stranded nucleic acid-CPE triplexes that yield distinct colorimetric responses for enabling naked eye detection of nucleic acids. Cationic poly[N,N,N-triethyl-3-((4-methylthiophen-3-yl)oxy)propan-1-aminium bromide] is utilized as the CPE reporter deposited on a polyvinylidene fluoride (PVDF) membrane for nucleic acid assay. A smart phone application is developed to capture and digitize the colorimetric response of the individual pixels of the digital images of CPE on the PVDF membrane, followed by an analysis using the algorithm. The proposed pixelated approach enables precise quantification of nucleic acid assay concentrations, thereby eliminating the margin of error involved in conventional methodologies adopted for interpretation of colorimetric responses, for instance, RGB analysis. The obtained results illustrate that a ubiquitous smart phone could be utilized for point of care colorimetric nucleic acids assays in complex matrices without requiring sophisticated software or instrumentation.


Assuntos
Colorimetria/métodos , Ácidos Nucleicos/sangue , Polieletrólitos/química , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Cátions/química , Colorimetria/instrumentação , Desenho de Equipamento , Humanos , Ácidos Nucleicos/análise , Papel , Sistemas Automatizados de Assistência Junto ao Leito , Polímeros/química , Polivinil/química , Smartphone , Tiofenos/química
17.
Nat Commun ; 11(1): 414, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964872

RESUMO

WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, stem cell regulation and tissue homeostasis. FZDs are linked to severe human pathology and are seen as a promising target for therapy. Despite intense efforts, no small molecule drugs with distinct efficacy have emerged. Here, we identify the Smoothened agonist SAG1.3 as a partial agonist of FZD6 with limited subtype selectivity. Employing extensive in silico analysis, resonance energy transfer- and luciferase-based assays we describe the mode of action of SAG1.3. We define the ability of SAG1.3 to bind to FZD6 and to induce conformational changes in the receptor, recruitment and activation of G proteins and dynamics in FZD-Dishevelled interaction. Our results provide the proof-of-principle that FZDs are targetable by small molecules acting on their seven transmembrane spanning core. Thus, we provide a starting point for a structure-guided and mechanism-based drug discovery process to exploit the potential of FZDs as therapeutic targets.


Assuntos
Proteínas Desgrenhadas/metabolismo , Descoberta de Drogas/métodos , Receptores Frizzled/agonistas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Piridinas/química , Tiofenos/química , Via de Sinalização Wnt/efeitos dos fármacos , Membrana Celular/metabolismo , Receptores Frizzled/química , Receptores Frizzled/metabolismo , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular/métodos , Morfolinas/farmacologia , Estudo de Prova de Conceito , Purinas/farmacologia , Piridinas/farmacologia , Receptor Smoothened/agonistas , Relação Estrutura-Atividade , Tiofenos/farmacologia
18.
Biochem Pharmacol ; 174: 113797, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31926936

RESUMO

BX795, a small molecule with an aminopyrimidine backbone, is a potent ATP-competitive inhibitor of phosphoinositide-dependent kinase 1 (PDK1) and TANK-binding kinase 1 (TBK1). BX795 has significant functions in various immune responses and cancer. Few reports on the anti-inflammatory effect of BX795 are available, and its molecular mechanisms have not been fully elucidated. In this study, lipopolysaccharide (LPS)-treated macrophages (RAW264.7 cells), luciferase reporter gene assay, knock-down and overexpression strategies, kinase assay, protein chip, immunoprecipitation, and immunoblotting analyses were employed to clarify the anti-inflammatory mechanism of BX795. BX795 was found to dose-dependently inhibit the production of pro-inflammatory mediators without exhibiting cytotoxicity. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor 3 (IRF3) are targeted by BX795 rather than nuclear factor (NF)-κB. Moreover, TBK1 and AKT, transforming growth factor activated kinase (TAK)-1/c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase kinase 4 (MKK4) for AP-1 activation, and Janus kinase 2 (JAK2)/STAT1 were inhibited by BX795. Consistent with these findings, BX795 strongly ameliorated inflammatory symptoms in colitis models. These results suggest that BX795 can suppress inflammatory responses triggered by Gram-positive bacteria by suppressing multiple pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiofenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Células RAW 264.7 , Tiofenos/química
19.
Org Biomol Chem ; 18(5): 912-919, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31919486

RESUMO

Cytosine 2'-deoxyribonucleoside dCTBdp and its triphosphate (dCTBdpTP) bearing tetramethylated thiophene-bodipy fluorophore attached at position 5 were designed and synthesized. The green fluorescent nucleoside dCTBdp showed a perfect dependence of fluorescence lifetime on the viscosity. The modified triphosphate dCTBdpTP was substrate to several DNA polymerases and was used for in vitro enzymatic synthesis of labeled oligonucleotides (ONs) or DNA by primer extension. The labeled single-stranded ONs showed a significant decrease in mean fluorescence lifetime when hybridized to the complementary strand of DNA or RNA and were also sensitive to mismatches. The labeled dsDNA sensed protein binding (p53), which resulted in the increase of its fluorescence lifetime. The triphosphate dCTBdpTP was transported to live cells where its interactions could be detected by FLIM but it did not show incorporation to genomic DNA in cellulo.


Assuntos
Compostos de Boro/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Hibridização de Ácido Nucleico , Nucleotídeos/química , Sondas de Oligonucleotídeos/metabolismo , Tiofenos/química , Sequência de Bases , Cátions , Linhagem Celular Tumoral , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Lipídeos/química , Nucleotídeos/síntese química , Ligação Proteica , Solventes/química , Espectrometria de Fluorescência , Temperatura , Viscosidade
20.
Macromol Rapid Commun ; 41(5): e1900540, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31977118

RESUMO

With a combination of atom transfer radical polymerization (ATRP), quasi-living Grignard metathesis method, and thiol-ene click reaction, an amphiphilic star-like rod-coil diblock copolymer poly(acrylic acid)-block-poly(3-hexylthiophene) comprising 21-arm inner coil-like PAA blocks and outer rod-like conjugated polymer poly(3-hexylthiophene) (P3HT) blocks with well-defined molecular structures and narrow molecular weight distribution is synthesized. First, the bromide end-groups of 21-arm star-like ATRP coil polymers PtBA-Br are converted successfully into reactive thioacetate end groups by post-functionalization using potassium thioacetate. Subsequently, 21-arm star-like coil polymers PtBA-SCOCH3 react with rod-like vinyl-functionalized P3HT to yield functional star-like rod-coil diblock copolymers PtBA-b-P3HT via thiol-ene click reaction, followed by selective hydrolysis of inner PtBA block into PAA block. The present synthetic approach enables the construction of well-defined star-like conformation with few structural limitations in a facile and highly efficient manner due to the robust and orthogonal nature of the thiol-ene click reaction. It may be extended to produce block copolymers with other topologies, such as cylindrical, hyperbranched, and dendritic structures.


Assuntos
Química Click , Polímeros/síntese química , Tiofenos/química , Resinas Acrílicas/química , Conformação Molecular , Polimerização , Polímeros/química , Compostos de Sulfidrila/química , Tiofenos/síntese química
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