Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 363
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Radiother ; 24(4): 332-334, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446537

RESUMO

Monte Carlo simulations of γ/fast electron-radiolysis of water show that the in situ formation of H3O+ temporarily renders each "native" isolated spur/track region very acidic. For pulsed (FLASH) irradiation with high dose rate, this early time, transient "acid-spike" response is shown to extend evenly across the entire irradiated volume. Since pH controls many cellular processes, this study highlights the need to consider these spikes of acidity in understanding the fundamental mechanisms underlying FLASH radiotherapy.


Assuntos
Elétrons , Oniocompostos/química , Dosagem Radioterapêutica , Água/química , Hidrogênio/efeitos da radiação , Concentração de Íons de Hidrogênio , Transferência Linear de Energia , Método de Monte Carlo , Neoplasias/radioterapia , Oniocompostos/análise , Radiólise de Impulso
2.
ACS Appl Mater Interfaces ; 11(40): 36939-36948, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513367

RESUMO

Stimuli-responsive biomaterials supply a promising solution to adapt to the complex physiological environment for different biomedical applications. In this study, a dynamic UV-triggered pH-responsive biosurface was constructed on titania nanotubes (TNTs) by loading photoacid generators, diphenyliodonium chloride, into the nanotubes, and grafting 2,3-dimethyl maleic anhydride (DMMA)-modified hyperbranched poly(l-lysine) (HBPLL) onto the surface. The local acidity was dramatically enhanced by UV irradiation for only 30 s, leading to the dissociation of DMMA and thereby the transformation of surface chemistry from negatively charged caboxyl groups to positively charged amino groups. The TNTs-HBPLL-DMMA substrate could better promote proliferation and spreading of rat bone mesenchymal stem cells (rBMSCs) after UV irradiation. The osteogenic differentiation of rBMSCs was enhanced because of the charge reversal in combination with the titania-based substrates.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Nanotubos/química , Titânio/farmacologia , Raios Ultravioleta , Fosfatase Alcalina/metabolismo , Animais , Compostos de Bifenilo/química , Adesão Celular/efeitos dos fármacos , Adesão Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Masculino , Anidridos Maleicos/síntese química , Anidridos Maleicos/química , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos da radiação , Nanotubos/ultraestrutura , Oniocompostos/química , Polilisina/síntese química , Polilisina/química , Ratos Sprague-Dawley , Propriedades de Superfície
3.
Molecules ; 24(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438596

RESUMO

Iodonium(III) salts bearing uracil moieties have recently appeared in the literature, but their structural scope and utilization are limited because of their hygroscopic characteristics. In this study, we describe our detailed investigations for synthesizing a series of uracil iodonium(III) salts derived with various structural motifs and counterions. These new compounds have been utilized as attractive synthetic modules in constructing functionalized nucleobase and nucleosides.


Assuntos
Oniocompostos/química , Uracila/química , Estrutura Molecular , Nucleosídeos/química
4.
Inorg Chem ; 58(13): 8293-8299, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31184865

RESUMO

Triphenylphosphonium (TPP+) species comprising multiple charges, i.e., bis-TPP+, are predicted to be superior mitochondrial-targeting vectors and are expected to have mitochondrial accumulations 1000-fold greater than TPP+, the current "gold standard". However, bis-TPP+ vectors linked by short hydrocarbon chains ( n < 5) are unable to be taken up by the mitochondria, thus hindering their development as mitochondrial delivery vectors. Through the incorporation of methylated TPP+ moieties (T*PP+), we successfully enabled the accumulation of bis-TPP+ with a short linker chain in isolated mitochondria, as measured by high performance liquid chromatography. These experimental results are further supported by molecular dynamics and ab initio calculations, revealing the strong correlations between mitochondria uptake and molecular volume, surface area, and chemical hardness. Most notably, the molecular volume has been shown to be a strong predictor of accumulation for both mono- and bis-TPP+ salts. Our study underscores the potential of T*PP+ moieties as alternative mitochondrial vectors to overcome low permeation into the mitochondria.


Assuntos
Mitocôndrias/metabolismo , Oniocompostos/metabolismo , Compostos Organofosforados/metabolismo , Transporte Biológico , Teoria da Densidade Funcional , Células HeLa , Humanos , Modelos Químicos , Simulação de Dinâmica Molecular , Estrutura Molecular , Oniocompostos/síntese química , Oniocompostos/química , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Relação Quantitativa Estrutura-Atividade , Termodinâmica
5.
Molecules ; 25(1)2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31905900

RESUMO

Iodonium salts are well established photoacid generators, cationic photoinitiators, as well as additives commonly used in photoredox catalytic cycles. However, as a strong limitation, iodonium salts are characterized by low light absorption properties for λ > 300 nm so that these latter cannot be activated with cheap, safe, and eco-friendly near UV or even visible light emitting diodes (LEDs). To overcome this drawback, the covalent linkage of an iodonium salt to a chromophore absorbing at longer wavelength is actively researched. With aim at red-shifting the absorption spectrum of the iodonium salt, the synthesis of new compounds combining within a unique chemical structure both the chromophore (here the naphthalimide scaffold) and the iodonium salt is presented. By mean of this strategy, a polymerization could be initiated at 365 nm with the modified iodonium salts whereas no polymerization could be induced with the benchmark iodonium salt i.e., Speedcure 938 at this specific wavelength. To examine the effect of the counter-anion on the photoinitiating ability of these different salts, five different counter-anions were used. Comparison between the different anions revealed the bis(trifluoromethane)sulfonimide salt to exhibit the best photoinitiating ability in both the free radical polymerization of acrylates and the cationic polymerization of epoxides. To support the experimental results, molecular orbital calculations have been carried out. By theoretical calculations, the initiating species resulting from the photocleavage of the iodonium salts could be determined. The cleavage selectivity and the photochemical reactivity of the new iodoniums are also discussed.


Assuntos
Oniocompostos/química , Sais/síntese química , Catálise , Processos Fotoquímicos , Polimerização , Polímeros/síntese química , Polímeros/química , Sais/química , Raios Ultravioleta
6.
Braz Oral Res ; 32: e116, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30462750

RESUMO

The aim of this study was to analyze the efficiency of experimental light-curing resin cements (ERCs) with a ternary photo-initiator system containing diphenyliodonium hexafluorphosphate (DPI) and different amines on retention of glass-fiber posts to dentin (GFP). ERCs formulations: a 1:1 mass ratio of 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenylpropane and triethyleneglycol dimethacrylate. Camphorquinone was used as initiator. Six experimental groups were established according to the amine used: [ethyl-4-(dimethylamino)benzoate-EDMAB or 2-(dimethylamino)ethyl methacrylate-DMAEMA] and the concentration of DPI (0, 0.5 mol%, 1 mol%). The resin cements Variolink II (dual- and light-cured versions) were used as commercial reference. Eighty recently extracted bovine incisors (n = 10) were selected for this study. The roots were prepared and the fiber posts were cemented with the resin cement specified for each experimental group. Specimens from coronal, middle, and apical thirds of the root were subjected to push-out bond strength test 24 hours after bonding. Data were subjected to split-plot ANOVA and the Tukey test (p = 0.05). ERCs containing DPI showed statistically significant higher bond strengths compared with ERCs without DPI. ERCs containing DPI were statistically similar to VARIOLINK II - dual-cured and superior to VARIOLINK II - light-cured (except for EDMAB - 1DPI in the medium third and DMAEMA - 1DPI in the coronal third). Different amines did not influence post retention. The apical root region showed the lowest bond strength for the groups EDAB-0DPI, DMAEMA-0DPI and VARIOLINK II light-cured. Light-cured ERCs containing DPI were efficient for GFP retention to radicular dentin, with similar behaviour to that of dual-curing commercial resin cement.


Assuntos
Compostos de Bifenilo/química , Dentina/efeitos dos fármacos , Cura Luminosa de Adesivos Dentários/métodos , Oniocompostos/química , Fotoiniciadores Dentários/química , Técnica para Retentor Intrarradicular , Cimentos de Resina/química , Ápice Dentário/efeitos dos fármacos , Análise de Variância , Compostos de Bifenilo/efeitos da radiação , Luzes de Cura Dentária , Dentina/efeitos da radiação , Vidro/química , Vidro/efeitos da radiação , Teste de Materiais , Metacrilatos/química , Metacrilatos/efeitos da radiação , Oniocompostos/efeitos da radiação , Fotoiniciadores Dentários/efeitos da radiação , Polimerização , Cimentos de Resina/efeitos da radiação , Fatores de Tempo , Ápice Dentário/efeitos da radiação , Fraturas dos Dentes , para-Aminobenzoatos/química , para-Aminobenzoatos/efeitos da radiação
7.
J Biol Chem ; 293(49): 19137-19147, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30287687

RESUMO

Ion-coupled transporters must regulate access of ions and substrates into and out of the binding site to actively transport substrates and minimize dissipative leak of ions. Within the single-site alternating access model, competitive substrate binding forms the foundation of ion-coupled antiport. Strict competition between substrates leads to stoichiometric antiport without slippage. However, recent NMR studies of the bacterial multidrug transporter EmrE have demonstrated that this multidrug transporter can simultaneously bind drug and proton, which will affect the transport stoichiometry and efficiency of coupled antiport. Here, we investigated the nature of substrate competition in EmrE using multiple methods to measure proton release upon the addition of saturating concentrations of drug as a function of pH. The resulting proton-release profile confirmed simultaneous binding of drug and proton, but suggested that a residue outside EmrE's Glu-14 binding site may release protons upon drug binding. Using NMR-monitored pH titrations, we trace this drug-induced deprotonation event to His-110, EmrE's C-terminal residue. Further NMR experiments disclosed that the C-terminal tail is strongly coupled to EmrE's drug-binding domain. Consideration of our results alongside those from previous studies of EmrE suggests that this conserved tail participates in secondary gating of EmrE-mediated proton/drug transport, occluding the binding pocket of fully protonated EmrE in the absence of drug to prevent dissipative proton transport.


Assuntos
Antiporters/metabolismo , Proteínas de Escherichia coli/metabolismo , Oniocompostos/metabolismo , Compostos Organofosforados/metabolismo , Prótons , Antiporters/química , Sítios de Ligação , Escherichia coli/química , Proteínas de Escherichia coli/química , Ácido Glutâmico/química , Histidina/química , Concentração de Íons de Hidrogênio , Oniocompostos/química , Compostos Organofosforados/química , Ligação Proteica , Conformação Proteica , Domínios Proteicos
8.
MAbs ; 10(7): 968-978, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30067433

RESUMO

The characterization of glycosylation is required for many protein therapeutics. The emergence of antibody and antibody-like molecules with multiple glycan attachment sites has rendered glycan analysis increasingly more complicated. Reliance on site-specific glycopeptide analysis is therefore necessary to fully analyze multi-glycosylated biotherapeutics. Established glycopeptide methodologies have generally utilized a priori knowledge of the glycosylation states of the investigated protein(s), database searching of results generated from data-dependent liquid chromatography-tandem mass spectrometry workflows, and extracted ion quantitation of the individual identified species. However, the inherent complexity of glycosylation makes predicting all glycoforms on all glycosylation sites extremely challenging, if not impossible. That is, only the "knowns" are assessed. Here, we describe an agnostic methodology to qualitatively and quantitatively assess both "known" and "unknown" site-specific glycosylation for biotherapeutics that contain multiple glycosylation sites. The workflow uses data-independent, all ion fragmentation to generate glycan oxonium ions, which are then extracted across the entirety of the chromatographic timeline to produce a glycan-specific "fingerprint" of the glycoprotein sample. We utilized both HexNAc and sialic acid oxonium ion profiles to quickly assess the presence of Fab glycosylation in a therapeutic monoclonal antibody, as well as for high-throughput comparisons of multi-glycosylated protein drugs derived from different clones to a reference product. An automated method was created to rapidly assess oxonium profiles between samples, and to provide a quantitative assessment of similarity.


Assuntos
Anticorpos Monoclonais/química , Produtos Biológicos/química , Terapia Biológica , Glicopeptídeos/química , Fragmentos Fab das Imunoglobulinas/química , Ácido N-Acetilneuramínico/química , Oniocompostos/química , Animais , Cromatografia Líquida , Glicosilação , Humanos , Espectrometria de Massas
9.
J Chromatogr A ; 1569: 193-199, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30076005

RESUMO

In this study, we propose a novel approach for the determination of total dissolved nitrogen (TDN) in seawater combining high-precision isotope dilution GC-MS with persulfate digestion. A 2 mL sample aliquot was digested with an alkaline solution of persulfate to convert nitrogen containing compounds to nitrate. Digested samples were spiked with 15NO3- internal standard and treated with aqueous triethyloxonium to convert the analyte into volatile EtONO2. This derivative was readily separated from the matrix under gaseous form and could be sampled from the headspace before GC-MS analysis. The resulting chromatograms showed a stable flat baseline with EtONO2 as the only eluting peak (retention time 2.75 min on a DB 5.625 column). Such an approach provides specificity and obviates the shortcomings of current detection methods employed to analyze seawater samples after digestion with persulfate. In negative chemical ionization mode, the method reached a detection limit of 0.5 µmol/kg TDN (7 ng/g N) and could be applied to quantify seawater samples with 1-25 µmol/kg TDN. On the upper end of the range, quantitation could be repeated within 1%, whereas on a 6 µmol/kg TDN sample repeatability was 2.3% on eight measurements. The method was employed in two proficiency testing exercises providing results in agreement with consensus values. We investigated the impact of reagent blank and we implemented a blank-matching optimal design to account for such contribution. Finally, we performed a study on the yield of persulfate oxidation for organic and inorganic nitrogen compounds typically present in seawater. Whilst nitrite and ammonium are fully converted to nitrate, more complex organic molecules showed recoveries varying from 70% to 100%.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Nitrogênio/análise , Oniocompostos/química , Água do Mar/química , Sulfatos/química , Água/química , Aminoácidos/análise , Calibragem , Técnicas de Diluição do Indicador , Limite de Detecção , Nitratos/análise , Nitritos/análise , Peptídeos/análise , Padrões de Referência , Solubilidade , Incerteza
10.
Int J Nanomedicine ; 13: 4045-4057, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022826

RESUMO

Background: Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide. Currently, the best treatment options for myocardial infarction focus on the restoration of blood flow as soon as possible, which include reperfusion therapy, percutaneous coronary intervention, and therapeutic thrombolytic drugs. Materials and methods: In the present study, we report the development of lipid-polymeric nanocarriers (LPNs) for mitochondria-targeted delivery of tanshinone IIA (TN). D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was linked to the triphenylphosphonium (TPP) cation. The LPNs were fabricated by nanoprecipitation method. LPNs were evaluated in vitro and in vivo in comparison with free drugs and other similar nanocarriers. Results: The mean diameter of TN/nanoparticles (NPs) was 89.6 nm, while that of TN/LPNs was 121.3 nm. The zeta potential of TN/NPs and TN/LPNs was -33.6 and -22.3 mV, respectively. Compared with free TN and TN/NPs, TN/LPNs exhibited significantly improved compatibility and therapeutic efficiency. In addition, the in vivo pharmacokinetics, biodistribution, and infarct therapy studies in Sprague Dawley rats showed that TPP-TPGS/TN/LPNs had better efficiency than their nonmodified TN/LPNs counterparts in all respects. Conclusion: These results indicated that the TPP-TPGS/TN/LPNs were promising nanocarriers for efficient delivery of cardiovascular drugs and other therapeutic agents for the treatment of CVDs.


Assuntos
Abietanos/uso terapêutico , Portadores de Fármacos/química , Lipídeos/química , Terapia de Alvo Molecular , Infarto do Miocárdio/tratamento farmacológico , Nanopartículas/química , Oniocompostos/química , Compostos Organofosforados/química , Vitamina E/química , Abietanos/sangue , Abietanos/farmacocinética , Abietanos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Infarto do Miocárdio/sangue , Oniocompostos/síntese química , Compostos Organofosforados/síntese química , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Eletricidade Estática , Distribuição Tecidual , Vitamina E/síntese química
11.
Artigo em Inglês | MEDLINE | ID: mdl-29866860

RESUMO

Blastocystis is an enteric parasite with extensive global prevalence. Studies have linked infection with this protist with a variety of gastrointestinal disorders, including irritable bowel syndrome. Due to the polymorphic nature of Blastocystis, studies on the parasite could be complicated, as results can be easily misinterpreted. Metronidazole is the commonly prescribed drug for Blastocystis infection, although there have been increasing reports of drug resistance. Hence, there is a need to identify alternative drugs to eliminate Blastocystis infection. In this study, LOPAC1280 was screened and drugs that can decrease the viability of three Blastocystis isolates in cultures were identified. Using apoptosis assay and imaging flow cytometry, phenotypic changes in Blastocystis cells after treatment were also analyzed to obtain insights into the possible mechanism of action of these drugs. Three drugs-diphenyleneiodonium chloride, auranofin, and BIX 01294 trihydrochloride hydrate-were effective against all three isolates tested. Repurposing of these drugs for Blastocystis treatment could be a way of combating metronidazole resistance relatively quickly and at a lower cost.


Assuntos
Antiprotozoários/farmacologia , Auranofina/farmacologia , Azepinas/farmacologia , Blastocystis/efeitos dos fármacos , Oniocompostos/farmacologia , Quinazolinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antiprotozoários/química , Antirreumáticos/química , Antirreumáticos/farmacologia , Apoptose/efeitos dos fármacos , Auranofina/química , Azepinas/química , Blastocystis/classificação , Blastocystis/crescimento & desenvolvimento , Blastocystis/isolamento & purificação , Infecções por Blastocystis/parasitologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Oniocompostos/química , Fosforilação/efeitos dos fármacos , Quinazolinas/química , Bibliotecas de Moléculas Pequenas/química
12.
Acta Pharmacol Sin ; 39(10): 1681-1692, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29849132

RESUMO

Breast cancer is the leading cause of cancer-related death for women, and multidrug resistance (MDR) is the major obstacle faced by chemotherapy for breast cancer. We have previously synthesized a doxorubicin (DOX) derivative by conjugating DOX with triphenylphosphonium (TPP) to achieve mitochondrial delivery, which induced higher cytotoxicity in drug-resistant breast cancer cells than DOX itself. Due to its amphiphilicity, TPP-DOX is difficult to physically entrap in nanocarriers. Thus, we linked it to hyaluronic acid (HA) by a novel ionic bond utilizing the specific bromide ion of TPP to form supra-molecular self-assembled structures (HA-ionic-TPP-DOX). The product was analyzed uisng 1H-NMR, 13C-NMR and mass spectrometry. The HA nanocarriers (HA-ionic-TPP-DOX) were shown to self-assemble into spherical nanoparticles, and sensitive to acidic pH in terms of morphology and drug release. Compared with free DOX, HA-ionic-TPP-DOX produced much greater intracellular DOX accumulation and mitochondrial localization, leading to increased ROS production, slightly decreased mitochondrial membrane potential, increased cytotoxicity in MCF-7/ADR cells and enhanced tumor targeting in vivo. In xenotransplant zebrafish model with the MCF-7/ADR cell line, both TPP-DOX and HA-ionic-TPP-DOX inhibited tumor cell proliferation without inducing significant side effects compared with free DOX. In addition, we observed a better anti-tumor effect of HA-ionic-TPP-DOX on MCF-7/ADR cells in zebrafish than that of TPP-DOX treatment. Furthermore, HA-ionic-DOX-TPP exhibited favorable biocompatibility and anti-tumor effects in MCF-7/ADR tumor-bearing nude mice in comparison with the effects of TPP-DOX and DOX, suggesting the potential of HA-ionic-TPP-DOX for the targeted delivery and controlled release of TPP-DOX, which can lead to the sensitization of resistant breast tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Ácido Hialurônico/química , Mitocôndrias/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Doxorrubicina/química , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oniocompostos/química , Compostos Organofosforados/química , Peixe-Zebra
13.
J Am Chem Soc ; 140(26): 8350-8356, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29939024

RESUMO

C(sp3)-H bond functionalization has emerged as a robust tool enabling rapid construction of molecular complexity from simple building blocks, and the development of asymmetric versions of this reaction creates a powerful methodology to access enantiopure sp3-rich materials. Herein, we report the stereoselective functionalization of C(sp3)-H bonds of cyclic ethers employing a photochemically active diaryliodonium salt in combination with an anionic phase-transfer catalyst. The synthetic strategy outlined herein allows for regio- and stereochemical control in the α-C-H acetalization of furans and pyrans using alcohol nucleophiles, thus providing the ability to control the configuration at the stereogenic exocyclic acetal carbon.


Assuntos
Acetais/síntese química , Éteres Cíclicos/química , Luz , Oniocompostos/química , Fosfatos/química , Acetais/química , Furanos/química , Estrutura Molecular , Piranos/química , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 28(13): 2289-2293, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29807796

RESUMO

TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Mitocôndrias/metabolismo , Adenosina Trifosfatases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Guanidinas/síntese química , Guanidinas/química , Guanidinas/farmacologia , Células HCT116 , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Estrutura Molecular , Oniocompostos/síntese química , Oniocompostos/química , Oniocompostos/farmacologia , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia
15.
J Phys Chem B ; 122(23): 6215-6223, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29771522

RESUMO

Internal ionizable groups are known to play important roles in protein functions. A mystery that has attracted decades of extensive experimental and theoretical studies is the apparent dielectric constants experienced by buried ionizable groups, which are much higher than values expected for protein interiors. Many interpretations have been proposed, such as water penetration, conformational relaxation, local unfolding, protein intrinsic backbone fluctuations, etc. However, these interpretations conflict with many experimental observations. The virtual mixture of multiple states (VMMS) simulation method developed in our lab provides a direct approach for studying the equilibrium of multiple chemical states and can monitor p Ka values along simulation trajectories. Through VMMS simulations of staphylococcal nuclease (SNase) variants with internal Asp or Glu residues, we discovered that cations were attracted to buried deprotonated acidic groups and the presence of the nearby cations were essential to reproduce experimentally measured p Ka values. This finding, combined with structural analysis and validation simulations, suggests that the proton released from a deprotonation process stays near the deprotonated group inside proteins, possibly in the form of a hydronium ion. The existence of a proton near a buried charge has many implications in our understanding of protein functions.


Assuntos
Nuclease do Micrococo/química , Oniocompostos/química , Cristalografia por Raios X , Cinética , Nuclease do Micrococo/genética , Nuclease do Micrococo/metabolismo , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Staphylococcus/enzimologia
16.
Rev Sci Instrum ; 89(4): 044704, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29716345

RESUMO

The compact potentiometer, based on an electronic circuit protected from electrostatic and electromagnetic interference, was developed for the measurement of low ion concentrations in liquids. The electronic circuit of the potentiometer, consisting of analogous and digital parts, enables the measurement of fA currents. This makes it possible to perform reliable measurements of ion concentrations in liquids that are as small as 10-8-10-7M. The instrument was tested using electrodes that were selective for tetraphenylphosphonium (TPP+) ions. It was demonstrated that the characteristic response time of the potentiometer electronic circuit to changes in the concentration of these ions in a liquid was in the order of 10 s. An investigation of TPP+ absorption by baker yeast has shown that this device can be successfully used for long term (several hours) measurements with zero signal drift, which was about 1 µV/s. Finally, due to the small dimensions of the electronic circuit (7.5 × 2 × 1.5 cm), this potentiometer can be easily installed at a large apparatus in the laboratory condition (≈25 °C), such as high pulsed electrical generators of magnetic fields that are used in electroporation studies of biological cells.


Assuntos
Íons/química , Potenciometria/instrumentação , Calibragem , Impedância Elétrica , Desenho de Equipamento , Oniocompostos/química , Compostos Organofosforados/química , Saccharomyces cerevisiae/química , Temperatura , Fatores de Tempo
17.
Biochim Biophys Acta Biomembr ; 1860(2): 329-334, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29038022

RESUMO

The present study demonstrated for the first time the interaction between adenosine 3',5'-cyclic monophosphate (cAMP), one of the most important signaling compounds in living organisms, and the mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1). The data obtained on model liquid membranes and human platelets revealed the ability of SkQ1 to selectively transport cAMP, but not guanosine 3',5'-cyclic monophosphate (cGMP), across both artificial and natural membranes. In particular, SkQ1 elicited translocation of cAMP from the source to the receiving phase of a Pressman-type cell, while showing low activity with cGMP. Importantly, only conjugate with plastoquinone, but not dodecyl-triphenylphosphonium, was effective in carrying cAMP. In human platelets, SkQ1 also appeared to serve as a carrier of cAMP, but not cGMP, from outside to inside the cell, as measured by phosphorylation of the vasodilator stimulated phosphoprotein. The SkQ1-induced transfer of cAMP across the plasma membrane found here can be tentatively suggested to interfere with cAMP signaling pathways in living cells.


Assuntos
Membrana Celular/metabolismo , AMP Cíclico/metabolismo , Membranas Artificiais , Oniocompostos/metabolismo , Compostos Organofosforados/metabolismo , Plastoquinona/metabolismo , Animais , Transporte Biológico , Plaquetas/metabolismo , GMP Cíclico/metabolismo , Membrana Eritrocítica/metabolismo , Humanos , Lipossomos/metabolismo , Oniocompostos/química , Compostos Organofosforados/química , Fosforilação , Plastoquinona/química , Ratos
18.
Talanta ; 178: 473-480, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29136850

RESUMO

In this study, a novel generation of deep eutectic solvents (DESs) was used as an acceptor phase in three-phase hollow fiber liquid phase microextraction (HF-LPME) based on two immiscible organic phases. It was compared with other common DESs for extraction and preconcentration of dydrogesterone (DYD) and cyproterone acetate (CPA) from urine and plasma samples. The extracted analytes were analyzed by high performance liquid chromatography with UV-vis detector (HPLC-UV). This phosphonium based DES due to low volatility, low price and multifunctionality introduced itself as worthy next generation of acceptor phase in HF-LPME. The factors affected on extraction efficiency of the analytes were investigated and optimized. The performance of the proposed method was studied in terms of linear ranges (LRs from 1 to 500µgL-1 with R2 ≥ 0.9946), precision (RSD% ≤ 6.3) and limits of detection (LODs in the range of 0.5-2µgL-1). Under the optimized conditions, preconcentration factors in the range of 187-428 were obtained. Finally, the method was applied to the analysis of DYD and CPA in human urine and plasma samples and desirable results were obtained.


Assuntos
Microextração em Fase Líquida/métodos , Oniocompostos/química , Solventes/química , Compostos de Tritil/química , Adolescente , Adulto , Acetato de Ciproterona/sangue , Acetato de Ciproterona/urina , Didrogesterona/sangue , Didrogesterona/urina , Feminino , Humanos , Adulto Jovem
19.
Biomaterials ; 154: 169-181, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29128845

RESUMO

Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy.


Assuntos
Liberação Controlada de Fármacos , Glicolipídeos/química , Micelas , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias/patologia , Oniocompostos/química , Compostos Organofosforados/química , Tamanho da Partícula , Transdução de Sinais/efeitos dos fármacos , Eletricidade Estática , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacos , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 148: 507-518, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29269132

RESUMO

In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells.


Assuntos
Bactérias/efeitos dos fármacos , Malária/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Oniocompostos/farmacologia , Animais , Bactérias/patogenicidade , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Malária/parasitologia , Oniocompostos/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA