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1.
Acc Chem Res ; 55(18): 2728-2739, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36053265

RESUMO

ConspectusMolecular fluorescent probes are an essential experimental tool in many fields, ranging from biology to chemistry and materials science, to study the localization and other environmental properties surrounding the fluorescent probe. Thousands of different molecular fluorescent probes can be grouped into different families according to their photophysical properties. This Account focuses on a unique class of fluorescent probes that distinguishes itself from all other probes. This class is termed photoacids, which are molecules exhibiting a change in their acid-base transition between the ground and excited states, resulting in a large change in their pKa values between these two states, which is thermodynamically described using the Förster cycle. While there are many different photoacids, we focus only on pyranine, which is the most used photoacid, with pKa values of ∼7.4 and ∼0.4 for its ground and excited states, respectively. Such a difference between the pKa values is the basis for the dual use of the pyranine fluorescent probe. Furthermore, the protonated and deprotonated states of pyranine absorb and emit at different wavelengths, making it easy to focus on a specific state. Pyranine has been used for decades as a fluorescent pH indicator for physiological pH values, which is based on its acid-base equilibrium in the ground state. While the unique excited-state proton transfer (ESPT) properties of photoacids have been explored for more than a half-century, it is only recently that photoacids and especially pyranine have been used as fluorescent probes for the local environment of the probe, especially the hydration layer surrounding it and related proton diffusion properties. Such use of photoacids is based on their capability for ESPT from the photoacid to a nearby proton acceptor, which is usually, but not necessarily, water. In this Account, we detail the photophysical properties of pyranine, distinguishing between the processes in the ground state and the ones in the excited state. We further review the different utilization of pyranine for probing different properties of the environment. Our main perspective is on the emerging use of the ESPT process for deciphering the hydration layer around the probe and other parameters related to proton diffusion taking place while the molecule is in the excited state, focusing primarily on bio-related materials. Special attention is given to how to perform the experiments and, most importantly, how to interpret their results. We also briefly discuss the breadth of possibilities in making pyranine derivatives and the use of pyranine for controlling dynamic reactions.


Assuntos
Corantes Fluorescentes , Prótons , Sulfonatos de Arila , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Água/química
2.
J Phys Chem Lett ; 13(34): 8104-8110, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35997534

RESUMO

The dynamics of excess protons in the protic ionic liquid (PIL) ethylammonium formate (EAF) have been investigated from femtoseconds to microseconds using visible pump mid-infrared probe spectroscopy. The pH jump following the visible photoexcitation of a photoacid (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt, HPTS) results in proton transfer to the formate of the EAF. The proton transfer predominantly (∼70%) occurs over picoseconds through a preformed hydrogen-bonded tight complex between HPTS and EAF. We investigate the longer-range and longer-time-scale proton-transport processes in the PIL by obtaining the ground-state conjugate base (RO-) dynamics from the congested transient-infrared spectra. The spectral kinetics indicate that the protons diffuse only a few solvent shells from the parent photoacid before recombining with RO-. A kinetic isotope effect of nearly unity (kH/kD ≈ 1) suggests vehicular transfer and the transport of excess protons in this PIL. Our findings provide comprehensive insight into the complete photoprotolytic cycle of excess protons in a PIL.


Assuntos
Líquidos Iônicos , Prótons , Sulfonatos de Arila/química , Formiatos , Concentração de Íons de Hidrogênio
3.
Int J Mol Sci ; 23(14)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35886992

RESUMO

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the ß carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 µM, low toxicity with CC50 = 59.7 µM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 µM, CC50 = 72.3 µM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.


Assuntos
Vírus Chikungunya , Animais , Antivirais/química , Sulfonatos de Arila/metabolismo , Sulfonatos de Arila/farmacologia , Chlorocebus aethiops , Desenho Assistido por Computador , Cumarínicos/farmacologia , Simulação de Acoplamento Molecular , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinonas/farmacologia , Células Vero , Replicação Viral
4.
Int J Mol Sci ; 23(10)2022 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-35628621

RESUMO

Descurainia sophia L. (flixweeds) is a noxious broad-leaf weed infesting winter wheat fields in China that has evolved high resistance to tribenuron-methyl. In this work, a brand new gene CYP77B34 was cloned from tribenuron-methyl-resistant (TR) D. sophia and transferred into Arabidopsis thaliana, and the sensitivities of Arabidopsis with or without the CYP77B34 transgene to herbicides with a different mode of actions (MoAs) were tested. Compared to Arabidopsis expressing pCAMBIA1302-GFP (empty plasmid), Arabidopsis transferring pCAMBIA1302-CYP77B34 (recombinant plasmid) became resistant to acetolactate synthase (ALS)-inhibiting herbicide tribenuron-methyl, protoporphyrinogen oxidase (PPO)-inhibiting herbicides carfentrazone-ethyl and oxyfluorfen. Cytochrome P450 inhibitor malathion could reverse the resistance to tribenuron-methyl, carfentrazone-ethyl and oxyfluorfen in transgenic Arabidopsis plants. In addition, the metabolic rates of tribenuron-methyl in Arabidopsis expressing CYP77B34 were significantly higher than those in Arabidopsis expressing pCAMBIA1302-GFP. Other than that, the transgenic plants showed some tolerance to very-long-chain fatty acid synthesis (VLCFAs)-inhibiting herbicide pretilachlor and photosystem (PS) II-inhibiting herbicide bromoxynil. Subcellular localization revealed that the CYP77B34 protein was located in the endoplasmic reticulum (ER). These results clearly indicated that CYP77B34 mediated D. sophia resistance to tribenuron-methyl and may have been involved in D. sophia cross-resistance to carfentrazone-ethyl, oxyfluorfen, pretilachlor and bromoxynil.


Assuntos
Arabidopsis , Herbicidas , Arabidopsis/genética , Sulfonatos de Arila , Sistema Enzimático do Citocromo P-450/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia
5.
J Environ Sci Health B ; 57(7): 526-540, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35502688

RESUMO

Retention is one of the processes controlling the behavior and fate of pesticides in soil. The objective of this work was to evaluate the adsorption and desorption of glyphosate, AMPA, and metsulfuron-methyl in the main horizons of a Typic Argiudoll destined for agricultural use. For this purpose, the batch equilibrium method was used at a range of concentrations for each compound. Desorption was performed in three consecutive steps after the adsorption experiment. The results obtained showed strong adsorption of glyphosate and AMPA in the three horizons, following the trend B > A > C, with weak desorption. Metsulfuron-methyl, on the other hand, showed weak adsorption in the three horizons, following the trend A > B > C, with relevant desorption. Our results allow us to identify metsulfuron-methyl as the compound that poses the greatest environmental risk in terms of the potential contamination of other areas and groundwater. However, despite their strong adsorption and weak desorption, glyphosate and AMPA also represent potential contaminants of other environmental matrices.


Assuntos
Herbicidas , Poluentes do Solo , Adsorção , Sulfonatos de Arila , Glicina/análogos & derivados , Herbicidas/análise , Solo , Poluentes do Solo/análise , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/análise
6.
Environ Sci Pollut Res Int ; 29(14): 20249-20264, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34727312

RESUMO

The efficacy of slow-release formulations of tribenuron-methyl (TBM) embedded in the matrix of degradable poly(3-hydroxybutyrate) blended with birch wood flour [polymer/wood flour/herbicide 50/30/20 wt.%] was compared with the efficacy of TBM as the active ingredient of the Mortira commercial formulation, which was applied as post-emergence spray to treat spring wheat cv. Novosibirskaya 15. The study was conducted in Central Siberia (in the environs of the city of Krasnoyarsk, Russia) from May to August 2020. The biological efficacy of the embedded TBM was 92.3%, which was considerably higher than the biological efficacy of the Mortira formulation used as the post-emergence spray (15.4%). The embedding of TBM into degradable blended matrix enabled long-duration functioning of this unstable herbicide in soil. The sensitivity of weed plants to TBM differed depending on the species. TBM was more effective against A. retroflexus and A. blitoides, which were killed at an earlier stage, than against C. album and G. aparine, whose percentage increased in the earlier stage and which were controlled by the herbicide less effectively and at later stages. On the plot treated with the embedded herbicide, the parameters of the wheat yield structure were the best, and the total yield was the highest: 3360 ± 40 kg/ha versus 3250 ± 50 kg/ha in the group of plants sprayed with the Mortira formulation. The grain produced in all groups was of high quality and was classified as Grade 1 food grain. The highest quality parameters (grain hectoliter mass, gluten, and protein contents) were obtained in the group of plants treated with the embedded herbicide. The study of the embedded TBM confirmed the high efficacy of the experimental formulation.


Assuntos
Herbicidas , Sulfonatos de Arila , Preparações de Ação Retardada/química , Herbicidas/química , Triticum/metabolismo
7.
Environ Sci Pollut Res Int ; 29(13): 19731-19740, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34718969

RESUMO

The present paper discussed the comparison of the persistence and mobility of metsulfuron-methyl from a residue field trial experiment and simulation using a VARLEACH model. The residue field trial experiment was performed at Sungai Buloh Oil Palm Estate, Selangor. The plots were treated with metsulfuron-methyl at two treatment rates of 15 g a.i ha-1 (T1) and 30 g a.i ha-1 (T2). Soil samples were collected at 0, 1, 3, 7, 14, 21, 30, 60 and 90 days after treatment (DAT) and analysed subsequently by HPLC-UV. The results show that metsulfuron-methyl degraded rapidly in the soil with the half-life (t½) of 6.3 days in T1 and 7.9 days in T2. The simulation of VARLEACH model gave similar pattern of persistence and mobility of metsulfuron-methyl in the soil profile. However, total residues and the mobility of the metsulfuron-methyl were poorly simulated by the VARLEACH model due to consistent overestimation of the quantified residues. Results indicated that the metsulfuron-methyl lost more rapidly than the prediction values from VARLEACH model. In this case, simulation models which use transformation routines similar and which include additional degraded processes such as leaching, volatilisation, plant uptake or runoff could be considered. Albeit, overestimated values on the concentrations of metsulfuron-methyl are reported using VARLEACH model, the model still can be used as rapid and fast approach to predict the behaviour of pesticide at minimum cost.


Assuntos
Herbicidas , Poluentes do Solo , Sulfonatos de Arila , Herbicidas/química , Solo/química , Poluentes do Solo/análise
8.
Pest Manag Sci ; 78(4): 1467-1473, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34951107

RESUMO

BACKGROUND: Descurainia sophia L. is one of the most notorious weeds infesting winter wheat in China. Mutations at Pro197 in acetolactate synthase (ALS) results in resistance of D. sophia to tribenuron-methyl and cross-resistance to many ALS inhibitors. Negative cross-resistance to imazethapyr was observed in tribenuron-methyl-resistant (TR) D. sophia with the Pro197Ser mutation in a previous study. In the present research, another TR D. sophia with the Pro197Ser mutation was obtained. To explore the mechanisms of negative cross-resistance, the ALS sensitivity, the absorption and metabolism of imazethapyr in tribenuron-methyl-susceptible (TS) and TR D. sophia were studied. RESULTS: The TR D. sophia population with the Pro197Ser mutation (pHB23) displayed negative cross-resistance to imazethapyr and no cross-resistance to imazamox and imazapic. In contrast, TR D. sophia populations with other Pro197 mutations had no or low resistance to imazethapyr. The ALS in the pHB23 population was more susceptible to imazethapyr than that in the TS population. There was no difference in the absorption of imazethapyr, imazamox, and imazapic between TS and pHB23 plants. However, the metabolism of imazethapyr in TS D. sophia was faster than that in pHB23 plants up to 1 week after treatment. There was no significant difference in the metabolism of imazamox and imazapic between TS and pHB23 plants. CONCLUSION: The TR D. sophia population with the Pro197Ser mutation exhibited negative cross-resistance to imazethapyr, which was likely due to reduced metabolism and increased sensitivity of ALS to imazethapyr. © 2021 Society of Chemical Industry.


Assuntos
Acetolactato Sintase , Brassicaceae , Herbicidas , Magnoliopsida , Sulfonatos de Arila , Brassicaceae/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Mutação , Ácidos Nicotínicos
9.
J Phys Chem B ; 125(45): 12539-12551, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34743512

RESUMO

Proton transfer reactions are ubiquitous in chemistry, especially in aqueous solutions. We investigate photoinduced proton transfer between the photoacid 8-hydroxypyrene-1,3,6-trisulfonate (HPTS) and water using fast fluorescence spectroscopy and ab initio molecular dynamics simulations. Photoexcitation causes rapid proton release from the HPTS hydroxyl. Previous experiments on HPTS/water described the progress from photoexcitation to proton diffusion using kinetic equations with two time constants. The shortest time constant has been interpreted as protonated and photoexcited HPTS evolving into an "associated" state, where the proton is "shared" between the HPTS hydroxyl and an originally hydrogen bonded water. The longer time constant has been interpreted as indicating evolution to a "solvent separated" state where the shared proton undergoes long distance diffusion. In this work, we refine the previous experimental results using very pure HPTS. We then use excited state ab initio molecular dynamics to elucidate the detailed molecular mechanism of aqueous excited state proton transfer in HPTS. We find that the initial excitation results in rapid rearrangement of water, forming a strong hydrogen bonded network (a "water wire") around HPTS. HPTS then deprotonates in ≤3 ps, resulting in a proton that migrates back and forth along the wire before localizing on a single water molecule. We find a near linear relationship between the emission wavelength and proton-HPTS distance over the simulated time scale, suggesting that the emission wavelength can be used as a ruler for the proton distance. Our simulations reveal that the "associated" state corresponds to a water wire with a mobile proton and that the diffusion of the proton away from this water wire (to a generalized "solvent-separated" state) corresponds to the longest experimental time constant.


Assuntos
Prótons , Água , Sulfonatos de Arila , Solventes , Espectrometria de Fluorescência
10.
Nat Chem ; 13(12): 1248-1256, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34697400

RESUMO

Companion diagnostics (CDx) are powerful tests that can provide physicians with crucial biomarker information that can improve treatment outcomes by matching therapies to patients. Here, we report a photoacoustic imaging-based CDx (PACDx) for the selective detection of elevated glutathione (GSH) in a lung cancer model. GSH is abundant in most cells, so we adopted a physical organic chemistry approach to precisely tune the reactivity to distinguish between normal and pathological states. To evaluate the efficacy of PACDx in vivo, we designed a blind study where photoacoustic imaging was used to identify mice bearing lung xenografts. We also employed PACDx in orthotopic lung cancer and liver metastasis models to image GSH. In addition, we designed a matching prodrug, PARx, that uses the same SNAr chemistry to release a chemotherapeutic with an integrated PA readout. Studies demonstrate that PARx can inhibit tumour growth without off-target toxicity in a lung cancer xenograft model.


Assuntos
Sulfonatos de Arila/química , Biomarcadores Tumorais/metabolismo , Corantes/química , Glutationa/metabolismo , Indóis/química , Neoplasias Pulmonares/tratamento farmacológico , Animais , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/efeitos da radiação , Linhagem Celular Tumoral , Corantes/síntese química , Corantes/efeitos da radiação , Desoxicitidina/análogos & derivados , Desoxicitidina/síntese química , Desoxicitidina/efeitos da radiação , Desoxicitidina/uso terapêutico , Desenho de Fármacos , Feminino , Células HEK293 , Humanos , Indóis/síntese química , Indóis/efeitos da radiação , Luz , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Técnicas Fotoacústicas/métodos , Pró-Fármacos/síntese química , Pró-Fármacos/efeitos da radiação , Pró-Fármacos/uso terapêutico , Método Simples-Cego , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Phys Chem Chem Phys ; 23(35): 19343-19351, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524310

RESUMO

We simulated Brownian diffusion and reaction-diffusion processes to study the influence of molecular rebinding on the reaction rates of bimolecular reactions. We found that the number of rebinding events, Nreb, is proportional to the target's size and inversely proportional to the diffusion coefficient D and simulation time-step Δt. We found the proportionality constant close to π-1/2. We confirmed that Nreb is defined as a ratio of the activation-limited rate constant ka to the diffusion-limited rate constant, kD. We provide the formula describing the reactivity coefficient κ, modelling the transient-native complex transition for the activation-controlled reaction rates. We show that κ is proportional to (D/Δt)1/2. Finally, we apply our rebinding-including reaction rate model to the real reactions of photoacid dissociation and protein association. Based on literature data for both types of reactions, we found the Δt time-scale. We show that for the photodissociation of a proton, the Δt is equal to 171 ± 18 fs and the average number of rebinding events is approximately equal to 40. For proteins, Δt is of the order of 100 ps with around 20 rebinding events. In both cases the timescale is similar to the timescale of fluctuation of the solvent molecules surrounding the reactants; vibrations and bending in the case of photoacid dissociation and diffusional motion for proteins.


Assuntos
Modelos Moleculares , Sulfonatos de Arila/química , Difusão , Cinética , Método de Monte Carlo , Proteínas/química , Proteínas/metabolismo , Prótons
12.
J Phys Chem B ; 125(36): 10273-10281, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34472354

RESUMO

The excited state proton transfer (ESPT) reaction from the photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS or pyranine) to an acetate molecule has been investigated in explicit aqueous solution via excited state ab initio molecular dynamics simulations based on hybrid quantum/molecular mechanics (QM/MM) potentials. In all the trajectories, the direct proton transfer has been observed in the excited state within 1 ps. We find that the initial structural configuration extracted from the ground state distribution strongly affects the ESPT kinetics. Indeed, the relative orientation of the proton donor-acceptor pair and the presence of a water molecule hydrogen bonded to the phenolic acid group of the pyranine are the key factors to facilitate the ESPT. Furthermore, we analyze the vibrational fingerprints of the ESPT reaction, reproducing the blue shift of the acetate CO stretching (COac), from 1666 to 1763 cm-1 testifying the transformation of acetate to acetic acid. Finally, our findings suggest that the acetate CC stretching (CCac) is also sensitive to the progress of the ESPT reaction. The CCac stretching is indeed ruled by the two vibrational modes (928 and 1426 cm-1), that in the excited state are alternately activated when the proton is shared or bound to the donor/acceptor, respectively.


Assuntos
Sulfonatos de Arila , Prótons , Acetatos , Água
13.
Plant Physiol Biochem ; 167: 705-712, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34500195

RESUMO

Uncontrolled application of herbicides in the agricultural field poses a severe risk to crops by affecting their yields. Therefore, methods are required to reduce the toxic effects of herbicides in plants. Studies indicate that silicon (Si) provides tolerance and enhances defence mechanism of the plant against abiotic stress. But its role in alleviating Metsulfuron methyl (Meth) herbicide induced toxicity in wheat seedlings is still not known. This study highlighted the potential of exogenous addition of Si in the alleviation of toxic effect of Meth herbicide in wheat seedlings. The exposure of wheat seedlings to Meth herbicide reduced the growth, photosynthetic pigments, antioxidant enzyme activity and nitric oxide (NO) content. Further, Meth herbicide also increased cell death and decreased cell viability in root tips. However, addition of Si reversed Meth-induced these alterations. Moreover, Si also activates antioxidant system which helps in scavenging of free radicals generated under Meth herbicide stress in wheat seedlings. Application of Si to Meth treated wheat seedlings also up-regulated silicon transporter gene Lsi1 (silicon influx transporter) and some of the antioxidant enzyme genes. All together, the data indicate that Si has capability of alleviating Meth herbicide stress in wheat seedlings but it appears that endogenous NO has a positive role in this endeavour of Si.


Assuntos
Plântula , Triticum , Antioxidantes , Sulfonatos de Arila/farmacologia , Estresse Oxidativo , Silício/farmacologia
14.
Biosens Bioelectron ; 194: 113612, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34507094

RESUMO

We have reported an optical indicator displacement assay (IDA) for heparin with a UV-vis absorbance and fluorescence dual-readout based on pyranine/methyl viologen (MV2+). Upon introducing heparin, pyranine/MV2+ shows a clearly observable increase in UV-vis absorbance and a turn-on of the fluorescence signal. We have demonstrated that the ionic nature of buffers significantly affects the pyranine displacement and the zwitterionic HEPES was most suitable for heparin sensing. After careful screening of experimental conditions, the pyranine/MV2+-based optical chemosensor exhibits a fast, sensitive, and selective response toward heparin. It shows dynamic linear concentration of heparin in the ranges of 0.1-40 U·mL-1 and 0.01-20 U·mL-1 for the absorptive and fluorescent measurements, respectively, which both cover the clinically relevant levels of heparin. As with the animal experiments, the optical chemosensor has been demonstrated to be selective and effective for heparin level qualification in rat plasma. The chemosensor is readily accessible, cost-effective, and reliable, which holds a great promise for potential application on clinical and biological studies. Furthermore, this IDA system can serve as an IMPLICATION logic gate with a reversible and switchable logical manner.


Assuntos
Técnicas Biossensoriais , Heparina , Animais , Sulfonatos de Arila , Corantes Fluorescentes , Paraquat , Ratos
15.
Bioorg Med Chem ; 46: 116344, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34438337

RESUMO

Based on a new pyrazole sulfonate synthetic method, a novel class of molecules with a basic structure of pyrazole N-aryl sulfonate have been designed and synthesized. The interest in conducting intensive research stems from quite evident anti-inflammatory effects exhibited by the compounds in preliminary animal experiments. A series of compounds were synthesized by different substitutions of the R1, R2, and R3 groups. Within the series, 4-iodophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate and phenyl 5-methyl-3-(4-(trifluoromethyl) phenyl)-1H-pyrazole-1-sulfonate exhibited excellent anti-inflammatory activity (% inhibition of auricular edemas = 27.0 and 35.9, respectively); the in vivo analgesic activity of phenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate and 2-chlorophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate was confirmed to be effective (inhibition ratio of writhing = 50.7% and 48.5% separately), and compounds phenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate , 4-iodophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate and 2-chlorophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate were identified as selective COX-2 inhibitors (SI = 455, 10,497 and >189 severally). In Acute Oral Toxicity assays conducted in vivo, the lethal dose 50 (LD50) of 4-iodophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate and 2-chlorophenyl 5-methyl-3-(p-tolyl)-1H-pyrazole-1-sulfonate to mice was >2000 mg/kg BW.


Assuntos
Sulfonatos de Arila/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , Animais , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
16.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34417291

RESUMO

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αß T cell receptors (TCR) and recognize α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells), but our knowledge of the antigens for type II NKT cells is limited. An early study identified a nonlipidic NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa drugs, but its mechanism of NKT cell activation remained unknown. Here, we demonstrate that a range of pentamethylbenzofuransulfonates (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug-like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d tetramers identified type II NKT cell populations expressing αßTCRs and γδTCRs, including those with variable and joining region gene usage (TRAV12-1-TRAJ6) that was conserved across donors. By trapping a CD1d-type II NKT TCR complex for direct mass-spectrometric analysis, we detected molecules that allow the binding of CD1d to TCRs, finding that both selected PBF family members and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that nonlipidic small molecules, which resemble sulfa drugs implicated in systemic hypersensitivity and drug allergy reactions, are targeted by a polyclonal population of type II NKT cells in a CD1d-restricted manner.


Assuntos
Antígenos CD1d/metabolismo , Sulfonatos de Arila/imunologia , Autoantígenos/metabolismo , Benzofuranos/imunologia , Lipídeos/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Apresentação de Antígeno/imunologia , Antígenos CD1d/imunologia , Autoantígenos/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia
17.
FASEB J ; 35(9): e21863, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34411334

RESUMO

Organic anion-transporting polypeptides, OATP1B1, OATP1B3, and OATP2B1 are multispecific membrane proteins mediating the hepatocellular uptake of structurally diverse endo- and exogenous compounds, including various kinds of drugs. Co-administration of OATP1B/2B1 substrates may lead to altered pharmacokinetics or even toxicity. Therefore, the study of the interaction with these OATPs is essential in drug development and is recommended by international regulatory agencies, the FDA, EMA, and PMDA. In general, radiolabeled indicators are used to measure drug interactions of OATPs, and, lately, fluorescent probes are also gaining wider application in OATP tests. However, all of the currently available methods (either radioactive or fluorescence-based) comprise multiple steps, including the removal of the indicator in the end of the experiment. Hence, they are not ideally suited for high-throughput screening. In the current study, in order to find an indicator allowing real-time assessment of hepatic OATP function, we searched for an activatable fluorogenic OATP substrate. Here, we show that 8-acetoxypyrene-1,3,6-trisulfonate (Ace), a fluorogenic derivative of the hepatic OATP substrate pyranine (8-hydroxypyrene-1,3,6-trisulfonate) enters the cells via OATP1B1/3 or OATP2B1 function. In living cells, Ace is then converted into highly fluorescent pyranine, allowing "no-wash" measurement of OATP function and drug interactions. Furthermore, we demonstrate that Ace can be used in an indirect assay termed as competitive counterflow suitable to distinguish between transported substrates and inhibitors of OATP1B1. The fluorescence-based methods described here are unique and open the way toward high-throughput screening of interactions between new molecular entities and OATPs.


Assuntos
Corantes Fluorescentes/análise , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Animais , Sulfonatos de Arila/análise , Sulfonatos de Arila/química , Sulfonatos de Arila/metabolismo , Linhagem Celular , Sobrevivência Celular , Corantes Fluorescentes/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Fígado/metabolismo
18.
Chemistry ; 27(53): 13279, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34363251

RESUMO

Invited for the cover of this issue are Anil Chandra, Loretta L. del Mercato and co-workers at the Institute of Nanotechnology of National Research Council and the University of Salento. The image depicts how negatively charged pH-sensitive pyranine (HPTS) molecules were successfully immobilized on silica microparticles (SMPs) without compromising the molecules' pH sensitivity. These resulting sensors can be used to measure pH in vitro and in vivo due to the cytocompatibility of HPTS molecules and SMPs. Read the full text of the article at 10.1002/chem.202101568.


Assuntos
Sulfonatos de Arila , Dióxido de Silício , Corantes Fluorescentes , Humanos , Concentração de Íons de Hidrogênio
19.
Chemistry ; 27(53): 13318-13324, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34231936

RESUMO

Pyranine (HPTS) is a remarkably interesting pH-sensitive dye that has been used for plenty of applications. Its high quantum yield and extremely sensitive ratiometric fluorescence against pH change makes it a very favorable for pH-sensing applications and the development of pH nano-/microsensors. However, its strong negative charge and lack of easily modifiable functional groups makes it difficult to use with charged substrates such as silica. This study reports a methodology for noncovalent HPTS immobilization on silica microparticles that considers the retention of pH sensitivity as well as the long-term stability of the pH microsensors. The study emphasizes the importance of surface charge for governing the sensitivity of the immobilized HPTS dye molecules on silica microparticles. The importance of the immobilization methodology, which preserves the sensitivity and stability of the microsensors, is also assessed.


Assuntos
Corantes Fluorescentes , Dióxido de Silício , Sulfonatos de Arila , Concentração de Íons de Hidrogênio , Espectrometria de Fluorescência
20.
J Food Sci ; 86(7): 3176-3187, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34176121

RESUMO

A hapten of metsulfuron-methyl was successfully designed and synthesized from 2-methylester-phenylsulfonamide and succinic anhydride, and the polyclonal antibody against metsulfuron-methyl was prepared by immunization procedure with the hapten-bovine serum albumin conjugate. A stable and sensitive direct competitive enzyme-linked immunosorbent assay (dcELISA) method had been developed under the optimal conditions. The sensitivity (IC50 ) was 37.03 ± 1.87 µg/L, and the detection line (IC15 ) was 1.57 ± 0.11 µg/L. Rice, wheat, oat, flaxseed, milk, and water were chosen to study the recovery test and the recovery rates were 83.11%-117.44% . The matrix effect was eliminated by a simple dilution of the sample extracts. The results from dcELISA were well agreement with the results from HPLC-MS. It was indicated that the developed method had good accuracy and stability. It could be applied for the detection of metsulfuron-methyl residues. It was worth mentioning that the antibody could recognize metsulfuron-methyl and tribenuron-methyl with cross-reactivities of 100% and 49.72%, respectively. In order to understand the cross-reactivity, molecular modeling including molecular alignment and electrostatic potential surfaces were introduced. It was found that the special group of metsulfuron-methyl played an important role, especially on C3 position of the phenyl group. PRACTICAL APPLICATION: A stable, sensitive, and low-cost dc ELISA method had been developed with good accuracy and applied in the determination of metsulfuron-methyl in foods. Molecular simulation was introduced to understand the specificity between the antibody and the analyst. It was a good method to study the cross-reactivity between the antibody and the analyst or analogue.


Assuntos
Sulfonatos de Arila/análise , Sulfonatos de Arila/química , Ensaio de Imunoadsorção Enzimática/métodos , Análise de Alimentos/métodos , Anticorpos/imunologia , Sulfonatos de Arila/imunologia , Oryza/química , Triticum/química
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