RESUMEN
We report a novel system consisting of a redox reaction and a highly efficient reductase-like nanozyme, silica-palladium nanoparticles (Pd@SiO2 NPs), as a novel detection platform for fluorometric sensing. In a proof-of-concept demonstration using an oligonucleotide as the detection target, a glass fiber-based sensor is fabricated by covalently conjugating two oligo probes, which are complementary to the adjacent segments of the target oligonucleotide, on Pd@SiO2 NPs and glass fiber, respectively. In the presence of the target oligonucleotide, the two probes are drawn together by the target through sequence-specific hybridization, bringing the Pd@SiO2 NPs to the glass fiber. When the glass fiber is subsequently immersed in a mixture of resazurin and ammonia borane solution, the Pd@SiO2 NPs on the glass fiber trigger the catalytic conversion of resazurin (blue, slightly fluorescent) to resorufin (pink, highly fluorescent) with massive signal amplification, indirectly signaling the presence of the target oligonucleotide. We show that the glass fiber-based fluorometric sensor can detect a target oligonucleotide associated with the BRAF mutation linearly in the concentration range of 20 to 400 pM with a detection limit (LOD) of 15 pM and the specificity to differentiate targets with single-base difference. These results demonstrate a new frontier for the development of a sensitive, specific, and inexpensive nonenzyme-based fluorometric sensing platform as an alternative to conventional enzyme-based assays.
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Fluorometría , Oxazinas , Xantenos , Oxazinas/química , Xantenos/química , Boranos/química , Dióxido de Silicio/química , Paladio/química , Amoníaco/análisis , Amoníaco/química , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Nanopartículas del Metal/química , Límite de Detección , Técnicas Biosensibles/métodos , HumanosRESUMEN
Fluorophores are considered powerful tools for not only enabling the visualization of cell structures, substructures, and biological processes, but also making for the quantitative and qualitative measurement of various analytes in living systems. However, most fluorophores do not meet the diverse requirements for biological applications in terms of their photophysical and biological properties. Hybridization is an important strategy in molecular engineering that provides fluorophores with complementarity and multifunctionality. This review summarizes the basic strategies of hybridization with four classes of fluorophores, including xanthene, cyanine, coumarin, and BODIPY with a focus on their structure-property relationship (SPR) and biological applications. This review aims to provide rational hybrid ideas for expanding the reservoir of knowledge regarding fluorophores and promoting the development of newly produced fluorophores for applications in the field of life sciences.
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Colorantes Fluorescentes , Xantenos , Colorantes Fluorescentes/química , Xantenos/química , IonóforosRESUMEN
Developing imaging tools that can report on the presence of disease-relevant analytes in multicellular organisms can provide insight into fundamental disease mechanisms as well as provide diagnostic tools for the clinic. Photoacoustic imaging (PAI) is a light-in, sound-out imaging technique that allows for high resolution, deep-tissue imaging with applications in pre-clinical and point-of-care settings. The continued development of near-infrared (NIR) absorbing small-molecule dyes promises to improve the capabilities of this emerging imaging modality. For example, new dye scaffolds bearing chemoselective functionalities are enabling the detection and quantification of disease-relevant analytes through activity-based sensing (ABS) approaches. Recently described strategies to engineer NIR absorbing xanthenes have enabled development of analyte-responsive PAI probes using this classic dye scaffold. Herein, we present current strategies for red-shifting the spectral properties of xanthenes via bridging heteroatom or auxochrome modifications. Additionally, we explore how these strategies, coupled with chemoselective spiroring-opening approaches, have been employed to create ABS probes for inâ vivo detection of hypochlorous acid, nitric oxide, copper (II), human NAD(P)H: quinone oxidoreductase isozyme 1, and carbon monoxide. Given the versatility of the xanthene scaffold, we anticipate continued growth and development of analyte-responsive PAI imaging probes based on this dye class.
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Técnicas Fotoacústicas , Xantenos , Técnicas Fotoacústicas/métodos , Xantenos/química , Humanos , Colorantes Fluorescentes/química , Monóxido de Carbono/análisis , Monóxido de Carbono/química , Óxido Nítrico/análisis , Óxido Nítrico/química , Cobre/química , Colorantes/química , AnimalesRESUMEN
Uropathogenic Escherichia coli, the most common cause for urinary tract infections, forms biofilm enhancing its antibiotic resistance. To assess the effects of compounds on biofilm formation of uropathogenic Escherichia coli UMN026 strain, a high-throughput combination assay using resazurin followed by crystal violet staining was optimized for 384-well microplate. Optimized assay parameters included, for example, resazurin and crystal violet concentrations, and incubation time for readouts. For the assay validation, quality parameters Z' factor, coefficient of variation, signal-to-noise, and signal-to-background were calculated. Microplate uniformity, signal variability, edge well effects, and fold shift were also assessed. Finally, a screening with known antibacterial compounds was conducted to evaluate the assay performance. The best conditions found were achieved by using 12 µg/mL resazurin for 150 min and 0.023% crystal violet. This assay was able to detect compounds displaying antibiofilm activity against UMN026 strain at sub-inhibitory concentrations, in terms of metabolic activity and/or biomass.
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Antibacterianos , Biopelículas , Violeta de Genciana , Ensayos Analíticos de Alto Rendimiento , Oxazinas , Escherichia coli Uropatógena , Xantenos , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Escherichia coli Uropatógena/efectos de los fármacos , Escherichia coli Uropatógena/fisiología , Ensayos Analíticos de Alto Rendimiento/métodos , Xantenos/química , Antibacterianos/farmacología , Violeta de Genciana/metabolismo , Oxazinas/farmacología , Oxazinas/metabolismo , Oxazinas/química , Pruebas de Sensibilidad Microbiana , Infecciones Urinarias/microbiología , HumanosRESUMEN
A series of novel near-infrared (NIR) xanthene-chalcone fluorophores were constructed through a modular synthesis with the electron-donating xanthene moiety and the electron-withdrawing chalcone moiety. These fluorophores are convenient for fluorescence imaging in living cells, benefiting from their NIR emissions (650-710 nm), large Stokes shifts (>100 nm), moderate quantum yields and low cytotoxicity. The substituted hydroxyl group of the xanthene-chalcone fluorophore HCA-E facilitates the development of multifunctional fluorescent probes. As an example, a highly sensitive and selective probe N-HCA-E for glutathione (GSH) detection was developed based on the fluorophore HCA-E. A 4-nitrobenzenesulfonyl (4-Ns) group was introduced to cage the hydroxyl group of HCA-E, which was used as a selective recognition site for the thiol of GSH and an effective fluorescence quencher. Probe N-HCA-E revealed NIR "turn-on" fluorescence (709 nm) for endogenous and exogenous GSH detection in lysosomes with a large Stokes shift (129 nm) and high anti-interference ability.
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Colorantes Fluorescentes , Glutatión , Imagen Óptica , Xantenos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/toxicidad , Colorantes Fluorescentes/síntesis química , Xantenos/química , Humanos , Glutatión/química , Imagen Óptica/métodos , Chalconas/química , Células HeLa , Lisosomas/química , Lisosomas/metabolismo , Rayos Infrarrojos , Chalcona/químicaRESUMEN
The first phytochemical investigation of the twig extract of Uvaria leptopoda resulted in the isolation and identification of three new tetrahydroxanthene-1,3(2H)-diones, uvarialeptones A-C, two new oxidized hexadiene derivatives, uvarialeptols A and B, together with ten known compounds. Their structures were elucidated by spectroscopic techniques and mass spectrometry. Uvarialeptones A and B were unprecedented tetrahydroxanthene-1,3(2H)-dione dimers which exhibited a cyclobutane ring via [2 + 2] cycloaddition from uvarialeptone C and 9a-O-methyloxymitrone, respectively. The structure of uvarialeptone A was confirmed by X-ray diffraction analysis using Mo Kα radiation. Compound 3 inhibited NO production at an IC50 value of 6.7 ± 0.1 µM.
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Uvaria , Uvaria/química , Estructura Molecular , Animales , Óxido Nítrico/biosíntesis , Ratones , Xantenos/farmacología , Xantenos/química , Cristalografía por Rayos X , Oxidación-Reducción , Células RAW 264.7RESUMEN
Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi, exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12k, which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery.
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Apoptosis , Piroptosis , Humanos , Xantenos/farmacología , Xantenos/química , Células A549 , Línea Celular TumoralRESUMEN
A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.
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Antineoplásicos , Apoptosis , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Metano/análogos & derivados , Metano/química , Metano/farmacología , Proliferación Celular/efectos de los fármacos , Xantenos/farmacología , Xantenos/químicaRESUMEN
Near-infrared region (NIR; 650-1700â nm) dyes offer many advantages over traditional dyes with absorption and emission in the visible region. However, developing new NIR dyes, especially organic dyes with long wavelengths, small molecular weight, and excellent stability and biocompatibility, is still quite challenging. Herein, we present a general method to enhance the absorption and emission wavelengths of traditional fluorophores by simply appending a charge separation structure, dihydropyridopyrazine. These novel NIR dyes not only exhibited greatly redshifted wavelengths compared to their parent dyes, but also displayed a small molecular weight increase together with retained stability and biocompatibility. Specifically, dye NIR-OX, a dihydropyridopyra-zine derivative of oxazine with a molecular mass of 386.2â Da, exhibited an absorption at 822â nm and an emission extending to 1200â nm, making it one of the smallest molecular-weight NIR-II emitting dyes. Thanks to its rapid metabolism and long wave-length, NIR-OX enabled high-contrast bioimaging and assessment of cholestatic liver injury in vivo and also facilitated the evalua-tion of the efficacy of liver protection medicines against cholestatic liver injury.
Asunto(s)
Colorantes Fluorescentes , Peso Molecular , Xantenos , Colorantes Fluorescentes/química , Xantenos/química , Pirazinas/química , Animales , Ratones , Estructura Molecular , Rayos Infrarrojos , Humanos , Imagen ÓpticaRESUMEN
Cell viability and metabolic activity are ubiquitous parameters used in biochemistry, molecular biology, and biotechnological studies. Virtually all toxicology and pharmacological projects include at some point the evaluation of cell viability and/or metabolic activity. Among the methods used to address cell metabolic activity, resazurin reduction is probably the most common. At variance with resazurin, resorufin is intrinsically fluorescent, which simplifies its detection. Resazurin conversion to resorufin in the presence of cells is used as a reporter of metabolic activity of cells and can be detected by a simple fluorometric assay. UV-Vis absorbance is an alternative technique but is not as sensitive. In contrast to its wide empirical "black box" use, the chemical and cell biology fundamentals of the resazurin assay are underexplored. Resorufin is further converted to other species, which jeopardizes the linearity of the assays, and the interference of extracellular processes has to be accounted for when quantitative bioassays are aimed at. In this work, we revisit the fundamentals of metabolic activity assays based on the reduction of resazurin. Deviation to linearity both in calibration and kinetics, as well as the existence of competing reactions for resazurin and resorufin and their impact on the outcome of the assay, are addressed. In brief, fluorometric ratio assays using low resazurin concentrations obtained from data collected at short time intervals are proposed to ensure reliable conclusions.
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Oxazinas , Xantenos , Indicadores y Reactivos , Oxazinas/química , Xantenos/química , FluorometríaRESUMEN
Nanoparticles have been used as antibacterial agents in several products. To optimize their effectiveness, synthesis processes and particle modifications have been developed, creating the need for a rapid screening method to investigate their potencies. Owing to the opacity and insolubility of nanoparticles, a classical method to determine antibacterial activity-such as the minimum inhibitory concentration (MIC), which relies on turbidimetry-might not apply to them. In this study, we demonstrate the potential of a dye (resazurin)-based assay as an indicator of bacterial growth to rapidly screen the antibacterial activities of both organic and inorganic nanomaterials against both gram-negative (E. coli) and gram-positive (S. aureus) bacteria. The results indicate that the resazurin-based assay successfully determine the MIC of organic lipid nanocarriers, and several inorganic nanoparticles. However, the use of resazurin require a precaution for nanoparticles with photocatalytic properties, which may cause dye degradation at higher concentrations. In this study, resazurin bleaching was observed at approximately >50 mg/ml of TiO2. In summary, the modified MIC assay with resazurin can evaluate antibacterial activity of nanomaterials, whose turbidity interferer conventional MIC assay. This modification conserves an advantage of MICs assay which are simple and reliable. This would be useful for screening of antibacterial nanomaterials.
Asunto(s)
Antibacterianos/administración & dosificación , Escherichia coli/efectos de los fármacos , Nanopartículas/administración & dosificación , Oxazinas/química , Staphylococcus aureus/efectos de los fármacos , Xantenos/química , Antibacterianos/química , Indicadores y Reactivos/química , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Pruebas de Sensibilidad Microbiana/métodos , Nanopartículas/química , Nefelometría y Turbidimetría/métodos , Aceites Volátiles/química , Tamaño de la Partícula , Plata/química , Titanio/química , Óxido de Zinc/químicaRESUMEN
V-shaped xanthene dyes capable of predicting absorption and emission wavelengths are described. These dyes were synthesized by bridging a xanthene ring and an aryl moiety of fluorescein through ether covalent bonds. These dyes showed longer absorption and emission wavelengths than those of the parent fluorescein. Furthermore, substituents introduced on the aryl moiety mainly affected the lowest unoccupied molecular orbital energy level of the molecule. Therefore, the Hammett substituent constants could be used to predict the absorption and emission wavelengths of the compound.
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Colorantes , Xantenos , Benzopiranos , Fluoresceína/química , Colorantes Fluorescentes/química , Xantenos/químicaRESUMEN
A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 µM against overexpressed EGFR-TK cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 µM against A431 and HeLa cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Compuestos Heterocíclicos/farmacología , Oxígeno/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Xantenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , National Cancer Institute (U.S.) , Oxígeno/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Estados Unidos , Xantenos/síntesis química , Xantenos/químicaRESUMEN
In this paper, a new Mn-based metal-organic framework [UoB-6] was obtained via a one-step ultrasonic irradiation method with the ligand (H2bdda: 4,4'-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))dibenzoic acid. The structural integrity of the synthesized BioMOF-Mn was corroborated by FT-IR, EDX, ICP, XRD, TEM, DLS, FESEM, and BET-BJH analyses. The aerobic oxidative domino reaction of benzyl alcohols or aldehydes with dimedone derivatives was performed in the presence of the UoB-6 catalyst to produce xanthene derivatives in good yields. Hot filtration and Hg poisoning tests proved the heterogeneous nature of the catalyst. Novel synthesized xanthene-based bis-aldehydes were introduced as potent HDAC1 inhibitors according to molecular docking calculations. Finally, the inhibitory activities of Mn-MOF nanoparticles were evaluated on Escherichia coli and Candida albicans. The MIC, MBC, and MFC values were determined from 2048 to 4096 µg·mL-1 according to antimicrobial susceptibility testing methods. The inhibitory effects of antimicrobial agents can be exacerbated when loaded on BioMOFs.
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Antiinfecciosos , Xantenos , Aldehídos/química , Antiinfecciosos/farmacología , Simulación del Acoplamiento Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Xantenos/química , Xantenos/farmacologíaRESUMEN
Fluorescein, eosin Y, and rose bengal are dyes used in clinical medicine and considered (photo-)chemically stable. Upon extensive irradiation with visible light in aqueous solutions, we found that these compounds release carbon monoxide (CO) - a bioactive gasotransmitter - in 40-100% yields along with the production of low-mass secondary photoproducts, such as phthalic and formic acids, in a multistep degradation process. Such photochemistry should be considered in applications of these dyes, and they could also be utilized as visible-light activatable CO-releasing molecules (photoCORMs) with biological implications.
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Colorantes Fluorescentes , Xantenos , Colorantes Fluorescentes/química , Xantenos/química , Luz , Rosa Bengala , FluoresceínaRESUMEN
Novel cyano-benzylidene xanthene derivatives were synthesized using one-pot and condensation reactions. A diprotic Brønsted acid (i.e., oxalic acid) was used as an effective catalyst for the promotion of the synthesis process of the new starting xanthene-aldehyde compound. Different xanthene concentrations (ca. 0.1-2.0 mM) were applied as corrosion inhibitors to control the alkaline uniform corrosion of aluminum. Measurements were conducted in 1.0 M NaOH solution using Tafel extrapolation and linear polarization resistance (LPR) methods. The investigated xanthenes acted as mixed-type inhibitors that primarily affect the anodic process. Their inhibition efficiency values were enhanced with inhibitor concentration, and varied according to their chemical structures. At a concentration of 2.0 mM, the best-performing studied xanthene derivative recorded maximum inhibition efficiency values of 98.9% (calculated via the Tafel extrapolation method) and 98.4% (estimated via the LPR method). Scanning electron microscopy (SEM) was used to examine the morphology of the corroded and inhibited aluminum surfaces, revealing strong inhibitory action of each studied compound. High-resolution X-ray photoelectron spectroscopy (XPS) profiles validated the inhibitor compounds' adsorption on the Al surface. Density functional theory (DFT) and Monte Carlo simulations were applied to investigate the distinction of the anticorrosive behavior among the studied xanthenes toward the Al (111) surface. The non-planarity of xanthenes and the presence of the nitrile group were the key players in the adsorption process. A match between the experimental and theoretical findings was evidenced.
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Aluminio , Xantenos , Ácidos/química , Adsorción , Aluminio/química , Corrosión , Xantenos/químicaRESUMEN
In this study, we demonstrate six novel xanthene derivatives and their spectroscopic and chemical properties. The presented synthesis examination allowed us to obtain two different compounds during one step, with open and closed lactone rings substituted with different length alkyl chains. Increasing the reaction efficiency to 77% was obtained using the microwave-assisted method. Moreover, the modification of O-alkylation synthesis in an ecofriendly way using a ball mill led to achieving exclusively one opened ring product. All of the synthesized compounds showed different spectroscopic behaviors in comparison with the different organic dyes; the typical concentration quenching of luminescence was not observed. The relationship between the length of the alkyl chain and the time of luminescence decay is presented. Synthetized closed forms of dyes turned out to be promising leuco dyes. For the first time, an ionic liquid was used as a developer of synthesized xanthene derivatives (as leuco dyes), which led to obtaining an irreversible thermochromic marker.
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Líquidos Iónicos , Benzopiranos , Colorantes/química , Líquidos Iónicos/química , Luminiscencia , Xantenos/químicaRESUMEN
Intratympanic injection of gentamicin has proven to be an effective therapy for intractable vestibular dysfunction. However, most studies to date have focused on the cochlea, so little is known about the distribution and uptake of gentamicin by the counterpart of the auditory system, specifically vestibular hair cells (HCs). Here, with a combination of in vivo and in vitro approaches, we used a gentamicin-Texas Red (GTTR) conjugate to investigate the mechanisms of gentamicin vestibulotoxicity in the developing mammalian utricular HCs. In vivo, GTTR fluorescence was concentrated in the apical cytoplasm and the cellular membrane of neonatal utricular HCs, but scarce in the nucleus of HCs and supporting cells. Quantitative analysis showed the GTTR uptake by striolar HCs was significantly higher than that in the extrastriola. In addition, the GTTR fluorescence intensity in the striola was increased gradually from 1 to 8 days, peaking at 8-9 days postnatally. In vitro, utricle explants were incubated with GTTR and candidate uptake conduits, including mechanotransduction (MET) channels and endocytosis in the HC, were inhibited separately. GTTR uptake by HCs could be inhibited by quinine, a blocker of MET channels, under both normal and stressed conditions. Meanwhile, endocytic inhibition only reduced GTTR uptake in the CoCl2 hypoxia model. In sum, the maturation of MET channels mediated uptake of GTTR into vestibular HCs. Under stressed conditions, MET channels play a pronounced role, manifested by channel-dependent stress enhanced GTTR permeation, while endocytosis participates in GTTR entry in a more selective manner.
Asunto(s)
Transporte Biológico/fisiología , Gentamicinas/farmacología , Gentamicinas/farmacocinética , Células Ciliadas Auditivas/metabolismo , Sáculo y Utrículo/embriología , Animales , Endocitosis/efectos de los fármacos , Femenino , Gentamicinas/química , Masculino , Moduladores del Transporte de Membrana/farmacología , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Quinina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sáculo y Utrículo/metabolismo , Coloración y Etiquetado , Enfermedades Vestibulares/tratamiento farmacológico , Enfermedades Vestibulares/patología , Xantenos/químicaRESUMEN
The cationic Ru-H complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1) was found to be an effective catalyst for the dehydrative C-H coupling reaction of phenols and aldehydes to form 2-alkylphenol products. The coupling reaction of phenols with branched aldehydes selectively formed 1,1-disubstituted benzofurans, while the coupling reaction with salicylaldehydes yielded xanthene derivatives. A normal deuterium isotope effect was observed from the coupling reaction of 3-methoxyphenol with benzaldehyde and 2-propanol/2-propanol-d8 (kH/kD = 2.3 ± 0.3). The carbon isotope effect was observed on the benzylic carbon of the alkylation product from the coupling reaction of 3-methoxyphenol with 4-methoxybenzaldehyde (C(3) 1.021(3)) and on both benzylic and ortho-arene carbons from the coupling reaction with 4-trifluorobenzaldehdye (C(2) 1.017(3), C(3) 1.011(2)). The Hammett plot from the coupling reaction of 3-methoxyphenol with para-substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H, F, Cl, CF3) displayed a V-shaped linear slope. Catalytically relevant Ru-H complexes were observed by NMR from a stoichiometric reaction mixture of 1, 3-methoxyphenol, benzaldehyde, and 2-propanol in CD2Cl2. The DFT calculations provided a detailed catalysis mechanism featuring an electrophilic aromatic substitution of the aldehyde followed by the hydrogenolysis of the hydroxy group. The calculations also revealed a mechanistic rationale for the strong electronic effect of the benzaldehdye substrates p-X-C6H4CHO (X = OMe, CF3) in controlling the turnover-limiting step. The catalytic C-H coupling method provides an efficient synthetic protocol for 2-alkylphenols, 1,1-disubstituted benzofurans, and xanthene derivatives without employing any reactive reagents or forming wasteful byproducts.
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Aldehídos/química , Complejos de Coordinación/química , Fenoles/química , Rutenio/química , Benzofuranos/síntesis química , Benzofuranos/química , Catálisis , Deshidratación , Estructura Molecular , Fenoles/síntesis química , Xantenos/síntesis química , Xantenos/químicaRESUMEN
In the face of the global threat from drug-resistant superbugs, there remains an unmet need for simple and accessible diagnostic tools that can perform important antibiotic susceptibility testing against pathogenic bacteria and guide antibiotic treatments outside of centralized clinical laboratories. As a potential solution to this important problem, we report herein the development of a microwell array-based resazurin-aided colorimetric antibiotic susceptibility test (marcAST). At the core of marcAST is a ready-to-use microwell array device that is preassembled with custom titers of various antibiotics and splits bacterial samples upon a simple syringe injection step to initiate AST against all antibiotics. We also employ resazurin, which changes from blue to pink in the presence of growing bacteria, to accelerate and enable colorimetric readout in our AST. Even with its simplicity, marcAST can accurately measure the minimum inhibitory concentrations of reference bacterial strains against common antibiotics and categorize the antibiotic susceptibilities of clinically isolated bacteria. With more characterization and refinement, we envision that marcAST can become a potentially useful tool for performing AST without trained personnel, laborious procedures, or bulky instruments, thereby decentralizing this important test for combating drug-resistant superbugs.