RESUMEN
Tertiary and allylic hydroxyl groups readily eliminate water during positive ion mode mass spectrometry and may show similar NMR spectra to their corresponding ethers. In a routine structure elucidation workflow, these factors can cause researchers to incorrectly assign diol moieties as ethers or vice versa, leading to inaccurate chemical structures. After facing this problem during our work on oxygenated sesquiterpenoids from a Fusarium sp. fungal strain, we became aware of this challenging issue. We examined the literature for oxygenated natural products bearing these functional groups, and with the aid of density functional calculations of NMR chemical shifts, we now report the structures of 15 natural products that should be revised. We further establish that derivatizing sub-micromolar amounts of alcohols to their sulfates can be used to distinguish these from their corresponding ethers using liquid chromatography negative ion mode mass spectrometry. Finally, we isolated lignoren/cyclonerodiol from the Fusarium sp. culture extract and supported its revised identity as cyclonerodiol using this sulfation approach. Our results suggest that ether-diol ambiguity could be a prevalent issue affecting the structure elucidation of oxygenated natural products and highlight the importance of using complementary techniques, such as sulfation with LC-(-)-ESI-MS or density functional calculations of NMR chemical shifts.
Asunto(s)
Productos Biológicos , Fusarium , Productos Biológicos/química , Estructura Molecular , Fusarium/química , Éteres/química , Oxígeno/química , Espectroscopía de Resonancia MagnéticaRESUMEN
Luminescence-based sensing provides a method for the rapid detection of nerve agents. Previous approaches have generally focused on sensing materials containing a nucleophilic group that can react with the electrophilic phosphorus atom found in nerve agents. Herein we report an alternative approach for the detection of phosphonofluoridate-based G-series nerve agents that utilizes the fact they contain hydrogen fluoride. We have developed silylated sensing materials based on an excited-state intramolecular proton transfer (ESIPT) reporter compound, 2-[benzo[d]thiazol-2-yl]phenol. Thin films of differently silylated 2-[benzo[d]thiazol-2-yl]phenol were found to react with the hydrogen fluoride found in di-iso-propyl fluorophosphate (DFP), a simulant of sarin (G-series nerve agent), and turn on the ESIPT emission of the reporter compound. The use of the ESIPT emission reduced the impact of background fluorescence and improved the sensitivity of the detection. The effectiveness of the approach was dependent on the stability of the silyl protecting group used, with the least sterically hindered (trimethylsilyl) found to be too unstable to the ambient environment while the most sterically hindered, e.g., tri-iso-propylsilyl and tert-butyldiphenylsilyl were found to be insufficiently reactive to be useful in a real detection scenario. The sensing material composed of the tert-butyl dimethylsilyl protected 2-[benzo[d]thiazol-2-yl]phenol was found to have the best balance between stability under ambient conditions, and reactivity and selectivity to hydrogen fluoride. In a 3 s exposure, it could detect hydrogen fluoride down to a concentration of around 23 ppm in DFP with 99% purity.
Asunto(s)
Ácido Fluorhídrico , Agentes Nerviosos , Protones , Ácido Fluorhídrico/química , Agentes Nerviosos/análisis , Agentes Nerviosos/química , Éteres/químicaRESUMEN
This study investigated the capability of electromembrane extraction (EME) as a general technique for peptides, by extracting complex pools of peptides comprising in total of 5953 different substances, varying in size from seven to 16 amino acids. Electromembrane extraction was conducted from a sample adjusted to pH 3.0 and utilized a liquid membrane consisting of 2-nitrophenyl octyl ether and carvacrol (1:1 w/w), containing 2% (w/w) di(2-ethylhexyl) phosphate. The acceptor phase was 50 mM phosphoric acid (pH 1.8), the extraction time was 45 min, and 10 V was used. High extraction efficiency, defined as a higher peptide signal in the acceptor than the sample after extraction, was achieved for 3706 different peptides. Extraction efficiencies were predominantly influenced by the hydrophobicity of the peptides and their net charge in the sample. Hydrophobic peptides were extracted with a net charge of +1, while hydrophilic peptides were extracted when the net charge was +2 or higher. A computational model based on machine learning was developed to predict the extractability of peptides based on peptide descriptors, including the grand average of hydropathy index and net charge at pH 3.0 (sample pH). This research shows that EME has general applicability for peptides and represents the first steps toward in silico prediction of extraction efficiency.
Asunto(s)
Interacciones Hidrofóbicas e Hidrofílicas , Péptidos , Péptidos/química , Péptidos/aislamiento & purificación , Membranas Artificiales , Técnicas Electroquímicas , Tamaño de la Partícula , Concentración de Iones de Hidrógeno , Éteres , OrganofosfatosRESUMEN
Photosynthesis system II (PS II) is an important target for the development of bioherbicides. In this study, a series of natural naphthoquinone derivatives containing diaryl ether were designed and synthesized based on the binding model of lawsone and PS II D1. Bioassays exhibited that most compounds had more than 80% inhibition of Portulaca oleracea and Echinochloa crusgalli roots at a dose of 100 µg/mL and compounds B4, B5, and C3 exhibited superior herbicidal activities against dicotyledonous and monocotyledon weeds to commercial atrazine. In particular, compound B5 exhibited excellent herbicidal activity at a dosage of 150 g a.i./ha. In addition, compared with atrazine, compound B5 causes less damage to crops. Molecular docking studies revealed that compound B5 effectively interacted with Pisum sativum PS II D1 via diverse interaction models, such as π-π stacking and hydrogen bonds. Molecular dynamics simulation studies and chlorophyll fluorescence measurements revealed that compound B5 acted on PS II. This is the first report of natural naphthoquinone derivatives targeting PS II and compound B5 may be a candidate molecule for the development of new herbicides targeting PS II.
Asunto(s)
Diseño de Fármacos , Echinochloa , Herbicidas , Simulación del Acoplamiento Molecular , Naftoquinonas , Malezas , Herbicidas/química , Herbicidas/farmacología , Herbicidas/síntesis química , Naftoquinonas/química , Naftoquinonas/farmacología , Echinochloa/efectos de los fármacos , Echinochloa/crecimiento & desarrollo , Malezas/efectos de los fármacos , Malezas/crecimiento & desarrollo , Relación Estructura-Actividad , Éteres/química , Éteres/farmacología , Complejo de Proteína del Fotosistema II/química , Complejo de Proteína del Fotosistema II/antagonistas & inhibidores , Complejo de Proteína del Fotosistema II/metabolismo , Estructura Molecular , Proteínas de Plantas/química , Raíces de Plantas/química , Raíces de Plantas/efectos de los fármacosRESUMEN
Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure-activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post-polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End-16, which demonstrates significant potential for treating bladder cancer (BLCA). End-16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End-16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti-BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.
Asunto(s)
Antineoplásicos , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Antineoplásicos/farmacología , Animales , Humanos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Éteres/química , Éteres/farmacología , Relación Estructura-ActividadRESUMEN
Bis-(2-Chloroisopropyl) ether (BCIPE) was used as a solvent for fats, greases, paint, varnish removers, and in spotting and cleaning solutions. However, BCIPE has not been commercially manufactured or used for numerous years. In experimental animal studies, BCIPE is moderately toxic following acute oral, dermal, and inhalation routes of exposure. BCIPE is a severe eye irritant but not a dermal irritant or dermal sensitizer. BCIPE was not genotoxic or mutagenic in in vitro and in vivo assays; it was not toxic in a 3-generation reproductive dietary study in rats. Short-term, repeated inhalation and oral exposure in rats produced increased liver and kidney weights and congestion; dermal exposure in rabbits did not produce any observable adverse effects. BCIPE did not produce a statistically significant increase in tumors in two different 2-year dietary studies in mice and rats. In mice, technical grade BCIPE produced increased incidences of alveolar/bronchiolar adenomas in females, hepatocellular carcinomas in males, and a low incidence of forestomach hyperplasia (in both sexes at the high-dose). Further investigation with technical grade BCIPE concluded that these effects were species- and dose-specific with limited, if any, relevance to humans. The NOAEL of 400 ppm (15 mg/kg/day) from the 2-year dietary study in female rats was considered the point of departure for the health-based WEEL derivation. After adjustment for duration of exposure, interindividual variability, and intraindividual variability, an 8-h time-weighted average (TWA) WEEL value of 3 ppm (21 mg/m3) was derived. This exposure limit is expected to provide a significant margin of safety against any potential adverse health effects in workers.
Asunto(s)
Nivel sin Efectos Adversos Observados , Animales , Ratas , Femenino , Conejos , Masculino , Humanos , Ratones , Solventes/toxicidad , Relación Dosis-Respuesta a Droga , Exposición Profesional/efectos adversos , Éteres/toxicidadRESUMEN
In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through 1H NMR, 13C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against Mythimna separata, Tetranychus cinnabarinus, Plutella xylostella, and Aphis medicaginis at a dosage of 500 µg/mL, and some title compounds were active towards Nilaparvata lugens at 500 µg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against M. separata, T. cinnabarinus, or A. medicaginis at 100 µg/mL, with the mortalities of compounds 8a, 8c, 8d, 8e, 8f, 8g, 8o, 8s, 8v, 8x, and 8z against A. medicaginis, in particular, all reaching 100%. Even when the dosage was lowered to 20 µg/mL, compound 8s also expressed 50% insecticidal activity against M. separata, and compounds 8a, 8e, 8f, 8o, 8v, and 8x displayed more than 60% inhibition rates against A. medicaginis. The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future.
Asunto(s)
Diseño de Fármacos , Insecticidas , Oximas , Pirazoles , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Insecticidas/química , Insecticidas/síntesis química , Insecticidas/farmacología , Animales , Relación Estructura-Actividad , Éteres/química , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Mariposas Nocturnas/efectos de los fármacosRESUMEN
In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 µM to 10 µM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.
Asunto(s)
Disponibilidad Biológica , Éteres , Fluorocarburos , Hígado , Hígado/metabolismo , Fluorocarburos/química , Fluorocarburos/farmacocinética , Fluorocarburos/metabolismo , Humanos , Administración Oral , Dispositivos Laboratorio en un Chip , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , AnimalesRESUMEN
In the presented study, the effectiveness of a siloxane polyether (HOL7) coating on glass against microbiological colonization was assessed using microalgae as a key component of widespread aerial biofilms. The siloxane polyether was successfully synthesized by a hydrosilylation reaction in the presence of Karstedt's catalyst. The product structure was confirmed by NMR spectroscopy and GPC analysis. In addition, the thermal stability of HOL7 was studied by thermogravimetric measurement. Subsequently, the surfaces of glass plates were modified with the obtained organosilicon derivative. In the next step, a microalgal experiment was conducted. A mixture of four strains of algal taxa isolated from building materials was used for the experiment-Chlorodium saccharophilum PNK010, Klebsormidium flaccidum PNK013, Pseudostichococcus monallantoides PNK037, and Trebouxia aggregata PNK080. The choice of these algae followed from their wide occurrence in terrestrial environments. Application of an organofunctional siloxane compound on the glass reduced, more or less effectively, the photosynthetic activity of algal cells, depending on the concentration of the compound. Since the structure of the compound was not based on biocide-active agents, its effectiveness was associated with a reduction in water content in the cells.
Asunto(s)
Microalgas , Siloxanos , Siloxanos/química , Microalgas/química , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Éteres/química , Éteres/farmacología , Vidrio/química , FotosíntesisRESUMEN
Activation of the aminopeptidase (AP) activity of leukotriene A4 hydrolase (LTA4H) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC50 of 0.12 µM. An X-ray crystal structure of LTA4H in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTA4H, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B4 (LTB4) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.
Asunto(s)
Epóxido Hidrolasas , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Animales , Ratones , Relación Estructura-Actividad , Humanos , Estructura Molecular , Aminopeptidasas/metabolismo , Aminopeptidasas/antagonistas & inhibidores , Éteres/farmacología , Éteres/química , Éteres/síntesis química , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Cristalografía por Rayos XRESUMEN
Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.
Asunto(s)
Liberación de Fármacos , Hidrogeles , Hidrogeles/química , Hidrogeles/síntesis química , Animales , Ratones , Acetales/química , Paclitaxel/química , Paclitaxel/farmacocinética , Éteres/química , Polietilenglicoles/química , Polímeros/química , Polímeros/síntesis química , Portadores de Fármacos/químicaRESUMEN
The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 µg/mL that was superior to that of the agricultural fungicide boscalid (2.2 µg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 µM that was superior to that of boscalid (7.9 µM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Fungicidas Industriales , Oximas , Pirazoles , Succinato Deshidrogenasa , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/química , Succinato Deshidrogenasa/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Relación Estructura-Actividad , Oximas/química , Oximas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Proteínas Fúngicas/química , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/metabolismo , Simulación del Acoplamiento Molecular , Rhizoctonia/efectos de los fármacos , Éteres/química , Éteres/farmacología , Estructura MolecularRESUMEN
Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is one of the most important targets for the discovery of green herbicides. In order to find novel PPO inhibitors with a higher herbicidal activity, a series of novel N-phenyltriazinone derivatives containing oxime ether and oxime ester groups were designed and synthesized based on the strategy of pharmacophore and scaffold hopping. Bioassay results revealed that some compounds showed herbicidal activities; especially, compound B16 exhibited broad-spectrum and excellent 100% herbicidal effects to Echinochloa crusgalli, Digitaria sanguinalis, Setaria faberii, Abutilon juncea, Amaranthus retroflexus, and Portulaca oleracea at a concentration of 37.5 g a.i./ha, which were comparable to trifludimoxazin. Nicotiana tabacum PPO (NtPPO) enzyme inhibitory assay indicated that B16 showed an excellent enzyme inhibitory activity with a value of 32.14 nM, which was similar to that of trifludimoxazin (31.33 nM). Meanwhile, compound B16 revealed more safety for crops (rice, maize, wheat, peanut, soybean, and cotton) than trifludimoxazin at a dose of 150 g a.i./ha. Moreover, molecular docking and molecular dynamics simulation further showed that B16 has a very strong and stable binding to NtPPO. It indicated that B16 can be used as a potential PPO inhibitor and herbicide candidate for application in the field.
Asunto(s)
Inhibidores Enzimáticos , Herbicidas , Simulación del Acoplamiento Molecular , Oximas , Proteínas de Plantas , Malezas , Protoporfirinógeno-Oxidasa , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Protoporfirinógeno-Oxidasa/química , Protoporfirinógeno-Oxidasa/metabolismo , Herbicidas/farmacología , Herbicidas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oximas/química , Oximas/farmacología , Relación Estructura-Actividad , Malezas/efectos de los fármacos , Malezas/enzimología , Proteínas de Plantas/química , Proteínas de Plantas/antagonistas & inhibidores , Proteínas de Plantas/metabolismo , Triazinas/química , Triazinas/farmacología , Ésteres/química , Ésteres/farmacología , Estructura Molecular , Éteres/química , Éteres/farmacología , Descubrimiento de DrogasRESUMEN
Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 µg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 µg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 µg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.
Asunto(s)
Fungicidas Industriales , Simulación del Acoplamiento Molecular , Pirazoles , Succinato Deshidrogenasa , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Humanos , Relación Estructura-Actividad , Fungicidas Industriales/farmacología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ascomicetos/efectos de los fármacos , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Relación Dosis-Respuesta a Droga , Éteres/química , Éteres/farmacología , Éteres/síntesis química , RhizoctoniaRESUMEN
To promote the rationalized and standardized application of star anise in braised poultry products, the effects of different concentrations of star anise (0 %, 0.1 %, 0.2 %, 0.3 %, and 0.4 %) on the aroma and taste compounds intensities of braised duck legs from the perspective of flavor were evaluated by using flavor omics approach combined with multivariate statistics. The volatile flavor results showed that there were 17 key aroma compounds with odor activity values (OAVs) > 1, including aldehydes, alcohols, ketones, furans, hydrocarbons, and ethers. Most of the aroma compounds related to lipid oxidation were significantly inhibited when the concentration of star anise reached 0.2 %, especially inhibited the concentrations of the unpleasant off-odorants containing hexanal, heptanal, 1-octen-3-ol, and 2-pentyl-furan by 30.27 %, 15.08 %, 30.30 %, and 41.63 %, respectively. And the flavor intensities of these compounds were negatively correlated with the concentration of star anise. Additionally, star anise gave braised duck legs characteristic aroma such as floral and herbal notes. The taste results revealed that the maximum umami value (4.36 g MSG/100 g) of braised duck legs was observed when the concentration of star anise reached 0.2 %. Six flavor markers were obtained via PLS-DA model, and the flavors of braised duck legs with different concentrations of star anise were distinguished. This study provided a vital theoretical basis for the rational application and flavor control of star anise in braised poultry products.
Asunto(s)
Patos , Illicium , Animales , Odorantes , Gusto , ÉteresRESUMEN
Isatropolone C from Streptomyces sp. CPCC 204095 features a fused cyclopentadienone-tropolone-oxacyclohexadiene tricyclic moiety in its structure. Herein, we report an isatropolone C dimer derivative, di-isatropolone C, formed spontaneously from isatropolone C in methanol. Notably, the structure of di-isatropolone C resolved by NMR reveals a newly formed cyclopentane ring to associate the two isatropolone C monomers. The configurations of four chiral carbons, including a ketal one, in the cyclopentane ring are assigned using quantum NMR calculations and DP4+ probability. The plausible molecular mechanism for di-isatropolone C formation is proposed, in which complex dehydrogenative C-C bond coupling may have happened to connect the two isatropolone C monomers. Like isatropolone C, di-isatropolone C shows the biological activity of inducing autophagy in HepG2 cells.
Asunto(s)
Autofagia , Carbono , Compuestos Heterocíclicos de Anillos Fusionados , Ciclopentanos , Éteres , PolímerosRESUMEN
This report demonstrates the first asymmetric synthesis of enantiopure structured triacylglycerols (TAGs) of the ABC type presenting three non-identical fatty acids, two of which are unsaturated. The unsaturated fatty acids included monounsaturated oleic acid (C18:1 n-9) and polyunsaturated linoleic acid (C18:2 n-6). This was accomplished by a six-step chemoenzymatic approach starting from (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The synthesis also benefited from the use of the p-methoxybenzyl (PMB) ether protective group, which enabled the incorporation of two different unsaturated fatty acids into the glycerol skeleton. The total of six such TAGs were prepared, four constituting the unsaturated fatty acids in the sn-1 and sn-2 positions, with a saturated fatty acid in the remaining sn-3 position of the glycerol backbone. In the two remaining TAGs, the different unsaturated fatty acids accommodated the sn-1 and sn-3 end positions, with the saturated fatty acid present in the sn-2 position. Enantiopure TAGs are urgently demanded as standards for the enantiospecific analysis of intact TAGs in fats and oils.
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Ácidos Grasos , Glicerol , Éteres , Ácido Linoleico , TriglicéridosRESUMEN
Oxygen in marine sediments regulates many key biogeochemical processes, playing a crucial role in shaping Earth's climate and benthic ecosystems. In this context, branched glycerol dialkyl glycerol tetraethers (brGDGTs), essential biomarkers in paleoenvironmental research, exhibit an as-yet-unresolved association with sediment oxygen conditions. Here, we investigated brGDGTs in sediments from three deep-sea regions (4045 to 10,100 m water depth) dominated by three respective trench systems and integrated the results with in situ oxygen microprofile data. Our results demonstrate robust correlations between diffusive oxygen uptake (DOU) obtained from microprofiles and brGDGT methylation and isomerization degrees, indicating their primary production within sediments and their strong linkage with microbial diagenetic activity. We establish a quantitative relationship between the Isomerization and Methylation index of Branched Tetraethers (IMBT) and DOU, suggesting its potential validity across deep-sea environments. Increased brGDGT methylation and isomerization likely enhance the fitness of source organisms in deep-sea habitats. Our study positions brGDGTs as a promising tool for quantifying benthic DOU in deep-sea settings, where DOU is a key metric for assessing sedimentary organic carbon degradation and microbial activity.
Asunto(s)
Bacterias , Sedimentos Geológicos , Oxígeno , Sedimentos Geológicos/microbiología , Sedimentos Geológicos/química , Oxígeno/metabolismo , Oxígeno/química , Bacterias/metabolismo , Bacterias/genética , Ecosistema , Éteres/metabolismo , Éteres/química , Lípidos/química , Metilación , Agua de Mar/microbiología , Agua de Mar/químicaRESUMEN
The advent of mRNA for nucleic acid (NA) therapeutics has unlocked many diverse areas of research and clinical investigation. However, the shorter intracellular half-life of mRNA compared with other NAs may necessitate more frequent dosing regimens. Because lipid nanoparticles (LNPs) are the principal delivery system used for mRNA, this could lead to tolerability challenges associated with an accumulated lipid burden. This can be addressed by introducing enzymatically cleaved carboxylic esters into the hydrophobic domains of lipid components, notably, the ionizable lipid. However, enzymatic activity can vary significantly with age, disease state, and species, potentially limiting the application in humans. Here we report an alternative approach to ionizable lipid degradability that relies on nonenzymatic hydrolysis, leading to a controlled and highly efficient lipid clearance profile. We identify highly potent examples and demonstrate their exceptional tolerability in multiple preclinical species, including multidosing in nonhuman primates (NHP).
Asunto(s)
Liposomas , Nanopartículas , Silicio , Animales , Humanos , Éter , ARN Mensajero/genética , ARN Mensajero/química , Lípidos/química , Nanopartículas/química , Éteres de Etila , Éteres , ARN Interferente Pequeño/genéticaRESUMEN
BACKGROUND: Pregnenolone and progesterone are the life-important steroid hormones regulating essential vital functions in mammals, and widely used in different fields of medicine. Microbiological production of these compounds from sterols is based on the use of recombinant strains expressing the enzyme system cholesterol hydroxylase/C20-C22 lyase (CH/L) of mammalian steroidogenesis. However, the efficiency of the known recombinant strains is still low. New recombinant strains and combination approaches are now needed to produce these steroid hormones. RESULTS: Based on Mycolicibacterium smegmatis, a recombinant strain was created that expresses the steroidogenesis system (CYP11A1, adrenodoxin reductase, adrenodoxin) of the bovine adrenal cortex. The recombinant strain transformed cholesterol and phytosterol to form progesterone among the metabolites. When 3-methoxymethyl ethers of sterols were applied as bioconversion substrates, the corresponding 3-ethers of pregnenolone and dehydroepiandrosterone (DHEA) were identified as major metabolites. Under optimized conditions, the recombinant strain produced 85.2 ± 4.7 mol % 3-methoxymethyl-pregnenolone within 48 h, while production of 3-substituted DHEA was not detected. After the 3-methoxymethyl function was deprotected by acid hydrolysis, crystalline pregnenolone was isolated in high purity (over 98%, w/w). The structures of steroids were confirmed using TLC, HPLC, MS and 1H- and 13C-NMR analyses. CONCLUSION: The use of mycolicybacteria as a microbial platform for the expression of systems at the initial stage of mammalian steroidogenesis ensures the production of valuable steroid hormones-progesterone and pregnenolone from cholesterol. Selective production of pregnenolone from cholesterol is ensured by the use of 3-substituted cholesterol as a substrate and optimization of the conditions for its bioconversion. The results open the prospects for the generation of the new microbial biocatalysts capable of effectively producing value-added steroid hormones.