RESUMO
The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects the lives of millions of indigenous people in Latin America. As medications to treat Chagas disease are limited to the application of benznidazole and nifurtimox, which are not ideal treatments for the chronic stage of the disease, the search for new antichagasic drug candidates is an important need. Ecdysone has previously been shown to interfere with the life cycle of T. cruzi. Here, we report the biological profiling and subsequent semisynthetic structure optimization of 47 ecdysteroids against T. cruzi with the aim of identifying selective trypanocidal ecdysteroids. Two moderately trypanocidal pharmacophores were identified: ecdysteroids containing a 6-tert-butyl oxime ether and a cinnamic ester moiety. These functional groups were combined into the structures of four new semisynthetic ecdysteroids (44-47), among which 44 exerted potent and selective trypanocidal activity (IC50 < 2 µM). Cellular infection assays showed that ecdysteroid 44 potently and efficiently inhibited amastigote replication as determined by trypomastigote release after cellular infection with an IC50 of 2.7 ± 0.1 µM. The compound was similarly potent to benznidazole (IC50 = 3.8 ± 0.7 µM) and more than 5-fold more cytotoxic toward T. cruzi over RAW264.7 host macrophages. Overall, the ecdysteroid cinnamate ester 44 is a novel trypanocidal lead structure that needs to be further characterized in follow-up studies.
Assuntos
Cinamatos , Tripanossomicidas , Trypanosoma cruzi , Trypanosoma cruzi/efeitos dos fármacos , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Cinamatos/farmacologia , Cinamatos/química , Estrutura Molecular , Animais , Ecdisteroides/farmacologia , Ecdisteroides/química , Camundongos , Oximas/farmacologia , Oximas/química , Ésteres/farmacologia , Ésteres/química , Doença de Chagas/tratamento farmacológico , Éteres/farmacologia , Éteres/química , Relação Estrutura-AtividadeRESUMO
Extraction of lipids and high-value products from highly wet microalgae requires significant energy for the drying pretreatment. In this study, we examined the direct extraction of lipids, ß-carotene, and polyphenolic compounds from wet Dunaliella salina using liquefied dimethyl ether (DME), which is effective in lipid extraction for biofuel production. The amount of DME-extracted ß-carotene was 7.0 mg/g, which was higher than that obtained from the chloroform-methanol extraction. Moreover, the total phenolic content extracted with DME and its antioxidant capacity were slightly higher than those extracted with chloroform-methanol. DME removed almost all the water and extracted 29.2 wt% of total lipids and 9.7 wt% of fatty acids. More lipids were extracted from wet samples by liquefied DME than by chloroform-methanol extraction. The C/N ratio of lipids extracted with DME was 112.0, higher than that of chloroform-methanol. The high C/N ratio suggests that nitrogen-containing phosphatidylcholines may be less easily extracted by liquefied DME and may be highly selective. However, the ratio of saturated fatty acids was 34.8%, lower than that of chloroform-methanol. Na+ and Mg2+ in the culture medium were not extracted using DME. Thus, using the extract with DME has both advantages and disadvantages compared to using the extract with chloroform-methanol; however, it has satisfactory extraction properties. DME is expected to be an environment-friendly alternative solvent because it does not require drying, which is necessary for conventional extraction solvents.
Assuntos
Lipídeos , Microalgas , Polifenóis , beta Caroteno , beta Caroteno/química , Microalgas/química , Polifenóis/isolamento & purificação , Polifenóis/química , Lipídeos/química , Antioxidantes/isolamento & purificação , Antioxidantes/química , Antioxidantes/farmacologia , Éteres/química , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/química , Solventes/química , Clorofórmio/química , Éteres MetílicosRESUMO
Coordination polymers (CPs) and metal-organic frameworks (MOFs) constitute a new class of antibacterial materials. Interest in them stems from their wide range of topology, dimensionality, and secondary building units that can be tuned by an appropriate choice of metal ions and ligands. In particular, silver-based species feature good antibacterial properties. In this study, we explored the coordination of three acetylenic dithioether RSCH2C≡CCH2SR [R = phenyl (LPh), cyclohexyl (LCy), or tert-butyl (LtBu)] ligands on several silver salts (silver tosylate, silver triflate, and silver trifluoroacetate). The crystallographic characterization evidenced the formation of a molecular macrocycle and six CPs with different dimensionalities, ranging from one to two dimensions. In most cases, they are composed of four-coordinated silver atoms in a tetrahedral environment. Their antibacterial activity was investigated against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. All CPs present good antibacterial properties against the tested bacteria with minimal inhibitory concentrations ranging from 5 to 40 µg of Ag/mL. Interestingly, we found that these values could not be correlated to their architecture or morphology or to the amount of silver released. The cytotoxicity of these compounds was also evaluated on normal human dermal fibroblasts, and three of these CPs were found to be biocompatible.
Assuntos
Antibacterianos , Escherichia coli , Testes de Sensibilidade Microbiana , Prata , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Escherichia coli/efeitos dos fármacos , Humanos , Staphylococcus aureus/efeitos dos fármacos , Prata/química , Prata/farmacologia , Ligantes , Cristalografia por Raios X , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Estrutura Molecular , Sais/farmacologia , Sais/química , Sais/síntese química , Modelos Moleculares , Sobrevivência Celular/efeitos dos fármacos , Éteres/química , Éteres/farmacologiaRESUMO
Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma.
Assuntos
Melanoma , Esqualeno , Animais , Camundongos , Esqualeno/química , Esqualeno/farmacologia , Humanos , Linhagem Celular Tumoral , Melanoma/patologia , Melanoma/tratamento farmacológico , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Melanoma Experimental/patologia , Melanoma Experimental/tratamento farmacológico , Metástase Neoplásica , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Éteres/farmacologia , Éteres/química , Proliferação de Células/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/químicaRESUMO
In this study, a new potentiometric sensor was developed for the determination of the local anesthetic drug procaine in pharmaceutical samples. Procaine (Pr)-Tetraphenlyborate (TPB) ion-pair was synthesized and used as a sensor material. Potentiometric sensors using the synthesized ion pair (Pr-TPB), poly(vinyl chloride) (PVC) and o-nitrophenyloctyl ether (o-NPOE) in different proportions were prepared and their performance properties were tested. Among the prepared sensors, the best potentiometric response characteristics were obtained with the sensor composition Pr-TPB:PVC:o-NPOE in the ratio of 6.0:32.0:62.0 (w/w %). The new procaine sensor developed in the present study had a near-Nernstian behavior of 54.1 ± 3.3 mV/per decade and a low detection limit of 3.18 × 10-5 mol L-1 in the concentration range of 1.0 × 10-1-1.0 × 10-4 mol L-1. Additionally, the sensor had a response time of less than 10 s and could work in a wide pH range for two different concentration values without being affected by pH changes. Finally, the new procaine potentiometric sensor was used to detect procaine in injection samples and successfully determined procaine concentrations with high recoveries.
Assuntos
Anestésicos Locais , Cloreto de Polivinila , Potenciometria , Procaína , Procaína/análise , Potenciometria/métodos , Anestésicos Locais/análise , Cloreto de Polivinila/química , Tetrafenilborato/química , Concentração de Íons de Hidrogênio , Limite de Detecção , ÉteresRESUMO
Hydrogen sulfide (H2S) is a gaseous signaling molecule that regulates various physiological and pathological processes in the central nervous system. It is vital to develop an effective method to detect H2S in vivo to elucidate its critical role. However, current fluorescent probes for accurate quantification of H2S still face big challenges due to complicated fabrication, small Stokes shift, unsatisfactory selectivity, and especially delayed response time. Herein, based on simple postsynthetic modification, we present an innovative strategy by confining H2S-triggered thiolysis of dinitrophenyl (DNP) ether within a luminescent metal-organic framework (MOF) to address those issues. Due to the cleavage of the DNP moiety by H2S, the nanoprobe gives rise to a remarkable fluorescence turn-on signal with a large Stokes shift of 190 nm and also provides high selectivity to H2S against various interferents including competing biothiols. In particular, by virtue of the unique structural property of the MOF, it exhibits an ultrafast sensing ability for H2S (only 5 s). Moreover, the fluorescence enhancement efficiency displays a good linear correlation with H2S concentration in the range of 0-160 µM with a detection limit of 0.29 µM. Importantly, these superior sensing performances enable the nanoprobe to measure the basal value and monitor the change of H2S level in the rat brain.
Assuntos
Encéfalo , Corantes Fluorescentes , Sulfeto de Hidrogênio , Estruturas Metalorgânicas , Sulfeto de Hidrogênio/análise , Sulfeto de Hidrogênio/química , Animais , Ratos , Estruturas Metalorgânicas/química , Encéfalo/metabolismo , Corantes Fluorescentes/química , Compostos de Sulfidrila/química , Éteres/química , Dinitrobenzenos/química , Dinitrobenzenos/análise , Limite de Detecção , Espectrometria de FluorescênciaRESUMO
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.
Assuntos
Ácido Fluorídrico , Agentes Neurotóxicos , Prótons , Ácido Fluorídrico/química , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Éteres/químicaRESUMO
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.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Peptídeos , Peptídeos/química , Peptídeos/isolamento & purificação , Membranas Artificiais , Técnicas Eletroquímicas , Tamanho da Partícula , Concentração de Íons de Hidrogênio , Éteres , OrganofosfatosRESUMO
Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.
Assuntos
Antibacterianos , Macrolídeos , Testes de Sensibilidade Microbiana , Quinolonas , Streptococcus pneumoniae , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Macrolídeos/química , Macrolídeos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Estrutura Molecular , Desenho de Fármacos , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Relação Dose-Resposta a Droga , Éteres/química , Éteres/farmacologia , Éteres/síntese químicaRESUMO
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.
Assuntos
Produtos Biológicos , Fusarium , Produtos Biológicos/química , Estrutura Molecular , Fusarium/química , Éteres/química , Oxigênio/química , Espectroscopia de Ressonância MagnéticaRESUMO
Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1 a) and of five benzofuran derivatives (2 a, 2 b, 2 c, 2 f and 2 g) by single crystal X-ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2 b, 2 e, and 2 g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition >60 %). Compound 2 e showed an IC50 of 0.2â µM and was selected for further analysis, results reinforce its anticancer potential.
Assuntos
Acetofenonas , Antineoplásicos , Benzofuranos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Éteres , Humanos , Benzofuranos/química , Benzofuranos/farmacologia , Benzofuranos/síntese química , Acetofenonas/química , Acetofenonas/farmacologia , Acetofenonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Éteres/química , Éteres/farmacologia , Éteres/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Cristalografia por Raios X , Linhagem Celular Tumoral , Células HCT116 , Células MCF-7RESUMO
This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.
Assuntos
Ácidos Borônicos , Éteres , Oxirredução , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Humanos , Éteres/química , Ácidos Borônicos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células/efeitos dos fármacosRESUMO
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.
Assuntos
Desenho de Fármacos , Echinochloa , Herbicidas , Simulação de Acoplamento Molecular , Naftoquinonas , Plantas Daninhas , Herbicidas/química , Herbicidas/farmacologia , Herbicidas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia , Echinochloa/efeitos dos fármacos , Echinochloa/crescimento & desenvolvimento , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Relação Estrutura-Atividade , Éteres/química , Éteres/farmacologia , Complexo de Proteína do Fotossistema II/química , Complexo de Proteína do Fotossistema II/antagonistas & inibidores , Complexo de Proteína do Fotossistema II/metabolismo , Estrutura Molecular , Proteínas de Plantas/química , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacosRESUMO
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.
Assuntos
Microalgas , Siloxanas , Siloxanas/química , Microalgas/química , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Éteres/química , Éteres/farmacologia , Vidro/química , FotossínteseRESUMO
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.
Assuntos
Desenho de Fármacos , Inseticidas , Oximas , Pirazóis , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Oximas/química , Oximas/farmacologia , Oximas/síntese química , Inseticidas/química , Inseticidas/síntese química , Inseticidas/farmacologia , Animais , Relação Estrutura-Atividade , Éteres/química , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Mariposas/efeitos dos fármacosRESUMO
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.
Assuntos
Disponibilidade Biológica , Éteres , Fluorocarbonos , Fígado , Fígado/metabolismo , Fluorocarbonos/química , Fluorocarbonos/farmacocinética , Fluorocarbonos/metabolismo , Humanos , Administração Oral , Dispositivos Lab-On-A-Chip , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , AnimaisRESUMO
In drug discovery, human organ-on-a-chip (organ chip) technology has emerged as an essential tool for preclinical testing, offering a realistic representation of human physiology, real-time monitoring, and disease modeling. Polydimethylsiloxane (PDMS) is commonly used in organ chip fabrication owing to its biocompatibility, flexibility, transparency, and ability to replicate features down to the nanoscale. However, the porous nature of PDMS leads to unintended absorption of small molecules, critically affecting the drug response analysis. Addressing this challenge, the precision drug testing organ chip (PreD chip) is introduced, an innovative platform engineered to minimize small molecule absorption while facilitating cell culture. This chip features a PDMS microchannel wall coated with a perfluoropolyether-based lubricant, providing slipperiness and antifouling properties. It also incorporates an ECM-coated semi-porous membrane that supports robust multicellular cultures. The PreD chip demonstrates its outstanding antifouling properties and resistance to various biological fluids, small molecule drugs, and plasma proteins. In simulating the human gut barrier, the PreD chip demonstrates highly enhanced sensitivity in tests for dexamethasone toxicity and is highly effective in assessing drug transport across the human blood-brain barrier. These findings emphasize the potential of the PreD chip in advancing organ chip-based drug testing methodologies.
Assuntos
Dimetilpolisiloxanos , Avaliação Pré-Clínica de Medicamentos , Dispositivos Lab-On-A-Chip , Humanos , Dimetilpolisiloxanos/química , Éteres/química , Fluorocarbonos/química , Sistemas MicrofisiológicosRESUMO
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.
Assuntos
Nível de Efeito Adverso não Observado , Animais , Ratos , Feminino , Coelhos , Masculino , Humanos , Camundongos , Solventes/toxicidade , Relação Dose-Resposta a Droga , Exposição Ocupacional/efeitos adversos , Éteres/toxicidadeRESUMO
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.
Assuntos
Antineoplásicos , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Antineoplásicos/farmacologia , Animais , Humanos , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Éteres/química , Éteres/farmacologia , Relação Estrutura-AtividadeRESUMO
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.