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1.
Nat Chem ; 13(1): 47-55, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33353970

RESUMO

Polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many polyether ionophores possess potent antimicrobial activity and a few selected compounds have the ability to target aggressive cancer cells. Nevertheless, ionophore function is believed to be associated with idiosyncratic cellular toxicity and, consequently, human clinical development has not been pursued. Here, we demonstrate that structurally novel polyether ionophores can be efficiently constructed by recycling components of highly abundant polyethers to afford analogues with enhanced antibacterial selectivity compared to a panel of natural polyether ionophores. We used classic degradation reactions of the natural polyethers lasalocid and monensin and combined the resulting fragments with building blocks provided by total synthesis, including halogen-functionalized tetronic acids as cation-binding groups. Our results suggest that structural optimization of polyether ionophores is possible and that this area represents a potential opportunity for future methodological innovation.


Assuntos
Antibacterianos/síntese química , Éteres/química , Ionóforos/química , Aldeídos/química , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Furanos/síntese química , Furanos/química , Humanos , Ionóforos/síntese química , Ionóforos/farmacologia , Lasalocida/síntese química , Lasalocida/química , Conformação Molecular , Monensin/síntese química , Monensin/química , Oxirredução
2.
Nature ; 585(7826): 603-608, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939090

RESUMO

Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.


Assuntos
Éteres/metabolismo , Ferroptose , Peroxissomos/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem Celular , Éteres/química , Feminino , Edição de Genes , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Peroxidação de Lipídeos , Masculino , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Peroxissomos/genética
3.
Toxicon ; 188: 122-126, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32991938

RESUMO

During a survey of the production of goniodomin A (GDA) by Alexandrium pseudogonyaulax in Danish coastal waters, Krock et al. (2018) obtained mass spectral evidence for the presence of a truncated congener, herein termed GD754, having a molecular weight 14 Da lower than GDA and assigned it as goniodomin B (GDB). An erroneous structure of GDB involving deletion of a methylene group between rings B and D had previously been reported by Espiña et al. (2016) but without experimental details. HPLC properties reported by Krock for GD754 point to it being a homolog of GDA. Comparison of mass spectral fragmentation data reported for GD754 with fragmentation data for GDA, show it to be a truncated form of GDA with the deletion involving a CH2 group from ring F or one of the two methyl substituents on ring F, not elsewhere on the molecule. On biosynthetic grounds, the GD754 congener is proposed to be 34-desmethyl-GDA. Further experimental work will be required to confirm this hypothesis.


Assuntos
Dinoflagelados , Éteres/toxicidade , Macrolídeos/toxicidade , Éteres/química , Macrolídeos/química , Toxinas Biológicas
4.
Nat Commun ; 11(1): 3362, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620794

RESUMO

Intrinsically and fully stretchable active-matrix-driven displays are an important element to skin electronics that can be applied to many emerging fields, such as wearable electronics, consumer electronics and biomedical devices. Here, we show for the first time a fully stretchable active-matrix-driven organic light-emitting electrochemical cell array. Briefly, it is comprised of a stretchable light-emitting electrochemical cell array driven by a solution-processed, vertically integrated stretchable organic thin-film transistor active-matrix, which is enabled by the development of chemically-orthogonal and intrinsically stretchable dielectric materials. Our resulting active-matrix-driven organic light-emitting electrochemical cell array can be readily bent, twisted and stretched without affecting its device performance. When mounted on skin, the array can tolerate to repeated cycles at 30% strain. This work demonstrates the feasibility of skin-applicable displays and lays the foundation for further materials development.


Assuntos
Materiais Biomiméticos/química , Elastômeros/química , Transistores Eletrônicos , Dispositivos Eletrônicos Vestíveis , Eletroquímica , Éteres/química , Estudos de Viabilidade , Fluorcarbonetos/química , Luminescência , Teste de Materiais , Ácidos Polimetacrílicos/química , Pele
5.
Nat Commun ; 11(1): 2890, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513962

RESUMO

Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.


Assuntos
Álcoois/química , Éteres/química , Hidrocarbonetos Policíclicos Aromáticos/química , Sulfóxidos/química , Elementos de Transição/química , Carbono/química , Catálise , Química Farmacêutica/métodos , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/química , Metais/química , Modelos Químicos , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Enxofre/química
6.
Food Chem ; 329: 127132, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504917

RESUMO

It has been proven that at increased temperature, sterols can undergo various chemical reactions e.g., oxidation, dehydrogenation, dehydration and polymerisation. The objectives of this study are to prove the existence of dimers and to quantitatively analyse the dimers (3ß,3'ß-disteryl ethers). Sterol-rich samples were heated at 180 °C, 200 °C and 220 °C for 1 to 5 h. Quantitative analyses of the 3ß,3'ß-disteryl ethers were conducted using liquid extraction, solid-phase extraction and gas chromatography coupled with mass spectrometry. Additionally, for the analyses, suitable standards were synthetized from native sterols. To identify the mechanism of 3ß,3'ß-disteryl ether formation at high temperatures, an attempt was made to use the proposed synthesis method. Additionally, due to the association of sterols and sterol derivatives with atherosclerosis, preliminary studies with synthetized 3ß,3'ß-disteryl ethers on endothelial cells were conducted.


Assuntos
Éteres/química , Esteróis/química , Linhagem Celular , Células Endoteliais , Éteres/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectrometria de Massas , Oxirredução , Extração em Fase Sólida , Temperatura
7.
Artigo em Inglês | MEDLINE | ID: mdl-32172172

RESUMO

Purification of small bioactive peptides from complex biological samples is a difficult task due to the interference of concentrated large biomolecules. In this study, a magnetic immobilized metal affinity chromatography matrix modified by poly (ethylene glycol) methyl ether (IMACM@mPEG) was prepared and applied for the rapid purification of angiotensin I-converting enzyme (ACE) inhibitory peptides from casein hydrolysate. The proposed IMACM@mPEG considerably reduced the non-specific adsorption of large proteins and exhibited improved purification efficiency towards ACE inhibitory peptides. A novel peptide with moderate ACE inhibitory activity (IC50 value of 274 ± 5 µM) was identified as LLYQEPVLGPVR. Lineweaver-Burk plot confirmed the non-competitive inhibition pattern of LLYQEPVLGPVR. The purified peptide was digested after simulated gastrointestinal digestion and produced shorter peptides which contributed to enhanced ACE inhibitory activity. These results indicated that the IMACM@mPEG is an effective method for the prepurification of ACE inhibitory peptide and the purified peptide LLYQEPVLGPVR may have potential as nutraceutical ingredient in functional foods for hypertension treatments.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Caseínas/química , Cromatografia de Afinidade/métodos , Éteres/química , Peptídeos/isolamento & purificação , Polietilenoglicóis/química , Adsorção , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Cobre/química , Óxido Ferroso-Férrico/química , Microesferas , Peptídeos/análise , Peptídeos/metabolismo , Hidrolisados de Proteína , Dióxido de Silício/metabolismo , Propriedades de Superfície
8.
Carbohydr Polym ; 234: 115880, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070503

RESUMO

Assemblies of carbohydrate polymers are important in a number of applications and improved methods for their fabrication are increasingly sought after. Herein, we report that an aqueous two-phase system of alginate (Alg) and hydroxypropyl cellulose with poly(methacrylic acid) graft chains (HPC-PMA) facilitated the assembly of Alg/HPC-PMA in both phases. Dynamically formed filamentous domains in a flow field were gelled by rapid complexation with cationic polyethyleneimine (PEI). The fabricated HPC-PMA gel filament morphologies can be switched between the bundled and dissociated gel filaments using a co-flow microfluidic device in response to the amount of supplied PEI crosslinker. Excess complexation of PEI contributes to the fabrication of cationic gel filaments; this contribution results in a dissociated structure due to electrostatic repulsion. In contrast, an appropriate amount of PEI resulted in a bundle structure. The proposed spinning method avoids the risk of nozzle clogging, and enables the one-step spinning of multiple gel filaments.


Assuntos
Celulose/síntese química , Éteres/síntese química , Ácidos Polimetacrílicos/química , Termodinâmica , Celulose/química , Éteres/química , Géis/síntese química , Géis/química , Íons/química , Tamanho da Partícula , Propriedades de Superfície
9.
Anal Chim Acta ; 1104: 1-9, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32106938

RESUMO

Electromembrane extraction (EME) in small, stagnant and chip-like devices has the potential for future in-field operation. Literature briefly discuss such systems, but performance suffered from evaporative losses of sample and acceptor. To address this, the current paper reports electromembrane extraction (EME) of five basic drugs (model analytes) from aqueous buffer solutions and whole blood samples under stagnant conditions in a completely closed system. A laboratory-made polyoxymethylene (POM) well plate served as compartment for the sample solution, while a commercially available well filter plate was used to immobilize 2-nitrophenyl octyl ether (NPOE) as supported liquid membrane (SLM) and as closed compartment for the acceptor solution. Major design parameters (sample compartment and electrode geometry) and operational parameters (sample volume, voltage and extraction time) were investigated and optimized. Electrode geometry was not very critical, but extraction efficiency increased with decreasing sample volume. Extraction from 50 µL aqueous buffer solution for 60 min and with a voltage of 75 V was considered exhaustive (sample was depleted), with recoveries ranging between 75% and 87% for loperamide, haloperidol, methadone, nortriptyline, and pethidine (RSD: 2-12%). Extraction from whole blood samples under optimized conditions yielded slightly lower recoveries, ranging between 57 and 96% (RSD: 3-12%). Stagnant EME was evaluated in combination with liquid chromatography-mass spectrometry (LC-MS) as a highly specific instrumental method, and provided evaluation data on methadone from blood samples in accordance with regulatory requirements (LOD: 0.4 ng/mL, LOQ: 1.4 ng/mL, RSD: 6-20%). This work has improved upon the design of stagnant EME, moving it further towards a viable in-field operation device.


Assuntos
Técnicas Eletroquímicas/métodos , Membranas Artificiais , Preparações Farmacêuticas/análise , Tampões (Química) , Cromatografia Líquida , Técnicas Eletroquímicas/instrumentação , Eletrodos , Éteres/química , Voluntários Saudáveis , Humanos , Limite de Detecção , Espectrometria de Massas , Preparações Farmacêuticas/sangue , Resinas Sintéticas/química
10.
Anal Chim Acta ; 1098: 86-93, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948590

RESUMO

Cytochrome P450 (CYP450), and in particular CYP3A4, is the most abundantly expressed CYP450 isozyme implicated in many drug-drug and medicinal plant-drug interactions. Therefore, incorporation of CYP3A4 enzyme screening at an early stage of drug discovery is preferable in order to avoid enzymatic interactions. Here we present for the first time a paper-based CYP3A4 immobilized sol-gel-derived a platform using resorufin benzyl ether as a fluorogenic enzyme substrate used to investigate enzyme activity. The fluorescence intensity of the product can be simply quantified by using a handheld digital microscope and an image analysis software. The limit of quantitation was 0.35 µM with good precision (RSDs < 4.1%). Furthermore, the assay of CYP3A4 activity on the developed paper-based device provided comparable results with those obtained from conventional well-plates (p > 0.05), while offering simplicity and lower cost. Kinetic parameters of the immobilized CYP3A4 in sol-gel coated paper were calculated from the Lineweaver-Burk plot, including Michaelis constant (Km) and maximum velocity (Vmax), which were 2.71 ±â€¯0.35 µM and 0.43 ±â€¯0.05 µM/min, respectively. Moreover, a functional test of these devices was conducted by assessments of known CYP3A4 inhibitors (i.e. ketoconazole, itraconazole) and inducers (i.e. phenytoin, carbamazepine). To further demonstrate the broad range of uses, the devices were utilized to assay plant extracts i.e. Areca catechu seeds, Camellia sinensis leaves, Eclipta prostrata aerial part, providing results in good agreement with previous studies. Furthermore, the sol-gel immobilized enzyme stored at 4 °C can increase storage stability, offering the activity of 86.3 ±â€¯0.4% after 3-weeks storage, equivalent to the activity of the free enzyme solution after 1-week storage. The developed paper-based devices offer versatility, portability and low-cost.


Assuntos
Derivados de Benzeno/química , Sistema Enzimático do Citocromo P-450/análise , Enzimas Imobilizadas/análise , Éteres/química , Oxazinas/química , Papel , Sistema Enzimático do Citocromo P-450/metabolismo , Ativação Enzimática , Enzimas Imobilizadas/metabolismo , Géis/química , Humanos , Estrutura Molecular
11.
Chem Commun (Camb) ; 56(13): 2012-2015, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-31961351

RESUMO

Here, we describe one simple Ir/hydrosilane catalytic system for chemoselective isomerization of 2-substituted allylic ethers. This facile strategy shows high efficiency towards a variety of substrates, including derivatives from bioactive molecules. The substituent at the α position of the olefins is supposed to be critical in retarding the alkene hydrosilylation process and leading the reaction to go through the isomerization pathway.


Assuntos
Éteres/química , Irídio/química , Silanos/química , Alcenos/química , Catálise , Complexos de Coordenação/química , Isomerismo
12.
Analyst ; 145(2): 513-522, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31761920

RESUMO

Plasmanyl and plasmenyl glycerophosphocholine are ether lipids featuring the 1-O-alkyl or 1-O-alk-1'-enyl ether linkage at the sn-1 position of the glycerol backbone, respectively. Aberrant levels of ether glycerophosphocholines (ether PCs) have been correlated with cellular dysfunctions and various human diseases. Profiling ether PCs with accurate structural information is challenging because of the common presence of isomeric and isobaric species in a lipidome. The Paternò-Büchi (PB) reaction, a double bond (C[double bond, length as m-dash]C) specific derivatization method, is capable of pinpointing C[double bond, length as m-dash]C locations in unsaturated lipids, when coupled with subsequent tandem mass spectrometry (MS/MS). In this study, we have tailored the acetone PB reaction for the analysis of ether PCs. PB-MS/MS via low energy collision-induced dissociation (CID) provides diagnostic ions specific to the alkenyl ether C[double bond, length as m-dash]C bond, which are different from those derived from the isolated C[double bond, length as m-dash]C bond in the alkyl or acyl chain, thereby facilitating the distinction of isomeric plasmenyl from plasmanyl PCs. PB-MS/MS coupled with high resolution MS and multi-stage MS/MS further enable confident identification of isomeric ether PCs and isobaric diacyl PCs from mixtures. A total of 45 ether PCs in human plasma have been identified for ether linkage type and chain composition, while 28 ether PCs have structures being fully characterized down to C[double bond, length as m-dash]C locations.


Assuntos
Éteres/sangue , Glicerilfosforilcolina/sangue , Lipídeos/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Éteres/química , Glicerilfosforilcolina/química , Humanos , Lipídeos/química , Estrutura Molecular
13.
Environ Sci Pollut Res Int ; 27(1): 907-920, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31820248

RESUMO

To understand the atmospheric chemistry of hydrofluoroethers, we have studied the oxidation of a highly fluorinated compound n-C2F5CF(OCH3)CF(CF3)2 (HFE-7300) by OH/Cl oxidants. Here, we have employed M06-2X functional along with a 6-31 + G(d,p) basis set to obtain the optimized structures, various forms of energies, and different modes of frequencies for all species. We have characterized energies of all species on the potential energy surface, and it indicates that H-abstraction from n-C2F5CF(OCH3)CF(CF3)2 by Cl atom is kinetically more dominant than the H-abstraction reaction initiated by OH radical. In contrast, the calculated energy change (ΔrH°298 and ΔrG°298) results govern that OH-initiated H-abstraction reaction is highly exothermic and spontaneous compared to the Cl-initiated H-abstraction reaction. Rate constants are estimated using transition state theory as well as canonical variation transition state theory at the temperature range 200-1000 K and 1 atm pressure. The calculated rate constants of the H-abstraction channels are found to be in good agreement with the reported experimental rate constant at 298 K. Moreover, we have estimated the atmospheric lifetimes of HFE-7300 for the reaction with OH radical and Cl atom and are found to be 1.75 and 153.93 years, respectively. Additionally, the global warming potentials for HFE-7300 molecule are also estimated for 20-, 100-, and 500-year time horizons. Further, subsequent aerial oxidation of product radical (n-C2F5CF(OCH2)CF(CF3)2) in the presence of NO radical is performed, and it produced alkoxy radical via formation of peroxy radical. This alkoxy radical undergoes unimolecular decompositions via two different ways and formed n-C2F5CF(OCHO)CF(CF3)2 and n-C2F5CF(OH) CF(CF3)2 products.


Assuntos
Poluentes Atmosféricos/química , Éteres/química , Oxidantes/química , Atmosfera/química , Aquecimento Global , Radical Hidroxila/química , Cinética , Modelos Químicos , Oxirredução , Termodinâmica
14.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842358

RESUMO

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4'-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1'-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.


Assuntos
Antineoplásicos/farmacologia , Cicloexanonas/farmacologia , Flavonas/farmacologia , Herpesvirus Humano 4/efeitos dos fármacos , Antineoplásicos/química , Cicloexanonas/química , Éteres/química , Flavonas/química , Herpesvirus Humano 4/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade , Fenômenos Fisiológicos Virais , Replicação Viral/efeitos dos fármacos
15.
Org Lett ; 21(24): 9934-9939, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31815495

RESUMO

The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.


Assuntos
Alquinos/química , Éteres/síntese química , Furanos/síntese química , Compostos Organometálicos/química , Platina/química , Piranos/síntese química , Catálise , Éteres/química , Furanos/química , Estrutura Molecular , Piranos/química , Estereoisomerismo
16.
J Org Chem ; 84(24): 15767-15776, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31738556

RESUMO

Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical and electronic properties. Many of the known methods to synthesize aryl trifluoromethyl ethers require harsh reagents and highly controlled reaction conditions and rarely occur when heteroaromatic units are present. The two-step O-trifluoromethylation of phenols via aryl xanthates is one such method that suffers from these drawbacks. Herein, we report a method for the synthesis of aryl trifluoromethyl ethers from phenols by the facile conversion of the phenol to the corresponding aryl and heteroaryl xanthates with newly synthesized imidazolium methylthiocarbonothioyl salts and conversion of these xanthates to the trifluoromethyl ethers under mild reaction conditions.


Assuntos
Éteres/síntese química , Hidrocarbonetos Fluorados/síntese química , Fenóis/química , Xantinas/química , Éteres/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular
17.
Prion ; 13(1): 185-196, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578923

RESUMO

Prion diseases are fatal transmissible neurodegenerative disorders that affect animals and humans. Prions are proteinaceous infectious particles consisting of a misfolded isoform of the cellular prion protein PrPC, termed PrPSc. PrPSc accumulates in infected neurons due to partial resistance to proteolytic digestion. Using compounds that interfere with the production of PrPSc or enhance its degradation cure prion infection in vitro, but most drugs failed when used to treat prion-infected rodents. In order to synergize the effect of anti-prion drugs, we combined drugs interfering with the generation of PrPSc with compounds inducing PrPSc degradation. Here, we tested autophagy stimulators (rapamycin or AR12) and cellulose ether compounds (TC-5RW or 60SH-50) either as single or combination treatment of mice infected with RML prions. Single drug treatments significantly extended the survival compared to the untreated group. As anticipated, also all the combination therapy groups showed extended survival compared to the untreated group, but no combination treatment showed superior effects to 60SH-50 or TC-5RW treatment alone. Unexpectedly, we later found that combining autophagy stimulator and cellulose ether treatment in cultured neuronal cells mitigated the pro-autophagic activity of AR12 and rapamycin, which can in part explain the in vivo results. Overall, we show that it is critical to exclude antagonizing drug effects when attempting combination therapy. In addition, we identified AR-12 as a pro-autophagic drug that significantly extends survival of prion-infected mice, has no adverse side effects on the animals used in this study, and can be useful in future studies.


Assuntos
Autofagia/efeitos dos fármacos , Celulose/uso terapêutico , Proteínas PrPSc/metabolismo , Doenças Priônicas/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Celulose/análogos & derivados , Sinergismo Farmacológico , Éteres/química , Éteres/uso terapêutico , Feminino , Camundongos , Proteínas PrPSc/antagonistas & inibidores , Doenças Priônicas/metabolismo , Proteólise/efeitos dos fármacos
18.
Nat Chem ; 11(12): 1124-1132, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31659310

RESUMO

Ring-opening metathesis polymerization of norbornene-based (macro)monomers is a powerful approach for the synthesis of macromolecules with diverse compositions and complex architectures. Nevertheless, a fundamental limitation of polymers prepared by this strategy is their lack of facile degradability, limiting their utility in a range of applications. Here we describe a class of readily available bifunctional silyl ether-based cyclic olefins that copolymerize efficiently with norbornene-based (macro)monomers to provide copolymers with backbone degradability under mildly acidic aqueous conditions and degradation rates that can be tuned over several orders of magnitude, depending on the silyl ether substituents. These monomers can be used to manipulate the in vivo biodistribution and clearance rate of polyethylene glycol-based bottlebrush polymers, as well as to synthesize linear, bottlebrush and brush-arm star copolymers with degradable segments. We expect that this work will enable preparation of degradable polymers by ROMP for biomedical applications, responsive self-assembly and improved sustainability.


Assuntos
Éteres/química , Plásticos/química , Polímeros/síntese química , Silanos/química , Estrutura Molecular , Polimerização , Polímeros/química
19.
J Org Chem ; 84(21): 13897-13907, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609610

RESUMO

A novel and practical photoredox-catalyzed generation of sulfamyl radicals followed by radical sulfonamidation of enol silyl ether has been described. Diverse functionalized ß-ketosulfonamides were prepared in modest to excellent yields under mild and economic reaction conditions through the present catalytic protocol. Furthermore, the methodology developed provides an efficient and convenient approach to the synthesis of the antiseizure drug Zonisamide.


Assuntos
Éteres/química , Processos Fotoquímicos , Silício/química , Sulfonamidas/química , Catálise
20.
J Mol Graph Model ; 93: 107453, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31569010

RESUMO

The nocturnal reactions of CH3CH2OCH2CH3, CHF2CF2OCH2CF3 and CF3CH2OCH3 initiated by NO3 radicals are important sources of alkyl radicals and nitric acids. In this paper, the thermodynamics and kinetics of CH3CH2OCH2CH3, CHF2CF2OCH2CF3 and CF3CH2OCH3 induced by NO3 radical in gas phase are studied in detail by BHandHLYP method combined with 6-311G(d,p) basis set, and the single point correction is calculated by relatively accurate CCSD(T) method. In the temperature range of 200-400 K, the rate constants of title reactions are fitted to the three-parameter Arrhenius formula: k1 = 1.13 × 10-40T9.24exp(1675.99/T) k2 = 2.23 × 10-23T2.81exp(-4476.24/T) k3 = 5.63 × 1043T-19.20exp(-9344.12/T) All the rate constants calculated by the canonical variational transition state theory and the small curvature tunneling are basically consistent with the limited experimental data. By comparing the reaction rate constants of ethyl ether and its isomer methyl propyl ether with NO3 radical at 293 ±â€¯2 K, the higher the symmetry is, the faster the reaction rate of ether is. Thermodynamic calculations and kinetic data of the title reactions indicate that the H-abstraction reactions at the -OCH2- sites are the main reaction pathways. The thermodynamic and kinetic data of the reaction CH3CH2OCH2CH3, CHF2CF2OCH2CF3 with NO3 radical, showing that the reaction activity could be reduced due to the addition of fluorine atoms, which is further verified by the enthalpies, Gibbs free energies of the title reactions and C-H bond dissociation energies of the CH3CH2OCH2CH3, CHF2CF2OCH2CF3 and CF3CH2OCH3 molecules. The reaction thermodynamics and kinetics are determined, and the formation mechanisms of the products are proposed, which are crucial to determine the influence of CH3CH2OCH2CH3, CHF2CF2OCH2CF3 and CF3CH2OCH3 on air quality, as well as its atmospheric lifetime and durability. The atmospheric lifetimes of CH3CH2OCH2CH3, CHF2CF2OCH2CF3 and CF3CH2OCH3 are evaluated in the NO3-concentration range of 5 × 108-2 × 109 molecule cm-3 to fully consider the effects of different regions on their nocturnal migration. The radiation efficiency and global warming potentials (GWPs) have been reported. The products of title reaction CH3CH2OCHCH3, CF3CHOCF2CHF2 and CF3CHOCH3 are further oxidized into organic nitrates in the presence of O2 and NO. Organic nitrites can be isomerized into organic nitrates or degraded to form CH3C(O•)HOCH2CH3, CF3C(O•)HOCF2CHF2 and CH3C(O•)HOCF3 alkoxy radicals and NO2. This work provides deep insight into the night migration and transformation mechanism of the three ethers.


Assuntos
Hidrocarbonetos/química , Nitratos/química , Álcoois/química , Éteres/química , Cinética , Modelos Teóricos , Temperatura , Termodinâmica
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