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Protein single-chain nanoparticles can outperform synthetic nanoparticles in biomedical applications due to enhanced biocompatibility. Compared to synthetic (co)polymers, the chemical complexity of proteins challenges chain conformation control. Here, we investigate the impact of the precursor chain conformation of bovine serum albumin (BSA) on the nanoparticle structure after intramolecular cross-linking. We explore the urea concentration (denaturant), pH, salt, cross-linker length, and concentration. Small-angle neutron scattering and dynamic light scattering experiments reveal a shrinking chain conformation upon cross-linking. However, the ability to collapse depends on solvent conditions: more expanded chains collapse more, whereas proteins that are already compact barely change in size upon cross-linking. Static light scattering measurements demonstrate that binding is primarily intramolecular. The use of a shorter cross-linker does not lead to collapse of extended chains. Overall, BSA exhibits a similar behavior to that of polymer nanoparticles, which then allows to harness the precursor conformation for morphological control.
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The synthesis of deuteriated tri-tert-butyl phosphine is reported. This synthesis is an adaptation of the known procedure for tri-tert-butyl phosphine via a Grignard intermediate.
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Fosfinas , Estrutura MolecularRESUMO
Photocatalysts formed from a single organic semiconductor typically suffer from inefficient intrinsic charge generation, which leads to low photocatalytic activities. We demonstrate that incorporating a heterojunction between a donor polymer (PTB7-Th) and non-fullerene acceptor (EH-IDTBR) in organic nanoparticles (NPs) can result in hydrogen evolution photocatalysts with greatly enhanced photocatalytic activity. Control of the nanomorphology of these NPs was achieved by varying the stabilizing surfactant employed during NP fabrication, converting it from a core-shell structure to an intermixed donor/acceptor blend and increasing H2 evolution by an order of magnitude. The resulting photocatalysts display an unprecedentedly high H2 evolution rate of over 60,000 µmol h-1 g-1 under 350 to 800 nm illumination, and external quantum efficiencies over 6% in the region of maximum solar photon flux.
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The vertical depth distributions of amine oxide surfactants, N,N-dimethyldodecyl amine N-oxide (DDAO) and N,N-dimethyltetradecyl amine N-oxide (DTAO), in poly(vinyl alcohol) (PVA) films were explored using neutron reflectometry (NR). In both binary and plasticized films, the two deuterated surfactants formed a single monolayer on the film surface with the remaining surfactant homogeneously distributed throughout the bulk of the film. Small-angle neutron scattering and mechanical testing revealed that these surfactants acted like plasticizers in the bulk, occupying the amorphous regions of PVA and reducing its glass-transition temperature. NR revealed little impact of plasticizer (glycerol) incorporation on the behavior of these surfactants in PVA. The surfactant molecular area in the segregated monolayer was smaller for DTAO than for DDAO, indicating that the larger molecule was more densely packed at the surface. Surface tension was used to assess the solution behavior of these surfactants and the effect of glycerol incorporation. Determination of molecular area of each surfactant on the solution surface revealed that the structures of the surface monolayers are remarkably consistent when water is placed by the solid PVA. Incorporation of glycerol caused a decrease of molecular area for DDAO and increase in molecular area for DTAO both in solution and in PVA. This suggests that the head group interactions, which normally limit the minimum area per adsorbed molecule, are modified by the length of the alkyl tail.
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The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of 3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformational behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial conformation.
Assuntos
Benzilaminas/síntese química , Cicloexanóis/síntese química , Benzilaminas/química , Cristalografia por Raios X , Cicloexanóis/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
Hydrotropism is a convenient way to increase the solubility of drugs by up to several orders of magnitude, and even though it has been researched for decades with both experimental and simulation methods, its mechanism is still unknown. Here, we use caffeine/sodium benzoate (CAF-SB) as model system to explore the behaviour of caffeine solubility enhancement in water through NMR spectroscopy and neutron total scattering. 1H NMR shows strong interaction between caffeine and sodium benzoate in water. Neutron total scattering combined with empirical potential structure refinement, a systematic method to study the solution structure, reveals π-stacking between caffeine and the benzoate anion as well as Coulombic interactions with the sodium cation. The strongest hydrogen bond interaction in the system is between benzoate and water, which help dissolve CAF-SB complex and increase the solubility of CAF in water. Besides, the stronger interaction between CAF and water and the distortion of water structure are further mechanisms of the CAF solubility enhancement. It is likely that the variety of mechanisms for hydrotropism shown in this system can be found for other hydrotropes, and NMR spectroscopy and neutron total scattering can be used as complementary techniques to generate a holistic picture of hydrotropic solutions.
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Cafeína , Benzoato de Sódio , Cafeína/química , Espectroscopia de Ressonância Magnética , Benzoatos , Água , NêutronsRESUMO
The elastic modulus and hydrophilicity of cross-linked poly(dimethylsiloxane) (PDMS) are tunable via cross-linker concentration and the addition of a simple surfactant, C12E4, before curing. However, the surfactant concentration, [C12E4], reduces the elastic modulus (73% lower for 6.3% w/w) because it reduces the extent of curing. This is likely because the hygroscopic surfactant results in water poisoning of the catalyst. Three distinct time-dependent hydrophilicity profiles were identified using water contact angle analysis with [C12E4] determining which profile was observed. This indicates the concentration-dependent phase behavior of C12E4 within PDMS films. Changes in phase behavior were identified using small-angle neutron scattering (SANS) and a compatibility study. No surface excess or surface segregation of surfactant was observed at the PDMS-air interface. However, a surface excess revealed by neutron reflectivity against a D2O interface indicates that the increase in hydrophilicity results from the migration of C12E4 to the film interface when exposed to water.
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Water-soluble nonionic surfactant, pentaethylene glycol monododecyl ether, C12E5, spontaneously blooms to the surface of spin-cast hydrophobic polyisoprenes, generating hydrophilic surfaces. This system provides a simple model for hydrophilic chemical modification of rubbery polymers that demonstrates surprisingly rich, complex, and unexpected behaviour. The vertical depth profiles were quantified using neutron reflectometry (NR) using a novel procedure to account for undulations in the film thickness. Surface properties were characterized using contact angle analysis and atomic force microscopy (AFM). Despite the low surface tension of the toluene solvent used in film preparation and the low surface energy of the polyisoprene (PI) matrix, NR depth profiles revealed clear evidence of surfactant segregation. This surface layer was typically thicker than a monolayer, but incomplete, yet was remarkably stable with respect to dissolution, even when exposed to hundreds of thousands of times the volume of water required to dissolve all the surfactant on the surface. Despite the apparent resistance to removal from the surface, water exposure does alter the subsequent wettability of the surface, with a hydrophilic-to-hydrophobic transition occurring after rinsing. Complementary AFM images of these C12E5/cis-PI films showed unexpected strand-like features on the surface of the film, which we attribute to a non-uniform lateral distribution of some of the surfactant. This surface structure becomes more evident after rinsing, and it appears that there are two distinct populations of surfactant on the PI film surface. We conclude that some of the bloomed surfactant exists as layers, which are relatively inert with respect to rinsing or surface modification, and some is laterally inhomogeneous. This latter population is primarily responsible for surface wetting behaviour but is not detected by specular NR.
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HYPOTHESIS: Biomimetic liquid crystalline systems are widely used in skin care cosmetics and topical pharmaceutical preparations. Our ability to rationally design such formulations, however, is hampered by our incomplete understanding of their structure on the nanoscale. EXPERIMENTS: Using polarized light microscopy and small-angle and wide-angle X-ray scattering, the molecular architecture and properties of a barrier formulation prepared from distearoylphosphatidylcholine mixed with long chain fatty acid and alcohols, with and without antimicrobial pentanediols are directly probed. The nature and composition of the phases identified are determined through small-angle neutron scattering studies using chain-deuterated components, and the detailed structure and dynamics of the gel network lamellae are determined through molecular dynamics simulations. FINDINGS: The formulations show molecular ordering with long and short periodicity lamellar phases and there is little change in these structures caused by changes in temperature, drying, or the application of shear stress. The diol-free formulation is demonstrated to be self-preserving, and the added pentanediols are shown to distribute within the interlamellar regions where they limit availability of water for microbial growth. In culmination of these studies, we develop a more complete picture of these complex biomimetic preparations, and thereby enable their structure-based design.
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Biomimética , Cristais Líquidos , Ácidos Graxos , Espalhamento a Baixo ÂnguloRESUMO
The Ireland-Claisen rearrangement of 3-alkoxy- and 3-aryloxy-substituted allyl glycinates is presented. This [3,3]-sigmatropic rearrangement route offers direct access to syn ß-alkoxy and ß-aryloxy α-amino acid systems. In particular, N,N-diboc glycine esters rearrange with excellent diastereoselectivities (dr > 25:1). The synthesis of substrates, rearrangement optimization, and a discussion of stereoselection are presented.
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Álcoois/química , Glicina/análogos & derivados , Glicina/química , Glicina/síntese química , Aminoácidos/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
The crystal structure of the small organic molecule, alloxan, has been explored using high-pressure neutron diffraction; its already efficiently-packed structure provides a 'chemical head-start' on the pressure experiment. At the highest pressure measured, alloxan reaches a density of 2.36 g cm-3-unprecedented for a C, H(D), N, O-containing organic material of appreciable molecular weight. Its crystal structure is stable until ca. 6.5 GPa above which the sample starts to undergo amorphisation.
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This aims to establish design rules for the influence of complex polymer matrices on the surface properties of small molecules. Here, we consider the dependence of the surface behaviour of some model additives on polymer matrix hydrophobicity. With stoichiometric control over hydrolysis, we generate systematic changes in matrix chemistry from non-polar, hydrophobic PVAc to its hydrolysed and hydrophilic analogue, PVA. With the changing degree of hydrolysis (DH), the behaviour of additives can be switched in terms of compatibility and surface activity. Sorbitol, a polar sugar-alcohol of inherently high surface energy, blooms to the surface of PVAc, forming patchy domains on surfaces. With the increasing DH of the polymer matrix, its surface segregation decreases to the point where sorbitol acts as a homogeneously distributed plasticiser in PVA. Conversely, and despite its low surface energy, octanoic acid (OA) surprisingly causes the increased wettability of PVAc. We attribute these observations to the high compatibility of OA with PVAc and its ability to reorient upon exposure to water, presenting a hydrophilic COOH-rich surface. The surfactant sodium dodecyl sulfate (SDS) does not show such a clear dependence on the matrix and formed wetting layers over a wide range of DH. Interestingly, SDS appears to be most compatible with PVAc at intermediate DH, which is consistent with the amphiphilic nature of both species under these conditions. Thus, we show that the prediction of the segregation is not simple and depends on multiple factors including hydrophobicity, compatibility, blockiness, surface energy, and the mobility of the components.
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Deep eutectic solvents (DES) are potentially greener solvents obtained through the complexation of simple precursors which, among other applications, have been investigated in recent years for their ability to support the self-assembly of amphiphilic molecules. It is crucial to understand the factors which influence surfactant solubility and self-assembly with respect to the interaction of the surfactant molecule with the DES components. In this work, small-angle neutron scattering (SANS) has been used to investigate the micellization of cationic (CnTAB) and anionic (SDS) surfactants in a ternary DES comprising choline chloride, urea, and glycerol, where the hydrogen bond donors are mixed in varying molar ratios. The results show that in each case either globular or rodlike micelles are formed with the degree of elongation being directly dependent on the composition of the DES. It is hypothesized that this composition dependence arises largely from the poor solubility of the counterions in the DES, especially at low glycerol content, leading to a tighter binding of the counterion to the micelle surface and giving rise to micelles with a high aspect ratio. This potential for accurate control over micelle morphology presents unique opportunities for rheology control or to develop templated syntheses of porous materials in DES, utilizing the solvent composition to tailor micelle shape and size, and hence the pore structure of the resulting material.
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The interactions between protein and surfactants play an important role in the stability and performance of formulated products. Due to the high complexity of such interactions, multi-technique approaches are required to study these systems. Here, an integrative approach is used to investigate the various interactions in a model system composed of human growth hormone and sodium dodecyl sulfate. Contrast variation small-angle neutron scattering was used to obtain information on the structure of the protein, surfactant aggregates and surfactant-protein complexes. 1H and 1H-13C HSQC nuclear magnetic resonance spectroscopy was employed to probe the local structure and dynamics of specific amino acids upon surfactant addition. Through the combination of these advanced methods with fluorescence spectroscopy, circular dichroism and isothermal titration calorimetry, it was possible to identify the interaction mechanisms between the surfactant and the protein in the pre- and post-micellar regimes, and interconnect the results from different techniques. As such, the protein was revealed to evolve from a partially unfolded conformation at low SDS concentration to a molten globule at intermediate concentrations, where the protein conformation and local dynamics of hydrophobic amino acids are partially affected compared to the native state. At higher surfactant concentrations the local structure of the protein appears disrupted, and a decorated micelle structure is observed, where the protein is wrapped around a surfactant assembly. Importantly, this integrative approach allows for the identification of the characteristic fingerprints of complex transitions as seen by each technique, and establishes a methodology for an in-detail study of surfactant-protein systems.
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Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBß in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBß alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.
Assuntos
Relógios Circadianos/imunologia , Ritmo Circadiano/imunologia , Homeostase/imunologia , Imunidade Inata , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Pneumonia/imunologia , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Homeostase/genética , Camundongos , Camundongos Transgênicos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Pneumonia/genética , Pneumonia/patologia , Proteólise , Sumoilação/genética , Sumoilação/imunologiaRESUMO
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
Assuntos
Aminas/síntese química , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Aminas/química , Aminas/farmacologia , Animais , Disponibilidade Biológica , Proteínas de Transporte/metabolismo , Linhagem Celular , Ritmo Circadiano , Glicina/análogos & derivados , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas de Ligação a RNA , Ensaio Radioligante , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologiaRESUMO
A diastereoselective Ireland-Claisen approach to beta-alkoxy alpha-amino acid esters is reported. Amino acid esters of enol ethereal allylic alcohols undergo facile syn-selective [3,3]-sigmatropic rearrangement via silyl ketene acetals. Substrate synthesis, rearrangement development, stereoselectivity, and product elaboration are discussed.