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1.
Chemosphere ; 259: 127502, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32650169

RESUMO

The reductive degradability and decomposition pathways of linear perfluorooctanesulfonate (L-PFOS) were investigated in a biomimetic system consisting of Ti(III)-citrate and Vitamin B12. Biomimetic degradation of L-PFOS could well be described by a first-order exponential decay model. Accompanied by the release of fluoride ion, technical PFOS could not only be transformed to perfluorocarboxylates (PFCAs) and perfluoroalkylsulfonates (PFSAs) with perfluoroalkyl carbon chain length < C8 (thereafter referred as carbon-chain-shortened degradation products), but also be transformed to PFCAs with perfluoroalkyl carbon chain length ≥ C8 (thereafter referred as carbon-chain-lengthened degradation products). Perfluorohexanesulfonate and perfluorotetradecanoate were the most abundant carbon-chain-shortened and -lengthened degradation products of technical PFOS, respectively. Based on the various degradation products detected during biomimetic reduction of linear [1,2,3,4-13C4]-PFOS, the degradation pathways of L-PFOS were proposed as follows: L-PFOS was first reduced to C8F17• radical by cleavage of C-S bond, and then transformed to PFOA through hydrolysis. However, the carbon-chain-shortened products were not generated through the sequential chain-shortening via C8F17• radicals and/or L-PFOS, while the carbon-chain-lengthened products were not formed via C8F17• radicals by stepwise addition of CF2 moiety. In fact, C8F17• radical and/or L-PFOS were further reduced to form CnF2n+1• (n = 1, 2, 3, 4) radicals, and these radicals were chain-lengthened by stepwise addition of C4F8 moiety and eventually transformed to various degradation products via hydrolysis (PFCAs) or combination reaction with sulfonyl hydroxide (PFSAs). All carbon-chain-lengthened chemicals were first reported as the degradation products during the decomposition of L-PFOS, while carbon-chain-shortened compounds were first identified as the biomimetic reduction products of L-PFOS.


Assuntos
Ácidos Alcanossulfônicos/química , Biomimética , Fluorcarbonetos/química , Ácido Cítrico/química , Flúor/química , Oxirredução , Ácidos Sulfônicos/química , Vitamina B 12/química
2.
J Chromatogr A ; 1625: 461269, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709321

RESUMO

Fluorous affinity means remarkably specific interaction between highly organic fluorides. This work aims to explore the potential of fluoro-functionalized stationary phase for the separation of organic fluorides by means of fluorous-fluorous interaction. Here, by using the Michael addition strategy between 1H,1H,2H,2H-perfluorodecanethiol (PFDT) and polydopamine (PD), a novel fluoro-functionalized stationary phase was synthesized for open-tubular capillary electrochromatography (OT-CEC). The PFDT@PD was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray Photoelectron Spectrometer (XPS). The PFDT@PD@capillary exhibited outstanding separation performance towards neutral compounds (such as alkylbenzenes and chlorobenzenes) and organic fluorides (such as fluorobenzenes and perfluoroalkyl methacrylates etc.) with high resolution and high separation efficiency by hydrophobic interaction and fluorous-fluorous interaction. In addition, the column shows good stability and reproducibility. The relative standard deviations (RSDs) of the retention time for intra-day (n = 5) and inter-day (n = 3) runs and between columns (n = 3) are less than 0.39%, 1.22% and 3.87%, respectively. This novel type of fluoro-functionalized stationary phase represents a great application potential in organic fluorides separation field.


Assuntos
Eletrocromatografia Capilar/métodos , Fluoretos/isolamento & purificação , Flúor/química , Compostos Orgânicos/isolamento & purificação , Eletro-Osmose , Indóis/química , Parabenos/análise , Parabenos/química , Polímeros/química , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Phys Chem Chem Phys ; 22(23): 13041-13048, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32478374

RESUMO

Chemical representations derived from deep learning are emerging as a powerful tool in areas such as drug discovery and materials innovation. Currently, this methodology has three major limitations - the cost of representation generation, risk of inherited bias, and the requirement for large amounts of data. We propose the use of multi-task learning in tandem with transfer learning to address these limitations directly. In order to avoid introducing unknown bias into multi-task learning through the task selection itself, we calculate task similarity through pairwise task affinity, and use this measure to programmatically select tasks. We test this methodology on several real-world data sets to demonstrate its potential for execution in complex and low-data environments. Finally, we utilise the task similarity to further probe the expressiveness of the learned representation through a comparison to a commonly used cheminformatics fingerprint, and show that the deep representation is able to capture more expressive task-based information.


Assuntos
Aprendizado Profundo , Bromo/química , Carbono/química , Cloro/química , Flúor/química , Hidrogênio/química , Iodo/química , Metais/química , Nitrogênio/química , Oxigênio/química , Fósforo/química , Enxofre/química
4.
Phys Chem Chem Phys ; 22(23): 13160-13170, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32495810

RESUMO

Understanding the relationship between the structure and the physicochemical attributes of crystalline pharmaceuticals requires high-resolution molecular details. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy is an indispensable tool for analyzing molecular structures, but often experiences challenges of low spectral resolution and sensitivity, particularly in the characterization of unlabeled pharmaceutical materials. Besides, the relatively long spin-lattice relaxation times in pharmaceutical crystals result in time-consuming data collections. In this study, we utilize ultrafast magic angle spinning (UF-MAS) of the sample at 60 and 110 kHz to enable proton and fluorine spectroscopies for probing the structural details of crystalline posaconazole. Paramagnetic relaxation enhancement (PRE), obtained by doping Cu(ii) ions into the crystalline lattice and coating on particle surface, is implemented to shorten the spin-lattice relaxation time for speeding up the ssNMR acquisition. Our results demonstrate a remarkably improved 1H and 19F resolution and sensitivity, which enables multi-dimensional 1H-1H and heteronuclear 1H-19F correlations. In combination with density functional theory (DFT) calculations of chemical shifts, molecular details of posaconazole are established in terms of 1H and 19F networks for identifying "head-to-tail" and "head-to-head" intermolecular packings, with presumably critical contacts that stabilize the crystalline structure. The PRE and UF-MAS techniques enable the high-resolution structure characterization of fluorinated drug molecules in pharmaceutical formulations at natural abundance.


Assuntos
Triazóis/análise , Cobre/química , Teoria da Densidade Funcional , Flúor/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Prótons
5.
Chemosphere ; 259: 127423, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32574847

RESUMO

It is vital to synthesis hydrogen peroxide via electrochemical reduction of oxygen since it is a green process to produce oxidant with wide applications including water/wastewater treatment. In this work, fluorine (F) was employed to modify carbon nanotube (CNT), and the obtained F doped CNT (F-CNT) catalyst was used to fabricate gas diffusion electrode (GDE). It was found that F doping could improve oxygen reduction activity and H2O2 selectivity, and then enhanced the H2O2 production. After modification, F-CNT prepared with 0.6 M HF (CNT-F-0.6) had much higher H2O2 production (47.6 mg L-1) and current efficiency (89.5%) than that of CNT (29.6 mg L-1, 70.1%) at bias voltage of -1.3 V (vs SCE) and pH 7. Moreover, the high catalytic activity of CNT-F-0.6 could maintain in 5 consecutive reaction cycles. The material characterization and electrochemical test indicated that F doping had no significant effects on the surface area of CNT, but improved the defect degree of CNT. The enhanced H2O2 production performance could be ascribed to the formation of CF2 and CF3 on the surface of F-doped CNT, which rendered the potential for practical application of novel carbon catalyst for GDE.


Assuntos
Flúor/química , Nanotubos de Carbono/química , Catálise , Eletrodos , Fluoretos , Peróxido de Hidrogênio/química , Oxirredução , Oxigênio , Águas Residuárias , Purificação da Água
6.
Nature ; 583(7817): 548-553, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480398

RESUMO

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.


Assuntos
Carbono/química , Flúor/química , Alcenos/química , Catálise , Cátions , Halogenação , Hidrogênio/química , Irídio/química , Compostos Organofosforados/química , Oxirredução , Paládio/química
7.
BMC Mol Cell Biol ; 21(1): 38, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450796

RESUMO

BACKGROUND: Detailed structural knowledge of enzyme-inhibitor complexes trapped in intermediate state is the key for a fundamental understanding of reaction mechanisms taking place in enzymes and is indispensable as a structure-guided drug design tool. Solution state NMR uniquely allows the study of active sites of enzymes in equilibrium between different tautomeric forms. In this study 1H, 19F and 15 N NMR spectroscopy has been used to probe the interaction contacts of inhibitors locked in transition states of the catalytic triad of a serine protease. It was demonstrated on the serotype II Dengue virus NS2B:NS3pro serine protease and its mutants, H51N and S135A, in complex with high-affinity ligands containing trifluoromethyl ketone (tfk) and boronic groups in the C-terminal of tetra-peptides. RESULTS: Monitoring 19F resonances, shows that only one of the two isomers of the tfk tetra-peptide binds with NS2B:NS3pro and that access to the bulk of the active site is limited. Moreover, there were no bound water found in proximity of the active site for any of the ligands manifesting in a favorable condition for formation of low barrier hydrogen bonds (LBHB) in the catalytic triad. Based on this data we were able to identify a locked conformation of the protein active site. The data also indicates that the different parts of the binding site most likely act independently of each other. CONCLUSIONS: Our reported findings increases the knowledge of the detailed function of the catalytic triad in serine proteases and could facilitate the development of rational structure based inhibitors that can selectively target the NS3 protease of Dengue type II (DENV2) virus. In addition the results shows the usefulness of probing active sites using 19F NMR spectroscopy.


Assuntos
Vírus da Dengue/enzimologia , Espectroscopia de Ressonância Magnética , Serina Proteases/química , Inibidores de Serino Proteinase/química , Sítios de Ligação , Catálise , Domínio Catalítico/genética , Vírus da Dengue/genética , Flúor/química , Hidrogênio/química , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Isótopos de Nitrogênio/química , Conformação Proteica , Serina Proteases/genética , Proteínas não Estruturais Virais/química , Água/química
8.
J Chromatogr A ; 1622: 461160, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32450990

RESUMO

The glutathione (GSH) trapping assay is commonly utilized for the screening and characterization of reactive metabolites produced by drug metabolism. This study describes a fluorous derivatization method for a more sensitive and selective analysis of reactive metabolites trapped by GSH using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, the GSH-trapped reactive metabolites, which were obtained after incubation of the test compounds with human liver microsome (HLM) in the presence of GSH and NADPH, were derivatized using the perfluoroalkylamine reagent through oxazolone chemistry. Since this reaction enabled the selective modification of the α-carboxyl group in GSH, the structural compositions of the metabolites were not affected by the derivatization. Furthermore, the selective analysis of the resulting derivatives could be performed using perfluoroalkyl-modified stationary phase LC separation via the interaction between the perfluoroalkyl-containing compounds, such as fluorous affinity, followed by detection with the precursor ion and/or enhanced product ion scan modes in MS/MS. Finally, we demonstrated the applicability of this method by analyzing perfluoroalkyl derivatives of some drug metabolites trapped by GSH in HLM incubation.


Assuntos
Cromatografia Líquida/métodos , Flúor/química , Glutationa/análise , Espectrometria de Massas em Tandem/métodos , Glutationa/química , Humanos , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo
9.
J Med Chem ; 63(11): 6225-6237, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32379447

RESUMO

Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor.


Assuntos
Flúor/química , Inibidores de Metaloproteinases de Matriz/química , Metaloproteinases da Matriz/metabolismo , Barbitúricos/química , Barbitúricos/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Inibidores de Metaloproteinases de Matriz/metabolismo , Metaloproteinases da Matriz/química , Conformação Molecular , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
10.
Mikrochim Acta ; 187(5): 276, 2020 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307592

RESUMO

A bimetallic nanostructure of Co/Cu for the non-enzymatic determination of glucose is presented. The heterostructure includes cobalt thin film on a porous array of Cu nanocolumns. Glancing angle deposition (GLAD) method was used to grow Cu nanocolumns directly on a fluorine-doped tin oxide (FTO) substrate. Then a thin film of cobalt was electrodeposited on the Cu nanostructures. Various characterization studies were performed in order to define the optimum nanostructure for the determination of glucose. The results showed remarkable boosting of the electrocatalytic activity of Co/Cu bimetallic structure compare to the responses achieved by the monometallic structures of Co or Cu. The sensor showed two linear response ranges for the determination of glucose at 0.55 V in 0.1 M NaOH, from 5 µM-1 mM and 2-9 mM. The sensitivity was 1741 (µA mM-1 cm-2) and 626 (µA mM-1 cm-2), respectively, while the detection limit for a signal-to-noise ratio of 3 was found to be 0.4 µM. The sensor exhibited excellent selectivity and was successfully applied to the determination of glucose in real human blood serum samples. Graphical Abstract Schematic representation of fabrication process of the glucose sensor of Co (Cobalt)/Cu (Copper) on Fluorine doped Tin Oxide (FTO). The current voltage plots show higher electrooxidation activity of the bimetallic nanostructure of Co/Cu/FTO relative to the bare Co/FTO.


Assuntos
Ligas/química , Técnicas Biossensoriais , Técnicas Eletroquímicas , Glucose/análise , Nanoestruturas/química , Cobalto/química , Cobre/química , Eletrodos , Flúor/química , Humanos , Tamanho da Partícula , Propriedades de Superfície , Compostos de Estanho/química
11.
Phys Med Biol ; 65(7): 075010, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32242527

RESUMO

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.


Assuntos
Alumínio/química , Flúor/química , Vidro/química , Método de Monte Carlo , Doses de Radiação , Samário/química , Terapia por Raios X , Radiometria , Dosagem Radioterapêutica , Síncrotrons
12.
J Med Chem ; 63(12): 6315-6386, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32182061

RESUMO

The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C-F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.


Assuntos
Desenho de Fármacos , Flúor/química , Halogenação , Preparações Farmacêuticas/química , Humanos
13.
Nature ; 580(7805): 621-627, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32179876

RESUMO

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Carbono/química , Técnicas de Química Sintética , Hidrogênio/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Androstenos/síntese química , Androstenos/química , Catálise , Agonismo Inverso de Drogas , Elétrons , Flúor/química , Hidroxilação , Ácidos de Lewis/química , Manganês/química , Metilação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Oxazolidinonas/síntese química , Oxazolidinonas/química , Oxirredução , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Tetrazóis/síntese química , Tetrazóis/química
14.
Chemosphere ; 251: 126319, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32169717

RESUMO

Electro-adsorption is attracting increasing attention as an emerging technology for removing ionic species from water but suffer from low selectivity. In this work, a bismuth/reduced graphene oxide nanocomposite electrode was fabricated by a facile and green method. Based on this material, an electrode with improved selectivity by electrochemistry deionization system was successfully fabricated. The bismuth nanoparticles were uniformly covered with reduced graphene oxide plates and the ratio of Bi on the whole materials is 79.56%. Bismuth/reduced graphene oxide showed ions selectivity in the order of Cl- > F- ≫ [Formula: see text] . The average Cl- removal capacity can reach as high as 62.59 mg g-1. Moreover, bismuth/reduced graphene oxide electrodes have good regeneration performance. Typically, in the 10 adsorption-desorption multicycles, the salt absorption/desorption capacity of the hybrid capacitive deionization system is stable and reversible. This research opened a hopeful window to design and synthesize effective materials to selectively remove the ionic species to purify the water.


Assuntos
Cloro/química , Flúor/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Adsorção , Bismuto/química , Técnicas Eletroquímicas , Eletroquímica , Eletrodos , Grafite , Íons , Cloreto de Sódio
15.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085409

RESUMO

Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.


Assuntos
Benzeno/química , Cloro/química , Receptores ErbB/antagonistas & inibidores , Flúor/química , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Apoproteínas/química , Sítios de Ligação , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Proteínas Mutantes/metabolismo , Análise de Componente Principal , Solventes/química , Especificidade por Substrato/efeitos dos fármacos , Termodinâmica
16.
Molecules ; 25(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069852

RESUMO

The fluorination of dendritic structures has attracted special attention in terms of self-assembly processes and biological applications. The presence of fluorine increases the hydrophobicity of the molecule, resulting in a better interaction with biological membranes and viability. In addition, the development of 19F magnetic resonance imaging (19F-MRI) has greatly increased interest in the design of new fluorinated structures with specific properties. Here, we present the synthesis of new water-soluble fluorinated carbosilane dendrons containing fluorinated chains in different positions on the skeleton, focal point or surface, and their preliminary supramolecular aggregation studies. These new dendritic systems could be considered as potential systems to be employed in drug delivery or gene therapy and monitored by 19F-MRI.


Assuntos
Imagem por Ressonância Magnética de Flúor-19/métodos , Silanos/química , Dendrímeros/química , Flúor/química , Micelas , Estrutura Molecular , Solubilidade
17.
J Biomol NMR ; 74(2-3): 193-204, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32088840

RESUMO

19F solid-state NMR is an excellent approach for measuring long-range distances for structure determination and for studying molecular motion. For multi-fluorinated proteins, assignment of 19F chemical shifts has been traditionally carried out using mutagenesis. Here we show 2D 19F-13C correlation experiments that allow efficient assignment of the 19F chemical shifts. We have compared several rotational-echo double-resonance-based pulse sequences and 19F-13C cross polarization (CP) for 2D 19F-13C correlation. We found that direct transferred-echo double-resonance (TEDOR) transfer from 19F to 13C and vice versa outperforms out-and-back coherence transfer schemes. 19F detection gives twofold higher sensitivity over 13C detection for the 2D correlation experiment. At MAS frequencies of 25-35 kHz, double-quantum 19F-13C CP has higher coherence transfer efficiencies than zero-quantum CP. The most efficient TEDOR transfer experiment has higher sensitivity than the most efficient double-quantum CP experiment. We demonstrate these 2D 19F-13C correlation experiments on the model compounds t-Boc-4F-phenylalanine and GB1. Application of the 2D 19F-13C TEDOR correlation experiment to the tetrameric influenza BM2 transmembrane peptide shows intermolecular 13C-19F cross peaks that indicate that the BM2 tetramers cluster in the lipid bilayer in an antiparallel fashion. This clustering may be relevant for the virus budding function of this protein.


Assuntos
Isótopos de Carbono/química , Flúor/química , Vírus da Influenza B/química , Marcação por Isótopo , Ressonância Magnética Nuclear Biomolecular , Proteínas da Matriz Viral/química
18.
Chemosphere ; 249: 126204, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088457

RESUMO

Spent potlining (SPL) as a hazardous solid waste has a high content of inorganic fluorine. This study aimed at characterizing its transformation, retention and leaching behaviors with(out) the addition of red mud (RM) during the SPL incineration. The RM addition positively affected its retention and leaching rates. Its Ca-containing compounds caused Na3AlF6 and NaF to turn into more CaF2. 30% RM converted water-soluble NaF into more stable CaF2 than did SPL at 850 °C, thus reducing the leaching rate by 45.15%. 30% RM captured HF through its Ca content and enhanced its retention rate by 66.96%. 66.01% of the total fluorine was stably retained in the bottom ash, and thus, significantly reduced the toxicity of the SPL incineration products. SiO2 and Al2O3 exerted a thermally positive effect on NaF turning into CaF2. The fluoride retention of the bottom ash was mainly dominated by CaF2 and NaF with(out) RM. Smaller, coarser and more loose structures of the co-incinerated solid particles pointed to a synergistic interaction between SPL and RM.


Assuntos
Flúor/química , Incineração , Modelos Químicos , Cinza de Carvão/química , Fluoretos , Resíduos Perigosos , Dióxido de Silício , Resíduos Sólidos , Termodinâmica , Água
19.
Chemosphere ; 248: 125979, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32028158

RESUMO

In China, the amount of phosphogypsum (PG) has exceeded 250 million tons with more than 55 million tons of growth rates each year. As the micro constituent, fluorine and phosphorus restrict the resourceful disposal of PG. This paper focused on chemical looping gasification (CLG) which used PG as an oxygen carrier, systematically investigated the gasification performance and chemical behavior of fluorine and phosphorus contained in PG during CLG process. Main conclusions are as follows. The main pollutant of chemical looping gasification process was HF, which was transformed from NaF. Phosphorus transformed from water-soluble phosphorus (Ca(H2PO4)2, Ca(HPO4)) into insoluble Ca3(PO4)2.20 reducing-oxidizing cycles were investigated, and a less and less fluorine content in oxygen carrier was found because its phase transformation from solid NaF to gaseous HF, and the phosphorus content in oxygen carrier changed slightly under the current conditions. The Ca3(PO4)2 particle layers existed in both the middle of the reduced solid particles and the middle of the cycled oxygen carrier particles, confirmed to actually act as a glue between the particles. Furthermore, transformation routes of fluorine and phosphorus during the CLG process were discussed and the generation of syngas in CLG process needed to be purified.


Assuntos
Sulfato de Cálcio/química , Flúor/química , Fósforo/química , China , Fluoretos , Gases , Oxigênio/química , Água
20.
Chemosphere ; 248: 125971, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32035380

RESUMO

As reported in Chemosphere by Colles et al. (2020), there are multiple pathways for human exposure to poly- and perfluoroalkyl substances (PFAS). Now, a new chemical formation of C-F bonds in drug delivery lead to concerns for human exposure as these inert chemical formations are resistance to metabolic degradation and excretion.


Assuntos
Carbono/química , Sistemas de Liberação de Medicamentos , Flúor/química , Fluoretos , Fluorcarbonetos , Humanos
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