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1.
Nat Commun ; 11(1): 5287, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082324

RESUMO

Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.


Assuntos
Receptores LHRH/química , Receptores LHRH/metabolismo , Sítios de Ligação , Cristalização , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Conformação Proteica em alfa-Hélice , Pirimidinas/química , Pirimidinas/metabolismo , Receptores LHRH/genética
2.
Nature ; 585(7826): 530-537, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32968259

RESUMO

Post-translational modifications (PTMs) greatly expand the structures and functions of proteins in nature1,2. Although synthetic protein functionalization strategies allow mimicry of PTMs3,4, as well as formation of unnatural protein variants with diverse potential functions, including drug carrying5, tracking, imaging6 and partner crosslinking7, the range of functional groups that can be introduced remains limited. Here we describe the visible-light-driven installation of side chains at dehydroalanine residues in proteins through the formation of carbon-centred radicals that allow C-C bond formation in water. Control of the reaction redox allows site-selective modification with good conversions and reduced protein damage. In situ generation of boronic acid catechol ester derivatives generates RH2C• radicals that form the native (ß-CH2-γ-CH2) linkage of natural residues and PTMs, whereas in situ potentiation of pyridylsulfonyl derivatives by Fe(II) generates RF2C• radicals that form equivalent ß-CH2-γ-CF2 linkages bearing difluoromethylene labels. These reactions are chemically tolerant and incorporate a wide range of functionalities (more than 50 unique residues/side chains) into diverse protein scaffolds and sites. Initiation can be applied chemoselectively in the presence of sensitive groups in the radical precursors, enabling installation of previously incompatible side chains. The resulting protein function and reactivity are used to install radical precursors for homolytic on-protein radical generation; to study enzyme function with natural, unnatural and CF2-labelled post-translationally modified protein substrates via simultaneous sensing of both chemo- and stereoselectivity; and to create generalized 'alkylator proteins' with a spectrum of heterolytic covalent-bond-forming activity (that is, reacting diversely with small molecules at one extreme or selectively with protein targets through good mimicry at the other). Post-translational access to such reactions and chemical groups on proteins could be useful in both revealing and creating protein function.


Assuntos
Luz , Processamento de Proteína Pós-Traducional/efeitos da radiação , Proteínas/química , Proteínas/metabolismo , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Sítios de Ligação , Carbono/química , Carbono/metabolismo , Enzimas/química , Enzimas/metabolismo , Ésteres/síntese química , Ésteres/química , Células HeLa , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/metabolismo , Indicadores e Reagentes/química , Oxirredução , Processos Fotoquímicos/efeitos da radiação , Domínios e Motivos de Interação entre Proteínas
3.
Nat Commun ; 11(1): 4761, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958762

RESUMO

Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.


Assuntos
Aminas/química , Aminas/síntese química , Hidrocarbonetos Fluorados/química , Técnicas de Química Sintética , Estrutura Molecular , Bibliotecas de Moléculas Pequenas , Estereoisomerismo
4.
Nat Commun ; 11(1): 2569, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444828

RESUMO

Methods for direct C-H trifluoromethoxylation of arenes and heteroarenes are rare, despite the importance of trifluoromethoxylated compounds for pharmaceuticals, agrochemicals, and material sciences. Especially selective C-H trifluoromethoxylation of pyridines remains a formidable challenge. Here we show a general late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagent with trifluoromethoxide anion. The reaction is mediated by silver salts under mild reaction conditions, exhibiting broad substrate scope and wide functional-group compatibility. In addition, ortho-position selective C-H trifluoromethoxylation of pyridines is observed. The method is not only applicable to the gram-scale synthesis of trifluoromethoxylated products but also allows efficient late-stage C-H trifluoromethoxylation of marketed small-molecule drugs, common pharmacophores and natural products.


Assuntos
Hidrocarbonetos Fluorados/química , Técnicas de Química Sintética , Piridinas/química , Compostos de Prata/química
5.
Ecotoxicol Environ Saf ; 199: 110679, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32402896

RESUMO

Chlordane is a worldwide banned organochlorine insecticide because of its hazard to animal and human health. It is also a persistent organic pollutant, which can affect either the soil or the aquatic life. The same applies to other chlorinated cyclodiene insecticides, such as dieldrin and aldrin. In turn, organofluorine compounds have a widespread use in agriculture. Therefore, density functional calculations and docking studies showed that the bioisosteric replacement of chlorines in the above-mentioned compounds by fluorines improves some physicochemical parameters used to estimate the toxicity and environmental risk of these compounds, as well as the ligand-enzyme (GABAA receptor-chloride channel complex) interactions related to their insecticidal activity. This work is an effort to provide an improved new class of organofluorine pesticides.


Assuntos
Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/química , Modelos Teóricos , Praguicidas/química , Receptores de GABA-A/química , Animais , Fenômenos Químicos , Halogenação , Humanos , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Clorados/toxicidade , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/toxicidade , Simulação de Acoplamento Molecular , Praguicidas/farmacologia , Praguicidas/toxicidade
6.
Food Chem ; 321: 126746, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32278276

RESUMO

This work describes the screening of twenty three per- and polyfluoroalkyl substances (PFASs) in twenty five paper and board (P/B) packaging materials and their migration to several food simulants (50% ethanol, 95% ethanol and Tenax®) at different conditions of time and temperature. A different migration pattern depending on the carbon chain length was observed; while short carbon chain PFASs tend to migrate more to 50% ethanol than to 95% ethanol, long chain PFASs showed the opposite trend. On the other hand, very low migration percentages of all PFASs to Tenax® were found. Finally, migration of 9 PFASs into real foods (cereals, rice and infant milk powder) for 6 months was quantified and compared with the results obtained with the simulants. As a result, significant underestimations of the PFASs migration to foodstuffs were obtained using Tenax®, especially for short carbon chain PFASs and milk powder.


Assuntos
Contaminação de Alimentos/análise , Embalagem de Alimentos , Hidrocarbonetos Fluorados/análise , Grão Comestível , Etanol/química , Hidrocarbonetos Fluorados/química , Papel , Polímeros/química , Temperatura
7.
Molecules ; 25(3)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32024162

RESUMO

In recent years, many papers describing ionic liquids (IL) as promising solvents in separation techniques have been published. The conscious choice of appropriate ionic liquid as absorption media in effective extraction of selected types of analytes requires deeper understanding of the analyte-IL interactions. Therefore, intensive research is conducted to determine the values of activity coefficient at infinite dilution, which allows us to characterize the nature of these interactions. Based on the inverse gas chromatography retention data, activity coefficients at infinite dilution γ 13 ∞ of 48 different organic compounds in the ionic liquids N-ethyl-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide [C2C1Mor][TFSI] and N-octyl-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide [C8C1Mor][TFSI] were determined. The measurements covered a broad range of volatile organic compounds, including n-alkanes, n-alkenes, n-alkynes, alcohols, aldehydes, ketones, aromatic compounds and common polar solvents, representing different types of interactions. Activity coefficients at infinite dilution were measured in the temperature range from 313.15 to 363.15 K. The excess partial molar enthalpies and entropies at infinite dilution were determined. Selectivity at infinite dilution was also calculated for exemplary separation processes in the hexane/benzene system. The obtained results were analyzed and compared with literature data for ionic liquids containing the same anion [TFSI]¯ and different cations. The study results indicate that some potential applications of the investigated ionic liquids in separation problems exist.


Assuntos
Hidrocarbonetos Fluorados/química , Imidas/química , Líquidos Iônicos/química , Modelos Químicos , Compostos Orgânicos/química , Solventes/química , Algoritmos , Soluções
8.
Environ Toxicol Chem ; 39(4): 775-786, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32022323

RESUMO

To accurately predict the environmental fate of per- and polyfluoroalkyl substances (PFAS), high-quality physicochemical property data are required. Because such data are often not available from experiments, assessment of the accuracy of existing property estimation models is essential. The quality of predicted physicochemical property data for a set of 25 PFAS was examined using COSMOtherm, EPI Suite, the estimation models accessible through the US Environmental Protection Agency's CompTox Chemicals Dashboard, and Linear Solvation Energy Relationships (LSERs) available through the UFZ-LSER Database. The results showed that COSMOtherm made the most accurate acid dissociation constant and air-water partition ratio estimates compared with literature data. The OPEn structure-activity/property Relationship App (OPERA; developed through the CompTox Chemicals Dashboard) estimates of vapor pressure and dry octanol-air partition ratios were the most accurate compared with other models of interest. Wet octanol-water partition ratios were comparably predicted by OPERA and EPI Suite, and the organic carbon soil coefficient and solubility were well predicted by OPERA and COSMOtherm. Acid dissociation of the perfluoroalkyl acids has a significant impact on their physicochemical properties, and corrections for ionization were included where applicable. Environ Toxicol Chem 2020;39:775-786. © 2020 SETAC.


Assuntos
Alcanos/química , Monitoramento Ambiental/métodos , Poluentes Ambientais/química , Hidrocarbonetos Fluorados/química , Modelos Químicos , Alcanos/análise , Alcanos/toxicidade , Poluentes Ambientais/análise , Poluentes Ambientais/toxicidade , Hidrocarbonetos Fluorados/análise , Hidrocarbonetos Fluorados/toxicidade , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Solubilidade , Termodinâmica , Estados Unidos , United States Environmental Protection Agency
9.
Molecules ; 25(3)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991642

RESUMO

Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by the photochemical activity of an electron donor-acceptor (EDA) complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences.


Assuntos
Alcenos/química , Hidrocarbonetos Fluorados/síntese química , Iodetos/química , Catálise , Hidrocarbonetos Fluorados/química , Processos Fotoquímicos
10.
J Med Chem ; 63(3): 1002-1031, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31894985

RESUMO

Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log P values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity-reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one- and two-fluorine 'deletions' within perfluoroalkyl groups. Quantum chemical log P calculations (SMD-MN15) based on solvent-dependent three-dimensional (3D) conformational analysis gave excellent correlations with experimental values, superior to Clog P predictions based on 2D structural motifs. The availability of a systematic collection of data based on a small number of parent molecules illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.


Assuntos
Hidrocarbonetos Fluorados/química , Interações Hidrofóbicas e Hidrofílicas , 1-Butanol/química , Halogenação , Conformação Molecular , Pentanóis/química
11.
Med Chem ; 16(1): 63-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30734682

RESUMO

BACKGROUND: A convenient approach to modulation of the inflammation has an influence on the production of inflammatory mediators - icosanoids, generated in arachidonic acid (AA) metabolism. The common therapeutic activity of non-steroidal anti-inflammatory drugs (NSAID), such as aspirin, includes inhibition of two crucial enzymes of AA metabolism - cyclooxygenase- 1 and -2 (COX-1/2), with certain risk for gastrointestinal and renal intolerance. Ever since the enrolment of COX-2, particularly overabundance of its main products prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in numerous pathological processes was recognized, it became a significant therapeutic target. OBJECTIVE: The aim of this study was to examine the effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in the inflammation process. METHODS: Trifluoromethyl compounds were synthesized from N-benzyl trifluoromethyl aldimine, commercially available 2-methyl or 2-phenyl α-bromo esters (ß-lactams trans-1 and trans-2 and trifluoromethyl ß-amino ester, respectively) and methyl 2-isocyanoacetate (2-imidazoline trans-4). The reactions proceeded with high geometric selectivity, furnishing the desired products in good yields. The influence of newly synthesized compounds on PGE2 and TXA2 production in human leukemic U937 macrophages on both enzyme activity and gene expression levels was observed. RESULTS: Among the tested trifluoromethyl compounds, methyl trans-1-benzyl-5-(trifluoromethyl)- 4,5-dihydro-1H-imidazole-4-carboxylate (trans-4) can be distinguished as the most powerful antiinflammatory agent, probably due to its trifluoromethyl-imidazoline moiety. CONCLUSION: Some further structural modifications in tested compounds and particularly in the synthesis of different trifluoromethyl imidazolines could contribute to the development of new COX-2 inhibitors and potent anti-inflammatory agents.


Assuntos
Dinoprostona/biossíntese , Hidrocarbonetos Fluorados/farmacologia , Macrófagos/efeitos dos fármacos , Tromboxano A2/biossíntese , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Células U937
12.
Chemosphere ; 240: 124947, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31568943

RESUMO

This work studies the effect of the cation and anion on the biodegradability and inhibition of imidazolium- and choline-based ionic liquids (ILs) using activated sludge. Six commercial ILs, formed by combination of 1-Butyl-3-methylimidazolium (Bmim+) and N,N,N-trimethylethanolammonium (Choline+) cations and chloride (Cl-), acetate (Ac-) and bis(trifluoromethanesulfonyl)imide (NTf2-) anions were evaluated, all representative counter-ions with markedly different toxicity and biodegradability. Inherent and fast biodegradability tests were used to evaluate both the microorganism inhibition and the IL biodegradability. In addition, the ecotoxicological response (EC50) of the ILs was studied using activated sludge and Vibrio fischeri (Microtox® test). Bmim+ and NTf2- can be considered as non-biodegradable, whereas aerobic microorganisms easily degraded Choline+ and Ac-. The biodegradation pattern of each cation/anion is nearly unaffected by counter-ion nature. Moreover, concentrations of CholineNTf2 higher than 50 mg/L caused a partial inhibition on microbial activity, in good concordance with its low EC50 (54 mg/L) measured by respiration inhibition test, which alerts on the negative environmental impact of NTf2-containing ILs on the performance of sewage treatment plants.


Assuntos
Aliivibrio fischeri/efeitos dos fármacos , Biodegradação Ambiental , Colina/análise , Hidrocarbonetos Fluorados/química , Imidazóis/análise , Imidazóis/química , Imidas/química , Compostos de Amônio Quaternário/química , Ecotoxicologia , Líquidos Iônicos/análise , Esgotos/química , Purificação da Água/métodos
13.
Molecules ; 24(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817797

RESUMO

Among the realm of visible light photocatalytic transformations, late-stage difluoromethylation reactions (introduction of difluoromethyl groups in the last stages of synthetic protocols) have played relevant roles as the CF2X group substitutions exert positive impacts on the physical properties of organic compounds including solubility, metabolic stability, and lipophilicity, which are tenets of considerable importance in pharmaceutical, agrochemical, and materials science. Visible-light-photocatalyzed difluoromethylation reactions are shown to be accomplished on (hetero)aromatic and carbon-carbon unsaturated aliphatic substrates under mild and environmentally benign conditions.


Assuntos
Alcenos/química , Carbono/química , Hidrocarbonetos Fluorados/química , Catálise , Estrutura Molecular , Compostos Orgânicos/química
14.
Org Lett ; 21(24): 9846-9851, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31789041

RESUMO

A convenient synthetic route to α,α-difluoroalkylphosphonates is described. Structurally diverse aldehydes are condensed with LiF2CP(O)(OCH2CH═CH2)2. The resultant alcohols are captured as the pentafluorophenyl thionocarbonates and efficiently deoxygenated with HSnBu3, BEt3, and O2, and then smoothly deblocked with CpRu(IV)(π-allyl)quinoline-2-carboxylate (1-2 mol %) in methanol as an allyl cation scavenger. These mild deprotection conditions provide access to free α,α-difluoroalkylphosphonates in nearly quantitative yield. This methodology is used to rapidly construct new bis-α,α-difluoroalkyl phosphonate inhibitors of PTPIB (protein phosphotyrosine phosphatase-1B).


Assuntos
Compostos Alílicos/química , Hidrocarbonetos Fluorados/farmacologia , Organofosfonatos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rutênio/química , Catálise , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
15.
Molecules ; 24(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835583

RESUMO

Enantiomerically pure derivatives of 2-amino-4,4,4-trifluorobutanoic acid are in great demand as bioisostere of leucine moiety in the drug design. Here, we disclose a method specifically developed for large-scale (>150 g) preparation of the target (S)-N-Fmoc-2-amino-4,4,4-trifluorobutanoic acid. The method employs a recyclable chiral auxiliary to form the corresponding Ni(II) complex with glycine Schiff base, which is alkylated with CF3-CH2-I under basic conditions. The resultant alkylated Ni(II) complex is disassembled to reclaim the chiral auxiliary and 2-amino-4,4,4-trifluorobutanoic acid, which is in situ converted to the N-Fmoc derivative. The whole procedure was reproduced several times for consecutive preparation of over 300 g of the target (S)-N-Fmoc-2-amino-4,4,4-trifluorobutanoic acid.


Assuntos
Butiratos/síntese química , Hidrocarbonetos Fluorados/síntese química , Alquilação , Butiratos/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , 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.
J Med Chem ; 62(24): 11348-11358, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31774672

RESUMO

The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target ß-catenin in this pathway. We now report that several "Wnt inhibitors" that allegedly target ß-catenin actually function as mitochondrial proton uncouplers that independently activate AMPK and concomitantly inhibit Wnt signaling. As expected for a process in which mitochondrial uncoupling diminishes ATP production, a mitochondrial proton uncoupler, FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and inhibited Wnt signaling. Also consistent with these findings, a well-known "Wnt inhibitor", FH535, functioned as a proton uncoupler, and in support of this finding, the N-methylated analog, 2,5-dichloro-N-methyl-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535-M), was inactive as an uncoupler and Wnt inhibitor. Apart from suggesting an opportunity to develop dual Wnt inhibitors and AMPK activators, these findings provide a cautionary tale that claims for Wnt inhibition alone require scrutiny as possible mitochondrial proton uncouplers or inhibitors of the electron transport chain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Encéfalo/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Mitocôndrias/efeitos dos fármacos , Ureia/farmacologia , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Metabolismo Energético , Ativação Enzimática , Ativadores de Enzimas/química , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocarbonetos Fluorados/química , Mitocôndrias/metabolismo , Consumo de Oxigênio , Sulfonamidas/química , Sulfonamidas/farmacologia , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
18.
J Phys Chem B ; 123(49): 10463-10469, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714083

RESUMO

The structure of fluorinated alcohols is a matter of considerable interest in view of wide-ranging biomolecular applications. The microheterogeneity of fluorinated alcohols in the liquid state, in particular, has been a matter of debate and discussion in recent years using experimental and theoretical methods, including neutron or X-ray diffraction, as well as density functional theory (DFT) and molecular dynamics (MD) simulations. Here, we show that 1H and 19F Overhauser dynamic nuclear polarization (ODNP) buildup curves in solution state at room temperature show unusual behavior that could offer a novel approach to investigate the structural heterogeneity and dynamics of such homogeneous liquids with improved sensitivity. A detailed analysis of multiexponential ODNP buildup curves as a function of microwave irradiation time is shown to evidence microheterogeneity in such systems. Experimental ODNP buildup rates are interpreted using simple motional models that yield the motional correlation times of the relevant species in solution. It may be emphasized that this information is not available from standard approaches of high-resolution nuclear magnetic resonance (NMR) spectroscopy. While the present study focuses on fluorinated alcohols, it is to be anticipated that this approach would be valuable in the study of molecular assemblies in the solution state, including peptides, surfactant systems, etc.


Assuntos
Álcoois/química , Teoria da Densidade Funcional , Hidrocarbonetos Fluorados/química , Simulação de Dinâmica Molecular , Temperatura , Espectroscopia de Ressonância Magnética , Peptídeos/química , Tensoativos/química
19.
Org Biomol Chem ; 17(47): 10097-10102, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31754683

RESUMO

New open-chain and water-soluble hypervalent iodine reagents were synthesized and used for the transfer of fluoroalkyl groups to sulfur atoms of cysteine and cysteine-containing peptides under biocompatible conditions. Some of the reagents displayed excellent reactivity despite their limited stability in aqueous media. In reactions with a short cysteine-containing peptide, in addition to the expected S-fluoroalkylated product, a range of side-products were obtained. The amount of side-products depended on the conditions used (type of reagent, concentration, and pH). With highly activated hypervalent iodine reagents, a new reactive mode was observed - reaction with disulfides to form fluoroalkyl thiols.


Assuntos
Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Indicadores e Reagentes/química , Indicadores e Reagentes/síntese química , Iodo/química , Compostos de Sulfidrila/química , Água/química , Alquilação , Estrutura Molecular , Solubilidade
20.
Org Lett ; 21(23): 9377-9380, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31742416

RESUMO

A method for the O-difluoromethylation of carboxylic acids using commercially available TMSCF2Br is disclosed. The devised benchtop reaction system is air-stable and offers mild reaction conditions while using readily available reagents and solvents. The method is applicable to both aliphatic and aromatic carboxylic acids while demonstrating compatibility with a range of commonly encountered functional groups. The difluoromethyl esters of FDA approved drugs and pharmaceutically relevant molecules are also presented, demonstrating the potential for late-stage functionalization.


Assuntos
Ácidos Carboxílicos/química , Ésteres/química , Hidrocarbonetos Fluorados/química , Metilação , Silanos/química
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