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1.
Biomed Khim ; 66(1): 18-29, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32116223

RESUMO

Mass spectrometric proteomic analysis at the sample preparation stage involves the artificial reduction of disulfide bonds in proteins formed between cysteine residues. Such bonds, when preserved in their native state, complicate subsequent enzymatic hydrolysis and interpretation of the research results. To prevent the re-formation of the disulfide bonds, cysteine residues are protected by special groups, most often by alkylation. In this review, we consider the methods used to modify cysteine residues during sample preparation, as well as possible artifacts of this stage. Particularly, adverse reactions of the alkylating agents with other amino acid residues are described. The most common alkylating compound used to protect cysteine residues in mass spectrometric proteomic analysis is iodoacetamide. However, an analysis of the literature in this area indicates that this reagent causes more adverse reactions than other agents used, such as chloroacetamide and acrylamide. The latter can be recommended for wider use. In the review we also discuss the features of the cysteine residue modifications and their influence on the efficiency of the search for post-translational modifications and protein products of single nucleotide substitutions.


Assuntos
Artefatos , Cisteína/química , Espectrometria de Massas , Proteômica , Alquilação
2.
Chem Commun (Camb) ; 56(16): 2495-2498, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32003367

RESUMO

Herein, we report the photocatalytic decarboxylative alkenylation reactions of N-(acyloxy)phthalimide derived from α-amino and α-hydroxy acids with 1,1-diarylethene, and with cinnamic acid derivatives through double decarboxylation, using sodium iodide and triphenylphosphine as redox catalysts. The reaction proceeds under mild irradiation conditions with visible blue light (440 nm or 456 nm) in an acetone solvent without recourse to transition-metal or organic dye based photoredox catalysts. The reaction proceeds via photoactivation of a transiently self-assembled chromophore from N-(acyloxy)phthalimide and NaI/PPh3. Solvation plays a crucial role in the reactivity.


Assuntos
Aminoácidos/química , Hidroxiácidos/química , Compostos Organofosforados/química , Iodeto de Sódio/química , Alquilação , Catálise , Descarboxilação , Estrutura Molecular , Oxirredução , Processos Fotoquímicos
3.
Chemistry ; 26(9): 1906-1921, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693220

RESUMO

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.


Assuntos
Compostos Alílicos/química , Produtos Biológicos/síntese química , Preparações Farmacêuticas/síntese química , Alquilação , Produtos Biológicos/química , Carbono/química , Catálise , Ciclização , Metais/química , Preparações Farmacêuticas/química , Estereoisomerismo
4.
Chem Biol Interact ; 315: 108905, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31765606

RESUMO

Mineral oils are widely applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.


Assuntos
Alquilantes/metabolismo , Microssomos Hepáticos/metabolismo , Naftalenos/metabolismo , Alquilação/fisiologia , Animais , Cromatografia Gasosa/métodos , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Oxirredução , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Ratos , Espectrometria de Massas em Tandem/métodos
5.
Nat Commun ; 10(1): 5611, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819057

RESUMO

Oxidation and alkylation of nucleobases are known to disrupt their base-pairing properties within RNA. It is, however, unclear whether organisms have evolved general mechanism(s) to deal with this damage. Here we show that the mRNA-surveillance pathway of no-go decay and the associated ribosome-quality control are activated in response to nucleobase alkylation and oxidation. Our findings reveal that these processes are important for clearing chemically modified mRNA and the resulting aberrant-protein products. In the absence of Xrn1, the level of damaged mRNA significantly increases. Furthermore, deletion of LTN1 results in the accumulation of protein aggregates in the presence of oxidizing and alkylating agents. This accumulation is accompanied by Hel2-dependent regulatory ubiquitylation of ribosomal proteins. Collectively, our data highlight the burden of chemically damaged mRNA on cellular homeostasis and suggest that organisms evolved mechanisms to counter their accumulation.


Assuntos
Estresse Oxidativo , Ribossomos/metabolismo , 4-Nitroquinolina-1-Óxido/metabolismo , Alquilação , Adutos de DNA/metabolismo , Dano ao DNA , Células HEK293 , Humanos , Metanossulfonato de Metila/farmacologia , Mutação/genética , Oxirredução , Peptídeos/metabolismo , Polirribossomos/metabolismo , Agregados Proteicos , Quinolonas/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/metabolismo , Ribossomos/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
6.
Top Curr Chem (Cham) ; 377(6): 38, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31732819

RESUMO

The concept of merging enamine activation catalysis with transition metal catalysis is an important strategy, which allows for selective chemical transformations not accessible without this combination. The amine catalyst activates the carbonyl compounds through the formation of a reactive nucleophilic enamine intermediate and, in parallel, the transition metal activates a wide range of functionalities such as allylic substrates through the formation of reactive electrophilic π-allyl-metal complex. Since the first report of this strategy in 2006, considerable effort has been devoted to the successful advancement of this technology. In this chapter, these findings are highlighted and discussed.


Assuntos
Aminas/química , Elementos de Transição/química , Alquilação , Alquinos/química , Catálise , Complexos de Coordenação/química , Ciclização , Cetonas/química , Estereoisomerismo
7.
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
8.
Nat Commun ; 10(1): 4847, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649248

RESUMO

It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogen Brucella abortus does encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required by B. abortus to face this stress in vitro and in a mouse infection model. Among these genes, ogt is found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair in B. abortus displays distinct features that are not present in model organisms such as Escherichia coli.


Assuntos
Brucella abortus/genética , Dano ao DNA/genética , Interações Hospedeiro-Patógeno/genética , Macrófagos/metabolismo , Estresse Fisiológico/genética , Alquilação , Animais , Brucella abortus/metabolismo , Brucelose , Metilação de DNA/genética , Reparo do DNA/genética , Camundongos , Células RAW 264.7 , Vacúolos/metabolismo
9.
Molecules ; 24(20)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623100

RESUMO

The ethylation of aryl alcohols by an ethyl moiety of boron trifluoride etherate is described. The reaction proceeded cleanly and afforded good yields of the corresponding aryl ethyl ethers. It tolerated the presence of functional groups such as aryl, alkyl, halogens, nitro, nitrile, and amino. However, the presence of amino or nitro groups ortho to a hydroxyl group of an aryl compound drastically reduced the yields of the anticipated products due to the chelation of the aforementioned functional groups with boron trifluoride etherate. A nitrogen atom in the aromatic ring system, as exemplified by hydroxypyridine and 8-hydroxyquinoline, completely inhibited the reaction. Resorcinol, hydroquinone, and aryl alcohols with aldehyde functions decomposed under the reaction conditions.


Assuntos
Álcoois/química , Boranos/química , Alquilação/efeitos dos fármacos , Boranos/farmacologia , Éteres , Estrutura Molecular
10.
Nat Commun ; 10(1): 4073, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501427

RESUMO

Several antitumor therapies work by increasing reactive oxygen species (ROS) within the tumor micromilieu. Here, we reveal that L-plastin (LPL), an established tumor marker, is reversibly regulated by ROS-induced thiol oxidation on Cys101, which forms a disulfide bridge with Cys42. LPL reduction is mediated by the Thioredoxin1 (TRX1) system, as shown by TRX1 trapping, TRX1 knockdown and blockade of Thioredoxin1 reductase (TRXR1) with auranofin. LPL oxidation diminishes its actin-bundling capacity. Ratiometric imaging using an LPL-roGFP-Orp1 fusion protein and a dimedone-based proximity ligation assay (PLA) reveal that LPL oxidation occurs primarily in actin-based cellular extrusions and strongly inhibits cell spreading and filopodial extension formation in tumor cells. This effect is accompanied by decreased tumor cell migration, invasion and extracellular matrix (ECM) degradation. Since LPL oxidation occurs following treatment of tumors with auranofin or γ-irradiation, it may be a molecular mechanism contributing to the effectiveness of tumor treatment with redox-altering therapies.


Assuntos
Actinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neoplasias/metabolismo , Alquilação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Extensões da Superfície Celular/metabolismo , Cisteína/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Modelos Biológicos , Mutação/genética , Oxirredução , Compostos de Sulfidrila/metabolismo , Tiorredoxina Redutase 1/metabolismo
11.
Chemistry ; 25(69): 15779-15785, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523878

RESUMO

A series of fluoroalkylated cyclic λ3 -iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.


Assuntos
Aminoácidos Aromáticos/química , Indóis/química , Peptídeos/química , Proteínas/química , Pirróis/química , Alquilação , Aminoácidos Aromáticos/síntese química , Radicais Livres/síntese química , Radicais Livres/química , Halogenação , Humanos , Indóis/síntese química , Modelos Moleculares , Peptídeos/síntese química , Proteínas/síntese química , Pirróis/síntese química
12.
Molecules ; 24(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540061

RESUMO

New 1,2,3-triazolium ionic liquid-supported chiral imidazolidinones were developed. The feasibility of the ionic liquid-supported imidazolidinones as chiral auxiliaries was demonstrated in sequential propionylation-alkylation-cleavage reactions, which provided the chiral product with good to excellent chemical yields (up to 90%) and high selectivities (up to 94% ee). The progress of the reactions could be monitored by TLC and NMR, and the ionic liquid-supported chiral auxiliaries could be recovered by simple extraction.


Assuntos
Imidazolidinas/química , Imidazolidinas/síntese química , Líquidos Iônicos/química , Líquidos Iônicos/síntese química , Alquilação , Estereoisomerismo
13.
Mar Pollut Bull ; 149: 110547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31542592

RESUMO

Polycyclic aromatic hydrocarbons (PAH) are a group of ubiquitous environmental pollutants among which some compounds show carcinogenic properties. The emission of PAH from anthropogenic and natural sources to the aquatic environment demands monitoring. In this study, ten different surface water samples were collected and analyzed for 48 different PAH compounds by gas chromatography-atmospheric-pressure-laser-ionization coupled to mass spectrometry (GC-APLI-MS) after liquid-liquid extraction. Results varied from 9.22 ng/L for fluoranthene in harbor water to 0.01 ng/L for 4-methylchrysene in Rhine river water. Overall low PAH concentrations were found in the samples. Toxic equivalent (TEQ) calculations were used to assess the potential environmental impact of the analyzed compounds. The results showed higher concentrations and TEQ for the samples from harbors in comparison to riverine and estuarine sampling locations. Suspected target analysis indicated the occurrence of alkylated PAH in the surface water samples.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes Químicos da Água/análise , Alquilação , Carcinógenos/análise , Estuários , Alemanha , Extração Líquido-Líquido , Rios , Sensibilidade e Especificidade
14.
Carbohydr Res ; 484: 107780, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479870

RESUMO

This work combined three classes of compounds in the same molecule "amino triazole-glycoside" and developed a convenient method for the synthesis of this type of compound via a one-pot two step reaction. Alkylation of amine derivatives with propargyl bromide to give propargylamine was performed in the first step subsequently followed by a 'click' reaction with various ß-azido-glycosides in the presence of CuI in aqueous solution to provide ß-amino triazole-glycosides. Thirty-two examples of glycosides were obtained in moderate to good yield using this one-pot procedure.


Assuntos
Química Click/métodos , Glicosídeos/síntese química , Alquilação , Aminas/química , Sequência de Carboidratos , Glicosídeos/química , Pargilina/análogos & derivados , Pargilina/química , Propilaminas/química , Triazóis/química
15.
Amino Acids ; 51(9): 1365-1375, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31471744

RESUMO

The regulatory role of protein cysteine phosphorylation is an under-researched area. The difficulty of accessing reference S-phosphorylated peptides (pCys-peptides) hampers progress in MS-driven cysteine phosphoproteomics, which requires targeted analytical procedures. This work describes an uncomplicated process for the conversion of disulfide-bridged protein into a complex model mixture of combinatorially modified peptides. Hen egg-white lysozyme was reduced with tris(2-carboxyethyl)phosphine (TCEP) followed by alkylation of cysteine with (3-acrylamidopropyl)trimethyl-ammonium chloride (APTA) and subsequent beta-elimination in aqueous Ba(OH)2 to yield modified polypeptides containing multiple dehydroalanine (Dha) residues. The conjugate addition of thiophosphoric acid to Dha residues followed by trypsinolysis led to numerous D/L phosphocysteine-containing peptides, which were identified by higher-energy collisional-dissociation tandem mass spectrometry (HCD-MS/MS). Our results show that some pCys-peptides produce prominent neutral losses of 80 Da, 98 Da and a weak 116 Da loss. These are similar to the neutral-loss triplets generated by phosphohistidine peptides.


Assuntos
Cisteína/química , Fosfopeptídeos/normas , Proteômica/métodos , Espectrometria de Massas em Tandem/normas , Alquilação , Dissulfetos/química , Muramidase/química , Peptídeos/síntese química , Peptídeos/química , Fosfopeptídeos/química , Proteínas/química , Espectrometria de Massas em Tandem/métodos
16.
Nat Commun ; 10(1): 4015, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488839

RESUMO

The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. Since natural products are the most valuable source for the discovery of therapeutics, the derivatization of natural products has been extensively investigated to generate molecules for biological screenings. However, most previous approaches only modified a limited number of functional groups, which resulted in a limited number of skeleta. Here we show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry - the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings. This library occupies a unique chemical space compared to selected diverse reference compounds. The diversification strategy developed herein for steroids can also be expanded to other types of natural products.


Assuntos
Produtos Biológicos/química , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Alquilação , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Engenharia Química/métodos , Humanos , Imidas , Estrutura Molecular , Oxirredução , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
17.
Nat Commun ; 10(1): 3553, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391461

RESUMO

Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. While C-H arylations emerged for peptide modifications, they are largely limited to highly reactive, expensive and/or toxic reagents, such as silver(I) salts, in superstoichiometric quantities. In sharp contrast, we herein establish the ruthenium(II)-catalyzed C-H alkylation on structurally complex peptides. The additive-free ruthenium(II)carboxylate C-H activation manifold is characterized by ample substrate scope, racemization-free conditions and the chemo-selective tolerance of otherwise reactive functional groups, such as electrophilic ketone, bromo, ester, amide and nitro substituents. Mechanistic studies by experiment and computation feature an acid-enabled C-H ruthenation, along with a notable protodemetalation step. The transformative peptide C-H activation regime sets the stage for peptide ligation in solution and proves viable in a bioorthogonal fashion for C-H alkylations on user-friendly supports by means of solid phase peptide syntheses.


Assuntos
Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Alquilação , Carbono/química , Catálise , Hidrogênio/química , Ligações de Hidrogênio , Rutênio/química
18.
Methods Mol Biol ; 1934: 93-125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256376

RESUMO

Even if a consensus sequence has been identified for a posttranslational modification, the presence of such a sequence motif only indicates the possibility, not the certainty that the modification actually occurs. Proteins can be glycosylated on certain amino acid side chains, and these modifications are designated as C-, N-, and O-glycosylation. C-mannosylation occurs on Trp residues within a relatively loosely defined consensus motif. N-glycosylated species are modified at Asn residues of Asn-Xxx-Ser/Thr/Cys sequons (where Xxx can be any amino acid except proline). N-linked oligosaccharides share a common core structure of GlcNAc2Man3. In addition, an enzyme, peptide N-glycosidase F (PNGase F), removes most of the common N-linked carbohydrates unaltered from proteins while hydrolyzing the originally glycosylated Asn residue to Asp. O-glycosylation occurs at Ser, Thr, and Tyr residues, usually in sequence stretches rich in hydroxy-amino acids. O-glycosylation lacks a common core structure. Mammalian proteins have been reported bearing O-linked N-acetylgalactosamine, fucose, glucose, xylose, mannose, and corresponding elongated structures, as well as N-acetylglucosamine. Chemical methods are used to liberate these oligosaccharides because no enzyme would remove all the different O-linked carbohydrates. Characterization of both N- and O-glycosylation is complicated by the fact that the same positions within a population of protein molecules may feature an array of different carbohydrate structures, or remain unmodified. This site-specific heterogeneity may vary by species and tissue, and may also be affected by physiological changes. For addressing site-specific carbohydrate heterogeneity mass spectrometry has become the method of choice. Reversed-phase HPLC directly coupled with electrospray ionization mass spectrometry (LC/ESI-MS/MS) offers the best solution. Using a mass spectrometer as online detector not only assures the analysis of every component eluting (mass mapping), but also at the same time diagnostic carbohydrate ions can be generated by collisional activation that permits the selective and specific detection of glycopeptides. In addition, ESI-compatible alternative MS/MS techniques, electron-capture and electron-transfer dissociation, aid glycopeptide identification as well as modification site assignments.


Assuntos
Glicoproteínas/química , Proteínas/química , Espectrometria de Massas por Ionização por Electrospray , Alquilação , Sequência de Aminoácidos , Cromatografia Líquida , Glicopeptídeos/química , Glicoproteínas/metabolismo , Glicosilação , Oligossacarídeos/química , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Espectrometria de Massas em Tandem
19.
Methods Mol Biol ; 1934: 163-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256379

RESUMO

Phosphorylation, the process by which a phosphate group is attached to a preexisting protein, is an evolutionarily and metabolically cheap way to change the protein's surface and properties. It is presumably for that reason that it is the most widespread protein modification: An estimated 10-30% of all proteins are subject to phosphorylation.MS-based methods are the methods of choice for the identification of phosphorylation sites; however biochemical pre-fractionation and enrichment protocols will be needed to produce suitable samples in the case of low-stoichiometry phosphorylation. Using emerging MS-based technology, the elucidation of the "phosphoproteome," a comprehensive inventory of phosphorylation sites, will become a realistic goal. However, validating these findings in a cellular context and defining their biological meaning remains a daunting task, which will inevitably require extensive and time-consuming additional biological research.


Assuntos
Cromatografia Líquida , Fosfoproteínas/química , Proteínas/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Alquilação , Sequência de Aminoácidos , Fosfoproteínas/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Proteoma , Proteômica/métodos
20.
Chem Pharm Bull (Tokyo) ; 67(9): 966-976, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257308

RESUMO

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Inflamação/metabolismo , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Estereoisomerismo
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