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1.
Chemistry ; 26(2): 379-383, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609031

RESUMO

Peptide alcohols are clinically important compounds that are underexplored in structure-activity relationship (SAR) studies in drug discovery. One reason for this underutilization is that current syntheses are laborious and time consuming. Herein, we describe the preparation and utility of Rink, Ramage, and Sieber-chloride resins, which enables the use of a general, easy and practical method for the attachment of fluorenylmethoxycarbonyl (Fmoc)-amino alcohols to a solid support, in the synthesis of peptide alcohols. This method is the first straightforward Fmoc/tBu synthesis of peptide alcohols starting from a pre-loaded resin. The synthesized peptide alcohols can be detached from the linkers through conventional methods. Treatment with trifluoroacetic acid (TFA) (95 %) and scavengers such as triisopropylsilane and water for 2 h is sufficient to obtain a fully deprotected peptide alcohol, while treatment with 20 % hexafluoroisopropanol in dichloromethane renders a fully protected peptide alcohol that can be further modified at the C-terminus. As examples, the new resins were used in straightforward, relatively rapid syntheses of the peptide alcohols octreotide, alamethicin, and a segment of trichogin GA IV, as well as the first synthesis of stapled peptide alcohols.


Assuntos
Amino Álcoois/química , Peptídeos/química , Peptídeos/síntese química , Fenilalanina/análogos & derivados , Fenilalanina/química , Poliestirenos/química , Ácido Trifluoracético/química
2.
Eur J Med Chem ; 182: 111645, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494472

RESUMO

As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent-kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluated. Compared with FA, the anticancer activity and solubility of most derivatives were significantly improved. Among them, compound 6d had the best activity, and its IC50 value against Esophageal cancer cells (TE-1) was up to 0.75 µM. Subsequent cellular mechanism studies showed that compound 6d could inhibit the proliferation of cancer cells, the formation of cell colonies, and increase the level of ROS on TE-1 cells. In addition, 6d could up-regulate the expressions of SAPK/JNK pathway-associated proteins (p-ASK1, p-MKK4 and p-JNK) and pro-apoptotic proteins (Bak, Bad and Noxa), remarkably increase the ratio of Bax to Bcl-2 and activate Cleaved Caspase-3/9/PARP. These results indicate that compound 6d induces apoptosis through the ROS/JNK/Bcl-2 pathway and holds promising potential as an anti-proliferative agent.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Ácido Trifluoracético/farmacologia , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ácido Trifluoracético/química , Células Tumorais Cultivadas
3.
J Chromatogr A ; 1604: 460494, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31488292

RESUMO

The objective of this study is to understand the behavior of a peptide in a medium containing supercritical carbon dioxide mixed with an alcohol (methanol) and acidic or basic additives in uncommonly high concentrations. Chirobiotic TAG is a chromatographic column made of silica bonded with a macrocyclic peptide, teicoplanin aglycone. With this stationary phase, two additives (trifluoroacetic acid and isopropylamine) were tested under extreme concentration conditions to observe the behavior of this peptide. Indeed, concentrations exceeding 1 M in the methanol co-solvent (>0.1 M overall concentration in the CO2-methanol mixture) were used whereas usual additive concentrations employed in supercritical fluid chromatography (SFC) rarely exceed 50 mM in the co-solvent. One purpose was to modify the apparent pH of the fluid, which is normally slightly acidic (around 5) and consequently possibly changing the ionization state of the peptide. Firstly, the effect of acidic and basic additives on the polarity and the apparent pH were evaluated with the help of color indicators. This served to assess the ionization state of the peptide under the selected operating conditions. Secondly, 54 achiral and 24 chiral molecules were injected in the chromatographic column at different levels of additives. The achiral species served at establishing retention models based on linear solvation energy relationships (LSER), while the chiral species were examined for their enantioresolution. From the LSER equations and observation of chromatograms, it appeared that specific interactions between the peptide-based stationary phase and the analytes evolved when increasing the concentration of additives, particularly hydrogen bonds and ionic interactions. A bare silica stationary phase (Acquity BEH) served as reference to deconvolute the contributions of silica support and bonded peptide. This study, with these extreme conditions of mobile phase, could be useful to understand the behavior of such peptides in SFC mobile phases and also improve the knowledge of the effects of additives in SFC, which should be helpful in the future prospect of analyzing large biomolecules in SFC.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Teicoplanina/análogos & derivados , Compostos Azabicíclicos/química , Ligações de Hidrogênio , Concentração de Íons de Hidrogênio , Íons , Metanol/química , Piperazinas/química , Solventes/química , Estereoisomerismo , Teicoplanina/química , Teicoplanina/isolamento & purificação , Ácido Trifluoracético/química
4.
J Chromatogr A ; 1598: 92-100, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30961963

RESUMO

A strategy for determining a suitable solvent gradient in silico in preparative peptide separations is presented. The strategy utilizes a machine-learning-based method, called ELUDE, for peptide retention time predictions based on the amino acid sequences of the peptides. A suitable gradient is calculated according to linear solvent strength theory by predicting the retention times of the peptides being purified at three different gradient slopes. The advantage of this strategy is that fewer experiments are needed to develop a purification method, making it useful for labs conducting many separations but with limited resources for method development. The preparative separation of met-enkephalin and leu-enkephalin was used as model solutes on two stationary phases: XBridge C18 and CSH C18. The ELUDE algorithm contains a support vector regression and is pre-trained, meaning that only 10-50 peptides are needed to calibrate a model for a certain stationary phase and gradient. The calibration is done once and the model can then be used for new peptides similar in size to those in the calibration set. We found that the accuracy of the retention time predictions is good enough to usefully estimate a suitable gradient and that it was possible to compare the selectivity on different stationary phases in silico. The absolute relative errors in retention time for the predicted gradients were 4.2% and 3.7% for met-enkephalin and leu-enkephalin, respectively, on the XBridge C18 column and 2.0% and 2.8% on the CSH C18 column. The predicted retention times were also used as initial values for adsorption isotherm parameter determination, facilitating the numerical calculation of overloaded elution profiles. Changing the trifluoroacetic acid (TFA) concentration from 0.05% to 0.15% in the eluent did not seriously affect the error in the retention time predictions for the XBridge C18 column, an increase of 1.0 min (in retention factor, 1.3). For the CSH C18 column the error was, on average, 2.6 times larger. This indicates that the model needs to be recalibrated when changing the TFA concentration for the CSH column. Studying possible scale-up complications from UHPLC to HPLC such as pressure, viscous heating (i.e., temperature gradients), and stationary-phase properties (e.g., packing heterogeneity and surface chemistry) revealed that all these factors were minor to negligible. The pressure effect had the largest effect on the retention, but increased retention by only 3%. In the presented case, method development can therefore proceed using UHPLC and then be robustly transferred to HPLC.


Assuntos
Técnicas de Química Analítica/métodos , Cromatografia de Fase Reversa , Aprendizado de Máquina , Peptídeos/isolamento & purificação , Adsorção , Peptídeos/química , Solventes/química , Temperatura Ambiente , Tempo , Ácido Trifluoracético/química
5.
Org Lett ; 21(7): 2459-2463, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30869905

RESUMO

A handle for the protection of the C-terminus of peptides after cleaving with low concentration of trifluoroacetic acid (2-4%) is reported. The handle prevents polymerization reactions in the convergent condensation of peptidic fragments. Moreover, it is traceless, being removed during the final deprotection step of the peptide synthesis. This cheap and convenient handle is easily attached to the solid support, causing no disturbance to peptide elongation and thus proving to be useful in the convergent synthesis of long peptides.


Assuntos
Fragmentos de Peptídeos/síntese química , Peptídeos/síntese química , Ácido Trifluoracético/química , Sequência de Aminoácidos , Liraglutida , Fragmentos de Peptídeos/química , Peptídeos/química
6.
Methods Mol Biol ; 1943: 1-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838606

RESUMO

Sequence-defined cationic lipo-oligomers containing unsaturated fatty acids are potent nucleic acid carriers that are produced by solid-phase supported synthesis. However, the trifluoroacetic acid (TFA)-mediated removal of acid-labile protecting groups and cleavage from the resin can be accompanied by side products caused by an addition of TFA to the double bonds of unsaturated fatty acids. These TFA adducts are converted into hydroxylated derivatives under aqueous conditions. Here we describe an optimized cleavage protocol (precooling cleavage solution to 4 °C, 20 min cleavage at 22 °C), which minimizes TFA adduct formation, retains the unsaturated hydrocarbon chain character, and ensures high yields of the synthesis.


Assuntos
Ácidos Graxos Insaturados/química , Nanopartículas/química , RNA Interferente Pequeno/genética , Transfecção/métodos , Sequência de Aminoácidos , Aminoácidos/química , Animais , Cátions/química , Linhagem Celular Tumoral , Terapia Genética/métodos , Humanos , Camundongos , Estrutura Molecular , Polimerização , Interferência de RNA , Temperatura Ambiente , Ácido Trifluoracético/química
7.
Molecules ; 24(5)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857232

RESUMO

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields.


Assuntos
Indóis/química , Iodo/química , Indicadores e Reagentes/química , Iodetos/química , Iodobenzenos/química , Estrutura Molecular , Ácido Trifluoracético/química
8.
ACS Comb Sci ; 21(3): 154-157, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30640439

RESUMO

The synthesis of different diketomorpholines via N-acyl-3,4-dihydro-2 H-1,4-oxazine-3-carboxylic acids is reported in this article. The key intermediates were prepared using a convenient solid-phase synthesis starting from polymer-supported Ser( tBu)-OH. After subsequent sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), alkylation with an α-bromoketone, cleavage of the 4-Nos group and acylation with an α-halocarboxylic acids, acid-mediated cleavage from the resin yielded dihydrooxazine-3-carboxylic acids in high crude purities. Depending on the reaction conditions, exposure to base resulted in cyclization to either oxazino[3,4- c][1,4]oxazine-diones or 3-methylidenemorpholine-2,5-diones. Further reaction with triethylsilane-trifluoroacetic acid (TES/TFA) led to olefin reduction, in the case of oxazino[3,4- c][1,4]oxazine-dione with full control of the newly formed stereocenter.


Assuntos
Morfolinas/síntese química , Polímeros/química , Técnicas de Síntese em Fase Sólida/métodos , Acilação , Alquilação , Ácidos Carboxílicos/química , Ciclização , Estrutura Molecular , Nitrobenzenos/química , Oxazinas/química , Silanos/química , Estereoisomerismo , Ácido Trifluoracético/química
9.
Sensors (Basel) ; 18(10)2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322092

RESUMO

Quinoxaline-based novel acid-responsive probe Q1 was designed on the basis of a conjugated donor-acceptor (D-A) subunit. Q1 shows colorimetric and fluorometric changes through protonation and deprotonation in dichloromethane. With the addition of the trifluoroacetic acid (TFA), UV-vis absorption spectral changes in peak intensity of Q1 was observed. Moreover, the appearance of a new peaks at 284 nm 434 nm in absorption spectra with the addition of TFA indicating protonation of quinoxaline nitrogen and form Q1.H⁺ and Q1.2H⁺. The emission spectra display appearance of new emission peak at 515 nm. The optical property variations were supported by time resolved fluorescence studies. The energy band gap was calculated by employing cyclic voltammetry and density functional calculations. Upon addition of triethylamine (TEA) the fluorescence emission spectral changes of Q1 are found to be reversible. Q1 shows color changes from blue to green in basic and acidic medium, respectively. The paper strip test was developed for making Q1 a colorimetric and fluorometric indicator.


Assuntos
Colorimetria/métodos , Quinoxalinas/química , Espectrometria de Fluorescência/métodos , Espectrofotometria Ultravioleta/métodos , Cor , Colorimetria/instrumentação , Eletroquímica/métodos , Etilaminas/química , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Nitrilos/química , Prótons , Quinoxalinas/síntese química , Fitas Reagentes/química , Espectrometria de Fluorescência/instrumentação , Ácido Trifluoracético/química
10.
J Pept Sci ; 24(11): e3130, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30353614

RESUMO

Triisopropylsilane (TIS), a hindered hydrosilane, has long been utilized as a cation scavenger for the removal of amino acid protecting groups during peptide synthesis. However, its ability to actively remove S-protecting groups by serving as a reductant has largely been mischaracterized by the peptide community. Here, we provide strong evidence that TIS can act as a reducing agent to facilitate the removal of acetamidomethyl (Acm), 4-methoxybenzyl (Mob), and tert-butyl (But ) protecting groups from cysteine (Cys) residues in the presence of trifluoroacetic acid (TFA) at 37 °C. The lability of the Cys protecting groups in TFA/TIS (98/2) in this study are in the order: Cys(Mob) > Cys(Acm) > Cys(But ), with Cys(Mob) being especially labile. Unexpectedly, we found that TIS promoted disulfide formation in addition to aiding in the removal of the protecting group. Our results raise the possibility of using TIS in orthogonal deprotection strategies of Cys-protecting groups following peptide synthesis as TIS can be viewed as a potential deprotection agent instead of merely a scavenger in deprotection cocktails based on our results. We also tested other common scavengers under these reaction conditions and found that thioanisole and triethylsilane were similarly effective as TIS in enhancing deprotection and catalyzing disulfide formation. Our findings reported herein show that careful consideration should be given to the type of scavenger used when it is desirable to preserve the Cys-protecting group. Additional consideration should be given to the concentration of scavenger, temperature of the reaction, and reaction time.


Assuntos
Cisteína/química , Peptídeos/síntese química , Silanos/química , Dissulfetos/química , Oxirredução , Peptídeos/química , Ácido Trifluoracético/química
11.
Biomacromolecules ; 19(11): 4396-4410, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30281286

RESUMO

The conformational analysis of spider dragline silks is difficult because of the amorphous character of the silks. In this article, the fractions of several conformations were determined for three 47-mer peptides, (Glu)4(Ala)6GlyGly12Ala13Gly14GlnGlyGlyTyrGlyGlyLeuGlySerGlnGly25Ala26Gly27-ArgGlyGlyLeuGlyGlyGlnGly35Ala36Gly37(Ala)6(Glu)4, with three underlined 13C-labeled blocks using a 13C CP/MAS NMR method. The conformations of the 13C-labeled sites change significantly depending on the location of the labeled blocks when treated with trifluoroacetic acid, low pH, and freeze-drying. The conformations of Ala36 and Gly37 residues are strongly influenced by the specific conformation of the (Ala)6 sequence at the C-terminal side, but those of other residues, Ala13 and Gly14, and Ala 26 and Gly27, are basically not influenced by the conformations of (Ala)6. Through hydration of the ß-sheet peptide, sharp peaks with random coil could be observed depending on the position of the residue, and this result could be interpreted via the change in the Ramachandran map obtained from the molecular dynamics simulation.


Assuntos
Fibroínas/química , Proteínas de Insetos/química , Espectroscopia de Ressonância Magnética/métodos , Fragmentos de Peptídeos/química , Seda/química , Aranhas/química , Ácido Trifluoracético/química , Animais , Isótopos de Carbono , Liofilização , Concentração de Íons de Hidrogênio , Conformação Molecular , Simulação de Dinâmica Molecular
12.
J Chromatogr A ; 1578: 35-44, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30340763

RESUMO

The separation mechanism of amino acid enantiomers using a chiral crown ether-bonded stationary phase, CROWNPAK CR-I(+), and acetonitrile (ACN)-rich mobile phases (MPs) was studied. The retention factors of proteinogenic l-amino acids (except proline) formed U-shaped plots against the ACN content in the MP with a sharp increase at a high ACN content, while d-amino acids showed much smaller increases or monotonous decreases in retention within the same range. The use of an acidic, highly organic MP with trifluoroacetic acid (TFA) provided a high enantioselectivity with a short separation time from the contribution of the increased binding of the ammonium group of the analytes to the crown ether functionality of the stationary phase and electrostatic repulsion counteracting the hydrophilic partition mechanism. Optimizing the sample diluent and MP alleviated the peak distortion caused by a moving water band that accompanied the hydrophilic interaction liquid chromatography-like elution conditions. The liquid chromatography/time-of-flight mass spectrometry method with the optimized MP - ACN/ethanol/water/TFA = 80/15/5/0.5 (v/v/v/v) - enabled the determination of eighteen pairs of proteinogenic amino acid enantiomers within 10 min. The conditions also provided the following advantages: (i) fast and highly reproducible separations under isocratic conditions, (ii) high sensitivity and low backpressure using the MP with a high organic content, and (iii) highly reliable peak identification by combining two columns (CR-I(+) and CR-I(-)), reversing the elution orders of the enantiomers.


Assuntos
Aminoácidos/isolamento & purificação , Técnicas de Química Analítica/métodos , Cromatografia Líquida , Éteres de Coroa/química , Espectrometria de Massas , Acetonitrilos/química , Aminoácidos/química , Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Ácido Trifluoracético/química , Água/química
13.
J Am Chem Soc ; 140(39): 12378-12382, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30247886

RESUMO

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.


Assuntos
Derivados de Benzeno/síntese química , Hidrocarbonetos Fluorados/síntese química , Tolueno/química , Ácido Trifluoracético/química
14.
J Sep Sci ; 41(18): 3631-3643, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30040174

RESUMO

The separation of natural products is grueling and time-consuming work with repeated isolations needed to obtain purified compounds. However, using counter-current chromatography, a unique liquid-liquid partition chromatography, constituents can usually be purified efficiently. During the separation of flavone dimers from Dysosma versipellis (Hance) by counter-current chromatography, the separation resolution and sample loading was impeded by the emulsification of the sample. By screening, trifluoroacetic acid was selected as the solvent modifier to eliminate the emulsification. Then, a quaternary solvent system of hexane/ethyl acetate/methanol/water (4:6:5:5 v/v/v/v) with trifluoroacetic acid at a low concentration of 0.5% v/v was used to purify the components from D. versipellis. Compared to that without trifluoroacetic acid, the separation resolution as well as the sample loading both increased greatly. In addition, flavone dimers in low concentrations could be enriched and purified at high sample loading. As a result, five podophyllotoxins and 11 flavonoids were purified and characterized by interpretation of spectroscopic data, in which two of eight flavone dimers were new and a known flavone dimer was first separated from this species.


Assuntos
Berberidaceae/química , Produtos Biológicos/isolamento & purificação , Flavonas/isolamento & purificação , Ácido Trifluoracético/química , Produtos Biológicos/química , Cromatografia Líquida de Alta Pressão , Distribuição Contracorrente , Dimerização , Flavonas/química
15.
Int J Pharm ; 548(1): 689-697, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30016672

RESUMO

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) - an estrogenic steroid molecule also containing an ethynyl functional group - to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications.


Assuntos
Dispositivos Anticoncepcionais Femininos , Sistemas de Liberação de Medicamentos , Estrogênios/química , Etinilestradiol/química , Elastômeros de Silicone/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ácido Trifluoracético/química
16.
ACS Comb Sci ; 20(8): 467-471, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-29969011

RESUMO

The synthesis of novel imidazole derivatives via immobilized α-acylamino ketones is reported in this article. The key intermediates were prepared from the Wang-piperazine resin-supported Fmoc-amino acids. After their sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), followed by alkylation with α-bromoketones and cleavage of Nos group, the resulting α-acylamino ketones were reacted with Fmoc-isothiocyanate. The corresponding Fmoc-thioureas were subjected to the Fmoc-cleavage and spontaneous ring-closure to imidazole scaffold. The resulting imidazole-thiones were alkylated with alkyl halides and oxidized using meta-chloroperbenzoic acid ( mCPBA). Trifluoroacetic acid (TFA)-mediated cleavage yielded the corresponding trisubstituted 2-alkylsulfonyl imidazoles in good crude purity and acceptable overall yields. In the case of sulfides, prepared from alkyl bromides, the unexpected products brominated at the C4 position of the imidazole were obtained.


Assuntos
Imidazóis/síntese química , Cetonas/química , Sulfonas/química , Alquilação , Aminoácidos/química , Ciclização , Fluorenos/química , Halogenação , Estrutura Molecular , Oxirredução , Piperazina/química , Técnicas de Síntese em Fase Sólida , Tionas/química , Tioureia/análogos & derivados , Tioureia/química , Ácido Trifluoracético/química
17.
Yakugaku Zasshi ; 138(6): 731-742, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29863038

RESUMO

 The combination of several aromatic rings and/or heterocycles can induce novel functions. This phenomenon is observed in porphyrin derivatives, commonly found in hemoglobin, in the active sites of P-450, etc. The ability of these structures to interact strongly with visible light accounts for today's increased interest in the development of rationally designed porphyrinoid-based optical materials. In the pharmaceutical sciences, designing near-IR materials can be a challenge due to the high transparency of near-IR light in biological samples. Phthalocyanines (Pcs) are robust organic dyes that are absorbed in visible light. A theoretical investigation of molecular orbitals of Pcs has revealed that the introduction of a phosphorus(V) atom into a macrocyclic core leads to a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap. Following these studies, we found that certain types of Pc phosphorus(V) complexes display main absorptions beyond 1000 nm. Additionally, phosphorus(V) complexes with other azaporphyrinoids have been designed and synthesized via a relatively simple procedure. These complexes showed novel optical properties which are potentially useful in the pharmaceutical and material sciences. Furthermore, we have overcome the problem of organic radicals and antiaromatic compounds, which are generally considered to be unstable, by using a combination of serendipitous synthetic methodologies and spectroscopic techniques. These novel azaporphyrin compounds are robust and free from transition metals. They are relatively easy to synthesize and also exhibit predictable properties.


Assuntos
Compostos Azo , Desenho de Drogas , Raios Infravermelhos , Porfirinas , Compostos Azo/síntese química , Compostos Azo/química , Indóis/química , Estrutura Molecular , Fósforo , Porfirinas/síntese química , Porfirinas/química , Análise Espectral , Ácido Trifluoracético/química
18.
Chem Commun (Camb) ; 54(66): 9127-9130, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-29882948

RESUMO

We report a simple and promising synthetic method to oxidize peptide hydrazides containing N-terminal thiazolidine as a protected cysteine. This yields the corresponding thioester via a peptide azide without decomposition of the thiazolidine ring. The newly developed protocol was validated by the synthesis of the bioactive peptide LacZα.


Assuntos
Ésteres/síntese química , Hidrazinas/química , Peptídeos/síntese química , Tiazolidinas/síntese química , Sequência de Aminoácidos , Cisteína/química , Ésteres/química , Peptídeos/química , Nitrito de Sódio/química , Tiazolidinas/química , Ácido Trifluoracético/química
19.
Anal Chem ; 90(11): 6601-6609, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29722972

RESUMO

Recent progress in top-down proteomics has driven the demand for chromatographic methods compatible with mass spectrometry (MS) that can separate intact proteins. Hydrophilic interaction liquid chromatography (HILIC) has recently shown good potential for the characterization of glycoforms of intact proteins. In the present study, we demonstrate that HILIC can separate a wide range of proteins exhibiting orthogonal selectivity with respect to reversed-phase LC (RPLC). However, the application of HILIC to the analysis of low abundance proteins (e.g., in proteomics analysis) is hampered by low volume loadability, hindering down-scaling of the method to column diameters below 2.1 mm. Moreover, HILIC-MS sensitivity is decreased due to ion suppression from the trifluoroacetic acid (TFA) often used as the ion-pair agent to improve the selectivity and efficiency in the analysis of glycoproteins. Here, we introduce a capillary-based HILIC-MS method that overcomes these problems. Our method uses RPLC trap-columns to load and inject the sample, circumventing issues of protein solubility and volume loadability in capillary columns (200 µm ID). The low flow rates and use of a dopant gas in the electrospray interface improve protein-ionization efficiencies and reduce suppression by TFA. Overall, this allows the separation and detection of small protein quantities (down to 5 ng injected on column) as indicated by the analysis of a mixture of model proteins. The potential of the new capillary HILIC-MS is demonstrated by the analysis of a complex cell lysate.


Assuntos
Proteínas/análise , Proteômica , Algoritmos , Cromatografia Líquida , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas , Ácido Trifluoracético/química
20.
Bioanalysis ; 10(10): 769-781, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29771135

RESUMO

AIM: Electromembrane extraction (EME) of weakly basic benzodiazepines was investigated (-1.47 < pKa < 5.01). MATERIALS & METHODS: 96-well EME was performed with strongly acidic conditions in the acceptor solution using 250-mM trifluoroacetic acid to maximize ionization. RESULTS & CONCLUSION: Recoveries more than 80% were obtained for analytes with pKa > 2, whereas EME was less efficient for substances with pKa < 2. The latter was trapped in the supported liquid membrane due to less acidic pH conditions in the acceptor solution close to the supported liquid membrane. EME followed by UHPLC-MS/MS analysis was evaluated from human plasma, and the results were in compliance with EMA guidelines. Both electrokinetic migration and passive diffusion contributed to mass transfer when performing EME of weakly basic analytes.


Assuntos
Benzodiazepinas/análise , Benzodiazepinas/isolamento & purificação , Eletroquímica/métodos , Membranas Artificiais , Benzodiazepinas/química , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Espectrometria de Massas em Tandem , Ácido Trifluoracético/química
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