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1.
Molecules ; 26(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499387

RESUMO

Two novel amphiphilic polyethylene amine terephthalate have been prepared via the glycolsis of polyethylene terephthalate (PET). The product, bis (2-hydroxyethyl terephthalate) (BHET), was converted to the corresponding dialkyl halide, bis(2-chloroethyl) terephthalate (BCET), using thionyl chloride (TC). This dialkyl compound was used for alkylation of dodecyl amine (DOA) and tetraethylenepentamine (TEPA) or pentaethylenehexamine (PEHA) to form the corresponding polyethylene amine terephthalate, i.e., DOAT and DOAP, respectively. Their chemical structure, surface tension, interfacial tension (IFT), and dynamic light scattering (DLS) were determined using different techniques. The efficiency of the prepared polyethylene amine terephthalate to demulsify water in heavy crude (W/O) emulsions was also determined and found to increase as their concentrations increased. Moreover, DOAT showed faster and higher efficiency, and cleaner separation than DOAP.


Assuntos
Petróleo/análise , Polietilenotereftalatos/química , Aminas/síntese química , Aminas/química , Difusão Dinâmica da Luz , Emulsões/química , Espectroscopia de Ressonância Magnética , Micelas , Estrutura Molecular , Polietilenotereftalatos/síntese química , Eliminação de Resíduos/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , Tensão Superficial , Tensoativos/síntese química , Tensoativos/química , Águas Residuárias/química
2.
Eur J Med Chem ; 213: 113215, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33516985

RESUMO

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Tirosina Quinase 3 Semelhante a fms/metabolismo
3.
Nat Commun ; 12(1): 19, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397992

RESUMO

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step.


Assuntos
Aminas/química , Aminas/síntese química , Teoria da Densidade Funcional , Ligantes , Rotação , Estereoisomerismo
4.
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
5.
Nature ; 581(7809): 415-420, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32268340

RESUMO

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10-14. However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.


Assuntos
Aminas/química , Aminas/síntese química , Técnicas de Química Sintética/métodos , Aldeídos/química , Alquilação , Aminação , Loratadina/análogos & derivados , Loratadina/síntese química , Loratadina/química
6.
J Enzyme Inhib Med Chem ; 35(1): 692-701, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32156165

RESUMO

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a-k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM).


Assuntos
Aminas/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Tiobarbitúricos/farmacologia , alfa-Glucosidases/metabolismo , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Glicosilação/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiobarbitúricos/síntese química , Tiobarbitúricos/química
7.
Nat Protoc ; 15(4): 1313-1337, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203487

RESUMO

Reductive aminations are an essential class of reactions widely applied for the preparation of different kinds of amines, as well as a number of pharmaceuticals and industrially relevant compounds. In such reactions, carbonyl compounds (aldehydes, ketones) react with ammonia or amines in the presence of a reducing agent and form corresponding amines. Common catalysts used for reductive aminations, especially for the synthesis of primary amines, are based on precious metals or Raney nickel. However, their drawbacks and limited applicability inspired us to look for alternative catalysts. The development of base-metal nanostructured catalysts is highly preferable and is crucial to the advancement of sustainable and cost-effective reductive amination processes. In this protocol, we describe the preparation of carbon-supported cobalt-based nanoparticles as efficient and practical catalysts for synthesis of different kinds of amines by reductive aminations. Template synthesis of a cobalt-triethylenediamine-terephthalic acid metal-organic framework on carbon and subsequent pyrolysis to remove the organic template resulted in the formation of supported single cobalt atoms and nanoparticles. Applying these catalysts, we have synthesized structurally diverse benzylic, aliphatic and heterocyclic primary, secondary and tertiary amines, including pharmaceutically relevant products, starting from inexpensive and easily accessible carbonyl compounds with ammonia, nitro compounds or amines and molecular hydrogen. To prepare this cobalt-based catalyst takes 26 h, and the reported catalytic reductive amination reactions can be carried out within 18-28 h.


Assuntos
Aminas , Técnicas de Química Sintética/métodos , Cobalto/química , Nanopartículas Metálicas/química , Aminação , Aminas/síntese química , Aminas/química , Estruturas Metalorgânicas/química
8.
Carbohydr Res ; 489: 107948, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062397

RESUMO

Rh/Al2O3 can be used as an effective chemo-selective reductive catalyst that combines the mild conditions of catalytic hydrogenation with high selectivity for azide moieties in the presence of other hydrogenolysis labile groups such as benzyl and benzyloxycarbonyl functionalities. The practicality of this strategy is exemplified with a range of azide-containing carbohydrate and amino acid derivatives.


Assuntos
Aminas/síntese química , Azidas/química , Ródio/química , Aminas/química , Configuração de Carboidratos , Catálise , Hidrogenação
9.
Org Biomol Chem ; 18(7): 1279-1336, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025682

RESUMO

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Lactonas/síntese química , Álcoois/síntese química , Álcoois/química , Alcenos/síntese química , Alcenos/química , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Compostos Heterocíclicos/química , Lactonas/química , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Estereoisomerismo
10.
Org Lett ; 22(4): 1681-1685, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32013445

RESUMO

We describe a strategy for the enantio- and diastereoselective synthesis of homoallylic α-trifluoromethyl amines by the catalytic hydroalkylation of terminal dienes. Trifluoromethyl-substituted isatin-derived azadienolate nucleophiles undergo γ-selective alkylation with a Pd-DTBM-SEGPHOS catalyst, which additionally promotes regioselective addition to the diene and delivers products in up to 86% yield, 10:1 dr, and 97.5:2.5 er.


Assuntos
Alcadienos/química , Aminas/síntese química , Complexos de Coordenação/química , Paládio/química , Alquilação , Aminas/química , Catálise , Estrutura Molecular , Estereoisomerismo
11.
J Recept Signal Transduct Res ; 40(1): 34-41, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910703

RESUMO

Synthesis of a series of new urea and thiourea compounds have been accomplished by the reaction of 2,3-dihydro-1H-inden-1-amine with various phenyl isocyanates and isothiocyanates. These compounds were evaluated for their antioxidant activity by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and nitric oxide (NO) radical scavenging assay methods including IC50 values. Some of the compounds exhibited potential activity in the two tested methods. Among the series of compounds, urea derivative linked with 4-bromo phenyl ring (4b), and thiourea derivatives bonded with phenyl ring (4e), 4-fluoro phenyl ring (4f) and 4-nitro pheyl ring (4h) were found to exhibit promising anti oxidant activity with low IC50 values. Where four of the title comounds exhibited higher bindig energies than the reference compound (Imatinib) in in silico molecular docking studies with Aromatase. All the synthesized compounds were characterized by IR, 1H, 13C NMR and mass spectral data.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Simulação por Computador , Tioureia/farmacologia , Ureia/farmacologia , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/química , Depuradores de Radicais Livres/química , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Óxido Nítrico/química , Picratos/química , Tioureia/síntese química , Tioureia/química , Ureia/síntese química , Ureia/química
12.
Molecules ; 25(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963685

RESUMO

Here, we report the formation of homochiral supramolecular thin film from achiral molecules, by using circularly polarized light (CPL) only as a chiral source, on the condition that irradiation of CPL does not induce a photochemical change of the achiral molecules. Thin films of self-assembled structures consisting of chiral supramolecular fibrils was obtained from the triarylamine derivatives through evaporation of the self-assembled triarylamine solution. The homochiral supramolecular helices with the desired handedness was achieved by irradiation of circularly polarized visible light during the self-assembly process, and the chiral stability of supramolecular self-assembled product was achieved by photopolymerization of the diacetylene moieties at side chains of the building blocks, with irradiation of circularly polarized ultraviolet light. This work provides a novel methodology for the generation of homochiral supramolecular thin film from the corresponding achiral molecules.


Assuntos
Aminas/química , Técnicas de Química Sintética , Luz , Aminas/síntese química , Teoria da Densidade Funcional , Estrutura Molecular , Polimerização
13.
Eur J Med Chem ; 185: 111866, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734023

RESUMO

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.


Assuntos
Acetamidas/farmacologia , Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Aminas/síntese química , Aminas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , HIV-1/enzimologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 186: 111882, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753514

RESUMO

A series of halogenated (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers (1a-9a, 1b-9b) were synthesized from their corresponding thiourea analogues (1-9). The synthesis pathway was confirmed by an X-ray crystallographic studies of 1a, 1b and 5a. Title derivatives were tested for their in vitro antitubercular activity against standard, "wild-type" and atypical mycobacteria. The highest therapeutic potential was attributed to isomeric N-(bromophenyl)tetrazoles 8a and 9a. Their growth-inhibitory effect against multidrug-resistant Mycobacterium tuberculosis Spec. 210 was 8-16-fold stronger than that of the first-line tuberculostatics. Other new tetrazole-derived compounds were also more or equally effective towards that pathogen comparing to the established pharmaceuticals. Among non-tuberculous strains, Mycobacterium scrofulaceum was the most susceptible to the presence of the majority of tetrazole derivatives. The synergistic interaction was found between 9a and streptomycin, as well as the additivity of both 8a and 9a in pairs with isoniazid, rifampicin and ethambutol. None of the studied compounds displayed antibacterial or cytotoxic properties against normal and cancer cell lines, which indicated their highly selective antimycobacterial effects.


Assuntos
Aminas/farmacologia , Antituberculosos/farmacologia , Mycobacterium/efeitos dos fármacos , Tetrazóis/farmacologia , Aminas/síntese química , Aminas/química , Antituberculosos/síntese química , Antituberculosos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
15.
Med Chem ; 16(1): 52-62, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30727906

RESUMO

BACKGROUND: EGFR is a clinically approved drug target in cancer. The first generation tyrosine kinase inhibitors targeting L858R mutated EGFR are routinely used to treat non-small cell lung cancer (NSCLC). However, the presence of a secondary mutation (T790M) tenders these inhibitors ineffective and thus results in the relapse of the disease. OBJECTIVE: New reversible inhibitors are required, which act against T790M/L858R (TMLR) double mutants and overcome resistance. METHOD: In the present study, various Fragment based QSAR (G-QSAR) models along with interaction terms have been studied for amino-pyrimidine derivatives having biological activity against TMLR mutant enzyme. RESULTS: The G-QSAR models developed using partial least squares regression via stepwise forward- backward variable selection technique showed the best results. The model showed a high correlation coefficient (r² = 0.86), cross-validation coefficient (q² = 0.81) and predicted correlation (predicted r² = 0.62), which indicated that the model is robust and predictive. Based on the model, it was revealed that at R1 position increasing saturated carbon (number of -CH atom connected with 3 single bonds i.e. SsssCHcount) and retention index (chi3) is desired for the enhancement of bioactivity. Additionally, at the R2 position, increasing lipophilic character (slogp) and at site R3, the polarizability of compound need to be increased for better inhibitory activity. We further studied the contribution of interactions among significant descriptors in enhancing the activity of the compounds. It revealed that the presence of Sum((R1-SsssCHcount, R2-slogp) and Mult(R1-chi3, R3-polarizabilityAHC) are the most significantly influencing descriptors. We further compared the variation in the most and least active compounds which established that retention of the above properties is essential for imparting significant inhibitory activity to these molecules. CONCLUSION: The study provides site specific information wherein chemical group variation influences the inhibitory potency of TMLR amino-pyrimidine inhibitors, which can be used for designing new molecules with the desired activity.


Assuntos
Aminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Quantitativa Estrutura-Atividade
16.
J Sep Sci ; 43(6): 1100-1106, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858708

RESUMO

A green and fast analytical method for the determination of l-methionine in human plasma is presented in this study. Preconcentration of the analyte was carried out by switchable solvent liquid phase microextraction after ethyl chloroformate derivatization reaction. Instrumental detection of the analyte was performed by means of gas chromatography-mass spectrometry. N,N-Dimethyl benzylamine was used in the synthesis of switchable solvent. Protonated N,N-dimethyl benzylamine volume, volume/concentration of sodium hydroxide, and vortex period were meticulously fixed to their optimum values. Besides, ethyl chloroformate, pyridine, and ethanol volumes were optimized in order to get high derivatization yield. After the optimization studies, limit of detection and quantitation values were attained as 3.30 and 11.0 ng/g, respectively, by the developed switchable solvent liquid phase microextraction gas chromatography-mass spectrometry method that corresponding to 76.7-folds enhancement in detection power of the gas chromatography-mass spectrometry system. Applicability and accuracy of the switchable solvent liquid phase microextraction-gas chromatography-mass spectrometry method were also checked by spiking experiments. Percent recovery results were ranged from 97.8 to 100.5% showing that human plasma samples could be analyzed for its l-methionine level by the proposed method.


Assuntos
Aminas/química , Ésteres do Ácido Fórmico/química , Microextração em Fase Líquida , Metionina/sangue , Ondas Ultrassônicas , Aminas/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Voluntários Saudáveis , Humanos , Estrutura Molecular , Solventes/química
17.
Sci Rep ; 9(1): 19075, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836785

RESUMO

Carboxyl-containing metabolites, such as bile acids and fatty acids, have many important functions and microbiota is involved in the production of them. In the previous study, we found that the chronic kidney disease (CKD) model mice raised under germ-free conditions provided more severe renal damage than the mice with commensal microbiota. However, the precise influence by the microbiome and carboxyl-containing metabolites to the renal functions is unknown. In this study, we aimed to develop a novel chemical isotope labeling-LC-MS/MS method using the 2-picolylamine and its isotopologue and applied the analysis of effects of microbiome and CKD pathophysiology. The developed semi-quantitative method provided the high accuracy not inferior to the absolute quantification. By comparing of four groups of mice, we found that both microbiota and renal function can alter the composition and level of these metabolites in both plasma and intestine. In particular, the intestinal level of indole-3-acetic acid, short-chain fatty acids and n-3 type of polyunsaturated fatty acid, which play important roles in the endothelial barrier function, were significantly lower in germ-free conditions mice with renal failure. Accordingly, it is suggested these metabolites might have a renoprotective effect on CKD by suppressing epithelial barrier disruption.


Assuntos
Aminas/química , Microbioma Gastrointestinal , Marcação por Isótopo , Metaboloma , Insuficiência Renal Crônica/microbiologia , Espectrometria de Massas em Tandem , Aminas/síntese química , Animais , Ácidos e Sais Biliares/metabolismo , Ceco/metabolismo , Cromatografia Líquida , Fezes/microbiologia , Indicadores e Reagentes , Redes e Vias Metabólicas , Camundongos , Organismos Livres de Patógenos Específicos
18.
Org Biomol Chem ; 17(45): 9778-9791, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701105

RESUMO

This study investigates the synthesis of ß-branched amines and ß-branched quaternary ammonium chloride ionic liquids as novel extractants. The synthesis methodology was tailored to facilitate the reaction scale-up and the use of biorenewable starting materials. The developed process is an overall green, easy and straightforward synthesis of ß-branched amines, and ammonium salts, starting from linear aldehydes. In order to evaluate the potential of the synthesised materials in applications, the rheology, density, thermal stability, chemical stability, phase transitions, and mutual solubility with water of the novel extractants was studied.


Assuntos
Líquidos Iônicos/síntese química , Compostos de Amônio Quaternário/síntese química , Aminas/síntese química , Aminas/química , Interações Hidrofóbicas e Hidrofílicas , Líquidos Iônicos/química , Estrutura Molecular , Compostos de Amônio Quaternário/química , Solubilidade , Água/química
19.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683699

RESUMO

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3',2':4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2-e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure-activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds.


Assuntos
Aminas/química , Aminas/síntese química , Antineoplásicos/química , Antineoplásicos/síntese química , Simulação de Acoplamento Molecular , Piridinas/química , Piridinas/síntese química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Chlorocebus aethiops , Células HeLa , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Termodinâmica , Células Vero
20.
J Med Chem ; 62(23): 10848-10866, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675226

RESUMO

Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.


Assuntos
Aminas/síntese química , Aminas/farmacologia , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/farmacologia , Aminas/química , Animais , Comportamento Animal/efeitos dos fármacos , Células HEK293 , Agonistas dos Receptores Histamínicos/química , Humanos , Memória/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Comportamento Social
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