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1.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072560

RESUMO

The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride (PTZ1) and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (PTZ2), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds PTZ1 and PTZ2 with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of PTZ1, two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of PTZ2, sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents.


Assuntos
Aminas/química , Aminas/farmacologia , Azul de Metileno/química , Azul de Metileno/farmacologia , Aminas/síntese química , DNA/química , Dimerização , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Espectroscopia de Ressonância Magnética , Azul de Metileno/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Espectrometria de Fluorescência , Relação Estrutura-Atividade
2.
Molecules ; 26(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066597

RESUMO

Thirty-three alkyl and aryl isothiocyanates, as well as isothiocyanate derivatives from esters of coded amino acids and from esters of unnatural amino acids (6-aminocaproic, 4-(aminomethyl)benzoic, and tranexamic acids), were synthesized with satisfactory or very good yields (25-97%). Synthesis was performed in a "one-pot", two-step procedure, in the presence of organic base (Et3N, DBU or NMM), and carbon disulfide via dithiocarbamates, with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO-) as a desulfurization reagent. For the synthesis of aliphatic and aromatic isothiocyanates, reactions were carried out in a microwave reactor, and selected alkyl isothiocyanates were also synthesized in aqueous medium with high yields (72-96%). Isothiocyanate derivatives of L- and D-amino acid methyl esters were synthesized, under conditions without microwave radiation assistance, with low racemization (er 99 > 1), and their absolute configuration was confirmed by circular dichroism. Isothiocyanate derivatives of natural and unnatural amino acids were evaluated for antibacterial activity on E. coli and S. aureus bacterial strains, where the most active was ITC 9e.


Assuntos
Química Orgânica/métodos , Isotiocianatos/síntese química , Morfolinas/química , Tolueno/química , Triazinas/química , Aminas/química , Antibacterianos/química , Técnicas de Química Sintética , Cromatografia , Dicroísmo Circular , Escherichia coli/efeitos dos fármacos , Indicadores e Reagentes , Isotiocianatos/análise , Isotiocianatos/química , Espectroscopia de Ressonância Magnética , Micro-Ondas , Solventes , Staphylococcus aureus/efeitos dos fármacos , Enxofre/química , Temperatura
3.
Molecules ; 26(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063713

RESUMO

Chitosan has many useful intrinsic properties (e.g., non-toxicity, antibacterial properties, and biodegradability) and can be processed into high-surface-area nanofiber constructs for a broad range of sustainable research and commercial applications. These nanofibers can be further functionalized with bioactive agents. In the food industry, for example, edible films can be formed from chitosan-based composite fibers filled with nanoparticles, exhibiting excellent antioxidant and antimicrobial properties for a variety of products. Processing 'pure' chitosan into nanofibers can be challenging due to its cationic nature and high crystallinity; therefore, chitosan is often modified or blended with other materials to improve its processability and tailor its performance to specific needs. Chitosan can be blended with a variety of natural and synthetic polymers and processed into fibers while maintaining many of its intrinsic properties that are important for textile, cosmeceutical, and biomedical applications. The abundance of amine groups in the chemical structure of chitosan allows for facile modification (e.g., into soluble derivatives) and the binding of negatively charged domains. In particular, high-surface-area chitosan nanofibers are effective in binding negatively charged biomolecules. Recent developments of chitosan-based nanofibers with biological activities for various applications in biomedical, food packaging, and textiles are discussed herein.


Assuntos
Quitosana/química , Cosmecêuticos/química , Embalagem de Alimentos , Têxteis , Aminas/química , Animais , Antibacterianos/química , Anti-Infecciosos/química , Antioxidantes/química , Cristalização , Filmes Comestíveis , Humanos , Nanofibras/química , Nanopartículas/química , Polímeros , Regeneração , Pele/patologia , Pele Artificial , Solubilidade , Engenharia Tecidual , Cicatrização
4.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072085

RESUMO

In the fast-developing field of tissue engineering there is a constant demand for new materials as scaffolds for cell seeding, which can better mimic a natural extracellular matrix as well as control cell behavior. Among other materials, polysaccharides are widely used for this purpose. One of the main candidates for scaffold fabrication is alginate. However, it lacks sites for cell adhesion. That is why one of the steps toward the development of suitable scaffolds for cells is the introduction of the biofunctionality to the alginate structure. In this work we focused on bone-sialoprotein derived peptide (TYRAY) conjugation to the molecule of alginate. Here the comparison study on four different approaches of peptide conjugation was performed including traditional and novel modification methods, based on 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxy succinimide (EDC/NHS), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), thiol-Michael addition and Cu-catalyzed azide-alkyne cycloaddition reactions. It was shown that the combination of the alginate amidation with the use of and subsequent Cu-catalyzed azide-alkyne cycloaddition led to efficient peptide conjugation, which was proven with both NMR and XPS methods. Moreover, the cell culture experiment proved the positive effect of peptide presence on the adhesion of human embryonic stem cells.


Assuntos
Alginatos/química , Biomimética , Peptídeos/química , Engenharia Tecidual , Tecidos Suporte , Aminas/química , Biomimética/métodos , Adesão Celular , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Click , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Peptídeos/farmacologia , Engenharia Tecidual/métodos
5.
Nat Commun ; 12(1): 3303, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083518

RESUMO

Peri-implant infection is one of the biggest threats to the success of dental implant. Existing coatings on titanium surfaces exhibit rapid decrease in antibacterial efficacy, which is difficult to promisingly prevent peri-implant infection. Herein, we report an N-halamine polymeric coating on titanium surface that simultaneously has long-lasting renewable antibacterial efficacy with good stability and biocompatibility. Our coating is powerfully biocidal against both main pathogenic bacteria of peri-implant infection and complex bacteria from peri-implantitis patients. More importantly, its antibacterial efficacy can persist for a long term (e.g., 12~16 weeks) in vitro, in animal model, and even in human oral cavity, which generally covers the whole formation process of osseointegrated interface. Furthermore, after consumption, it can regain its antibacterial ability by facile rechlorination, highlighting a valuable concept of renewable antibacterial coating in dental implant. These findings indicate an appealing application prospect for prevention and treatment of peri-implant infection.


Assuntos
Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Peri-Implantite/prevenção & controle , Peri-Implantite/terapia , Titânio/farmacologia , Aminas/administração & dosagem , Aminas/química , Aminas/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Materiais Revestidos Biocompatíveis/administração & dosagem , Materiais Revestidos Biocompatíveis/química , Implantes Dentários , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Teste de Materiais , Osseointegração/efeitos dos fármacos , Peri-Implantite/microbiologia , Porosidade , Coelhos , Propriedades de Superfície , Titânio/administração & dosagem , Titânio/química
6.
Food Chem ; 361: 130147, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051597

RESUMO

Triple quadrupole mass spectrometry has been the main technique for HAAs analysis in recent decade, while it requires extensive optimization of compound-dependent parameters. A novel method based on HPLC-Q-Orbitrap-HRMS was developed firstly for simultaneous determination of eighteen HAAs. Extraction and purification conditions were optimized and the developed method was validated in terms of linearity, accuracy and precision. Results indicated eighteen HAAs and two internal standards could be separated in 12 min using a gradient elution program. The full MS/dd-MS2 scan was adopted for analysis, which indicated favorable recoveries (71.3-114.8%) along with LODs and LOQs in the ranges of 0.02-0.6 and 0.05-2.0 µg/kg, respectively. Internal standards used for calibration could effectively reduce quantification errors produced by matrix effects. The validated method was successfully applied for HAAs analysis in roasted and pan-fried meat and was confirmed to be an alternative method when triple quadrupole mass spectrometry is absent in lab.


Assuntos
Aminas/análise , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos/análise , Carne/análise , Espectrometria de Massas em Tandem/métodos , Aminas/química , Calibragem , Culinária , Análise de Alimentos/métodos , Compostos Heterocíclicos/química , Limite de Detecção , Reprodutibilidade dos Testes
7.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916755

RESUMO

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.


Assuntos
Compostos de Boro/síntese química , Cumarínicos/química , Ácido Fólico/química , Aminas/química , Compostos de Boro/química , Ácidos Carboxílicos/química , Glicina/química
8.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805408

RESUMO

N-heteroaryl substituted adamantane-containing amines are of substantial interest for their perspective antiviral and psychotherapeutic activities. Chlorine atom at alpha-position of N-heterocycles has been substituted by the amino group using convenient nucleophilic substitution reactions with a series of adamantylalkylamines. The prototropic equilibrium in these compounds was studied using NMR spectroscopy. The introduction of the second amino substituent in 4-amino-6-chloropyrimidine, 2-amino-chloropyrazine, and 1-amino-3-chloroisoquinoline was achieved using Pd(0) catalysis.


Assuntos
Aminas/química , Adamantano/química , Aminação , Catálise , Estrutura Molecular , Pirazinas/química
9.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805491

RESUMO

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites.


Assuntos
Aminas/química , Aminas/farmacologia , Preparações Farmacêuticas/química , Fenômenos Bioquímicos , Remoção de Radical Alquila , Oxirredução
10.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801602

RESUMO

Supramolecular fibrous materials in biological systems play important structural and functional roles, and therefore, there is a growing interest in synthetic materials that mimic such fibrils, especially those bearing enzymatic reactivity. In this study, we investigated the self-assembly and enzymatic post-modification of short aromatic peptide amphiphiles (PAs), Fmoc-LnQG (n = 2 or 3), which contain an LQG recognition unit for microbial transglutaminase (MTG). These aromatic PAs self-assemble into fibrous structures via π-π stacking interactions between the Fmoc groups and hydrogen bonds between the peptides. The intermolecular interactions and morphologies of the assemblies were influenced by the solution pH because of the change in the ionization states of the C-terminal carboxy group of the peptides. Moreover, MTG-catalyzed post-modification of a small fluorescent molecule bearing an amine group also showed pH dependency, where the enzymatic reaction rate was increased at higher pH, which may be because of the higher nucleophilicity of the amine group and the electrostatic interaction between MTG and the self-assembled Fmoc-LnQG. Finally, the accumulation of the fluorescent molecule on these assembled materials was directly observed by confocal fluorescence images. Our study provides a method to accumulate functional molecules on supramolecular structures enzymatically with the morphology control.


Assuntos
Peptídeos/química , Transglutaminases/química , Aminas/química , Sítios de Ligação , Biomimética/métodos , Cadaverina/química , Ácidos Carboxílicos/química , Enzimas , Escherichia coli/enzimologia , Corantes Fluorescentes/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Microscopia Confocal , Nanoestruturas/química , Ligação Proteica , Domínios Proteicos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
11.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925230

RESUMO

Cyclodextrins (CyDs) are water-soluble host molecules possessing a nanosized hydrophobic cavity. In the realm of molecular recognition, this cavity is used not only as a recognition site but also as a reaction medium, where a hydrophobic sensor recognizes a guest molecule. Based on the latter concept, we have designed a novel supramolecular sensing system composed of Zn(II)-dipicolylamine metal complex-based azobenzene (1-Zn) and 3A-amino-3A-deoxy-(2AS,3AS)-γ-cyclodextrin (3-NH2-γ-CyD) for sensing adenosine-5'-triphosphate (ATP). 1-Zn showed redshifts in the UV-Vis spectra and induced circular dichroism (ICD) only when both ATP and 3-NH2-γ-CyD were present. Calculations of equilibrium constants indicated that the amino group of 3-NH2-γ-CyD was involved in the formation of supramolecular 1-Zn/3-NH2-γ-CyD/ATP. The Job plot of the ICD spectral response revealed that the stoichiometry of 1-Zn/3-NH2-γ-CyD/ATP was 2:1:1. The pH effect was examined and 1-Zn/3-NH2-γ-CyD/ATP was most stable in the neutral condition. The NOESY spectrum suggested the localization of 1-Zn in the 3-NH2-γ-CyD cavity. Based on the obtained results, the metal coordination interaction of 1-Zn and the electrostatic interaction of 3-NH2-γ-CyD were found to take place for ATP recognition. The "reaction medium approach" enabled us to develop a supramolecular sensing system that undergoes multi-point interactions in water. This study is the first step in the design of a selective sensing system based on a good understanding of supramolecular structures.


Assuntos
Compostos Azo/química , Ciclodextrinas/química , gama-Ciclodextrinas/química , Trifosfato de Adenosina , Aminas/química , Dicroísmo Circular , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Ácidos Picolínicos/química , Solubilidade , Água/química , Zinco , beta-Ciclodextrinas
12.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800017

RESUMO

Metal-organic frameworks (MOFs) have become one of the versatile solid materials used for a wide range of applications, such as gas storage, gas separation, proton conductivity, sensors and catalysis. Among these fields, one of the more well-studied areas is the use of MOFs as heterogeneous catalysts for a broad range of organic reactions. In the present review, the employment of MOFs as solid catalysts for the Henry reaction is discussed, and the available literature data from the last decade are grouped. The review is organized with a brief introduction of the importance of Henry reactions and structural properties of MOFs that are suitable for catalysis. The second part of the review discusses the use of MOFs as solid catalysts for the Henry reaction involving metal nodes as active sites, while the third section provides data utilizing basic sites (primary amine, secondary amine, amides and urea-donating sites). While commenting on the catalytic results in these two sections, the advantage of MOFs over other solid catalysts is compared in terms of activity by providing turnover number (TON) values and the structural stability of MOFs during the course of the reaction. The final section provides our views on further directions in this field.


Assuntos
Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/metabolismo , Amidas/química , Aminas/química , Catálise , Domínio Catalítico , Cobre/química , Ureia/química
13.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807775

RESUMO

We describe the synthesis of fluorogenic arylureas and amides and their interaction with primary or secondary amines under air and light in organic-aqueous mixtures to give rise to a new class of persistent organic radicals, described on the basis of their electron paramagnetic resonance (EPR), as well as UV-vis, fluorescence, NMR, and quantum mechanics calculations, and their prospective use as multi-signal reporters in a smart label for fish freshness.


Assuntos
Amidas/síntese química , Aminas/química , Produtos Pesqueiros/análise , Corantes Fluorescentes/síntese química , Análise de Alimentos/métodos , Amidas/química , Animais , Espectroscopia de Ressonância de Spin Eletrônica , Fluorescência , Corantes Fluorescentes/química , Radicais Livres/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Perciformes
14.
Food Chem ; 355: 129646, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33892412

RESUMO

Herein, the effects of oven bag use belong to different brands on heterocyclic aromatic amine (HAA) formation and bisphenol-A (BPA) migration in cooked chicken meats (breast and leg) were investigated. Samples were also analyzed in terms of some qualitative properties (fatty acid profile, water, fat, pH, TBARS, cooking loss). Both oven bag use and meat type had an effect on qualitative properties of the samples. Total HAA amount changed between 6.53 and 42.32 ng/g, and HAA content was higher in breast meat. Total BPA content in samples cooked with oven bag ranged between non-quantified to 63.78 ng/g. Oven bag use reduced the total HAA amount at the rate of 12 - 68.82%, while it caused the BPA migration depends on the brand. However, it can be noted that the HAA and BPA levels were not at a level to pose a risk to human health in any of the samples.


Assuntos
Aminas/química , Compostos Benzidrílicos/análise , Galinhas , Culinária/instrumentação , Compostos Heterocíclicos/análise , Compostos Heterocíclicos/química , Carne/análise , Fenóis/análise , Animais , Temperatura Alta
15.
Life Sci ; 277: 119532, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33891943

RESUMO

PURPOSE: The rise in consumption of dietary supplements containing the trace amines p-tyramine, p-synephrine and p-octopamine has been associated with cardiovascular side effects. Since renal blood flow plays an important role in blood pressure regulation, this study investigated the mechanisms of action of these trace amines on isolated porcine renal arteries. MAIN METHODS: Contractile responses to amines were investigated in noradrenaline-depleted rings of porcine main renal arteries in the absence and presence of the α1-adrenoceptor antagonist, prazosin (1 µM), ß-adrenoceptor antagonist, propranolol (1 µM), or the trace amine-associated receptor (TAAR-1) antagonist, EPPTB (RO-5212773; 100 nM or 100 µM). KEY FINDINGS: All three amines induced constrictor responses of similar magnitude and potency. However, their mechanisms of action on the renal artery appeared to differ. Depleting endogenous noradrenaline stores significantly reduced maximum responses to tyramine and synephrine, but less for octopamine. When direct responses were examined after depleting tissues of noradrenaline, responses to synephrine and octopamine, but not tyramine, were reduced in the presence of prazosin(1 µM) and potentiated in the presence of propranolol (1 µM) or L-NNA (100 µM). Generally, vasoconstrictor responses remaining after noradrenaline-depletion and α-adrenoceptor blockade were not affected by the TAAR-1 antagonist EPPTB (0.1-100 µM), although responses to low concentration of synephrine and octopamine were enhanced by this antagonist. SIGNIFICANCE: Tyramine appears to mediate constriction of the renal artery mainly via an indirect sympathomimetic mechanism, whereas synephrine and octopamine exert additional direct effects on α1-adrenoceptors and possibly contractile TAAR (not TAAR-1). The two amines also activate simultaneous inhibitory responses via ß-adrenoceptors, TAAR-1 and nitric oxide release.


Assuntos
Aminas/metabolismo , Aminas/farmacologia , Artéria Renal/metabolismo , Aminas/química , Animais , Feminino , Norepinefrina/farmacologia , Octopamina/farmacologia , Fenetilaminas/farmacologia , Propranolol/farmacologia , Artéria Renal/efeitos dos fármacos , Suínos , Simpatomiméticos/farmacologia , Sinefrina/farmacologia , Tiramina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
16.
Molecules ; 26(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809715

RESUMO

An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Iminas/química , Nitrilas/química , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Células A549 , Aminas/química , Antineoplásicos/síntese química , Ácidos Carboxílicos/química , Catálise , Linhagem Celular Tumoral , Cianetos/química , Humanos
17.
Nat Commun ; 12(1): 2257, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859198

RESUMO

Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1ß (MIP-1ß) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.


Assuntos
Antivirais/farmacologia , Materiais Biomiméticos/química , Biomimética/métodos , Quimiocina CCL4/farmacologia , Infecções por HIV/tratamento farmacológico , Aminas/química , Antivirais/química , Linhagem Celular Tumoral , Quimiocina CCL4/química , Quimiocina CCL4/genética , Quimiocina CCL4/isolamento & purificação , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Mioglobina/química , Oxirredução , Processamento de Proteína Pós-Traducional , Quinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/química , Ubiquitina/química , Replicação Viral/efeitos dos fármacos
18.
Artigo em Inglês | MEDLINE | ID: mdl-33706187

RESUMO

Ion pair-reversed phase (IP-RP) HPLC is one of the most widely used methods for the analysis of oligonucleotide impurities. The method is compatible with mass spectrometry and has been used to guide the development of improved synthesis and purification approaches. The ability to detect and characterize impurities depends on the reagents and the IP buffer system employed, as each can directly affect the degree of chromatographic separation and the sensitivity of detection by MS. Previous work in our laboratory has shown that small alkyl amines are suitable IP reagents for the analysis of impurities in phosphate diester oligonucleotides and can be used to differentiate among individual members of composite impurity families. The addition of an alkyl acid often further enhances peak separation, but at the detriment of ion signal. An improved method with increased chromatographic performance and sensitivity of detection is presented here. Improvements were mainly realized through the use of lower concentrations of small alkyl amine (i.e., 5 mM) and acid (0.5 mM) IP reagents, and ammonium bicarbonate (20 mM) as a buffer. The improved capabilities of the new method are demonstrated by separation of the individual components of the composite n - 1 impurity in a set of four production-scale batches of a single oligonucleotide. Addition of the alkyl acid resulted in resolution of most individual n - 1 impurities. The observed enhanced sensitivity of detection allowed multiple reaction monitoring (MRM) experiments, which were used to differentiate among unresolved impurities.


Assuntos
Aminas/química , Cromatografia de Fase Reversa/métodos , Contaminação de Medicamentos , Oligonucleotídeos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Oligonucleotídeos/análise , Oligonucleotídeos/química
19.
Phys Chem Chem Phys ; 23(10): 5919-5926, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33662075

RESUMO

Second-order rate constants of the reduction of histidine radicals by tryptophan were obtained for all combinations of the two amino acids and their N-acetyl derivatives. For the dipeptide N-acetyl histidine-tryptophan, contributions from inter- and intramolecular reduction were revealed. The pH dependences of the rate constants were found to be determined by the protonation state of the amino group of tryptophan. Proton coupled electron transfer is proposed as a reaction mechanism.


Assuntos
Dipeptídeos/química , Histidina/química , Triptofano/química , Aminas/química , Transporte de Elétrons , Radicais Livres/química , Concentração de Íons de Hidrogênio , Estrutura Molecular , Oxirredução , Fármacos Fotossensibilizantes/química , Prótons
20.
J Enzyme Inhib Med Chem ; 36(1): 758-763, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33715570

RESUMO

We report the first activation study of the ß-class carbonic anhydrase (CA, EC 4.2.1.1) encoded in the genome of the protozoan pathogen Trichomonas vaginalis, TvaCA1. Among 24 amino acid and amine activators investigated, derivatives incorporating a second carboxylic moiety, such as L-Asp, L- and D-Glu, were devoid of activating effects up to concentrations of 50 µM within the assay system, whereas the corresponding compounds with a CONH2 moiety, i.e. L-Gln and L-Asn showed modest activating effects, with activation constants in the range of 26.9 - 32.5 µM. Moderate activation was observed with L- and D-DOPA, histamine, dopamine, serotonin, (2-Aminoethyl)pyridine/piperazine and morpholine (KA's ranging between 8.3 and 14.5 µM), while the best activators were L-and D-Trp, L-and D-Tyr and 4-amino-Phe, which showed KA's ranging between 3.0 and 5.1 µM. Understanding in detail the activation mechanism of ß-CAs may be relevant for the design of enzyme activity modulators with potential clinical significance.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Anidrases Carbônicas/metabolismo , Trichomonas vaginalis/enzimologia , Aminas/química , Aminoácidos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade
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