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1.
Org Biomol Chem ; 17(43): 9524-9528, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31659363

RESUMO

Dimeric benzoboroxoles that are covalently linked by a short scaffold enhance selective anti-tubercular activity. These multimeric benzoboroxole compounds are capable of engaging the specific extracellular Mycobacterium tuberculosis glycans, do not lead to the evolution of resistance and bypass the need to cross the impermeable mycobacterial cell envelope barrier.


Assuntos
Antituberculosos/farmacologia , Ácidos Borônicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Células A549 , Antituberculosos/síntese química , Antituberculosos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Dimerização , Eritrócitos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular
2.
Int J Nanomedicine ; 14: 8059-8072, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632018

RESUMO

Background: Compared with random copolymers, block copolymerization is easier to prepare for nanoparticles with core-shell structure, and they will have better glucose sensitivity and higher insulin loading. Purpose: In our study, insulin-loaded poly (3-acrylamidophenylboronic acid-block-N-vinyl caprolactam) p(AAPBA-b-NVCL) nanoparticles were successfully prepared and were glucose-sensitive, which could effectively lower the blood sugar levels within 72 hrs. Methods: The polymer of p(AAPBA-b-NVCL) was produced by reversible addition-fragmentation chain transfer polymerization based on different ratios of 3-acrylamidophenylboronic acid (AAPBA) and N-vinylcaprolactam (NVCL), and its structure was discussed by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance . Next, the polymer was manufactured into the nanoparticles, and the characteristics of nanoparticles were detected by dynamic light scattering, lower critical solution temperature, and transmission electron microscopy. After that, the cell and animal toxicity of nanoparticles were also investigated. Results: The results demonstrated that p(AAPBA-b-NVCL) was successfully synthesized, and can be easily self-assembled to form nanoparticles. The new nanoparticles included monodisperse submicron particles, with the size of the nanoparticle ranged between 150 and 300nm and are glucose- and temperature-sensitive. Meanwhile, insulin can be easily loaded by p(AAPBA-b-NVCL) nanoparticles and an effective sustained release of insulin was observed when the nanoparticles were placed in physiological saline. Besides, MTT assay revealed that cell viability was more than 80%, and mice demonstrated no negative impact on blood biochemistry and heart, liver, spleen, lung, and kidney after intraperitoneal injection of 10 mg/kg/d of nanoparticles. This suggested that the nanoparticles were low-toxic to both cells and animals. Moreover, they could lower the blood sugar level within 72h. Conclusion: Our research suggested that these p(AAPBA-b-NVCL) nanoparticles might have the potential to be applied in a delivery system for insulin or other hypoglycemic proteins.


Assuntos
Acrilamidas/química , Ácidos Borônicos/química , Caprolactama/química , Sistemas de Liberação de Medicamentos , Glucose/análise , Insulina/administração & dosagem , Nanopartículas/química , Acrilamidas/síntese química , Animais , Glicemia/metabolismo , Ácidos Borônicos/síntese química , Caprolactama/análogos & derivados , Caprolactama/síntese química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Hidrodinâmica , Concentração de Íons de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Células NIH 3T3 , Nanopartículas/ultraestrutura , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Temperatura Ambiente
3.
Anal Chim Acta ; 1080: 153-161, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31409465

RESUMO

A red-emitting and ratiometric fluorescence probe 1 for detecting H2O2, based on a styrylnaphthalimide-boronate ester was developed. Upon a H2O2-mediated hydrolysis of boronate ester, probe 1 was transformed to 2 with a ratiometric fluorescence change, decrease at 535 and increase at 640 nm. It was also found that the fluorescent reaction of 1 with H2O2 in solution could be completed within 10 min and the detection limit was estimated to be 0.30 µM. Moreover, this ratiometric change was highly selective for H2O2 over other redox species, metal ions, and anions. Also, this system was found to be capable of detecting H2O2 in the pH range of 6-9. Furthermore, probe 1 was preferentially accumulated into the endoplasmic reticulum (ER) in the live HeLa cells, and an increased H2O2 level in the presence of an ER stress inducer, thapsigargin was revealed.


Assuntos
Ácidos Borônicos/química , Corantes Fluorescentes/química , Peróxido de Hidrogênio/análise , Naftalimidas/química , Estirenos/química , Ácidos Borônicos/síntese química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Naftalimidas/síntese química , Estirenos/síntese química , Tapsigargina/farmacologia
4.
Eur J Med Chem ; 180: 449-456, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330446

RESUMO

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 µM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 µM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Movimento Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
5.
Talanta ; 204: 431-437, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357316

RESUMO

Peroxynitrite anion (ONOO-), one of the reactive nitrogen species (RNS), plays momentous roles in physiological and pathological processes especially in a range of oxidative stress-related diseases. Moreover, abundant ONOO- is generated in the liver tissues of drug-induced liver injury. We report herein a novel small molecule fluorescent probe KC-ONOO for monitoring ONOO- based on boronate. The probe displayed high sensitivity and good selectivity towards ONOO-. A good linear relationship was observed between the fluorescent intensity at 530 nm and the concentration of ONOO- ranged 0-10 µM with a detection limit of 1.5 × 10-8 M. Furthermore, our probe was successfully applied for imaging ONOO- in living cells and drug-damaged liver tissues with low cytotoxicity, demonstrating the probe KC-ONOO has great potential to further elucidate more biological roles of ONOO-.


Assuntos
Benzotiazóis/química , Ácidos Borônicos/química , Cumarínicos/química , Corantes Fluorescentes/química , Ácido Peroxinitroso/análise , Animais , Benzotiazóis/síntese química , Benzotiazóis/toxicidade , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cumarínicos/síntese química , Cumarínicos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Limite de Detecção , Fígado/patologia , Masculino , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Ácido Peroxinitroso/química
6.
Org Lett ; 21(10): 3760-3763, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31066564

RESUMO

Site-selective oxidation of vicinal bis(boronates) is accomplished through the use of trimethylamine N-oxide in 1-butanol solvent. The reaction occurs with good efficiency and selectivity across a range of substrates, providing 2-hydro-1-boronic esters which are shown to be versatile intermediates in the synthesis of chiral building blocks.


Assuntos
Compostos de Boro/síntese química , Ácidos Borônicos/síntese química , Compostos de Boro/química , Ácidos Borônicos/química , Estrutura Molecular , Oxirredução
7.
Analyst ; 144(11): 3643-3648, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073567

RESUMO

Using fluorescent probes to detect endogenous hydrogen peroxide, which is associated with many diseases in the human body, remains an essential technique. Cyanine fluorochromes are a class of dyes that have attracted much attention and are widely used in the synthesis of fluorescent probes. In this article, a novel near-infrared (NIR) fluorescence probe for the detection of hydrogen peroxide was constructed and successfully applied to imaging endogenous hydrogen peroxide in vivo. Notably, probe 1 was designed by connecting 4-(bromomethyl)benzeneboronic acid pinacol ester as the sensing unit to the IR-780 hemicyanine skeleton, which exhibits excellent properties like NIR fluorescence emission over 700 nm. Probe 1 has satisfactory sensitivity to hydrogen peroxide with a low detection limit of 0.14 µM (S/N = 3), attributed to a responding mechanism that leads to the oxidation of phenylboronic acid pinacol ester and thereby releases fluorophore 2. Moreover, probe 1 displays excellent selectivity towards hydrogen peroxide over other substances. Taking advantage of these properties, the probe proved to be cell-permeable. Based on the results of N-acetylcysteine and rotenone together, probe 1 is capable of clearly visualizing endogenously produced hydrogen peroxide in living HepG2 cells and mice. The superior performance of the probe, as a reliable chemical tool, makes it of great potential application for exploring the role played by hydrogen peroxide in biological systems.


Assuntos
Ácidos Borônicos/química , Corantes Fluorescentes/química , Peróxido de Hidrogênio/análise , Indóis/química , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Indóis/síntese química , Indóis/toxicidade , Limite de Detecção , Camundongos Endogâmicos BALB C , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Oxirredução , Rotenona/farmacologia , Temperatura Ambiente
8.
Nanoscale ; 11(21): 10167-10171, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31112182

RESUMO

We have introduced a non-hormonal hyperglycemia treatment strategy by using an injectable glucose-responsive boronic acid- zwitterionic nanogel. The synthesized system, similar to an artificial liver, is capable of storing/releasing glucose at high/low blood glucose concentrations. In vivo performance revealed that the injection of the nanogels can effectively regulate blood glucose in type 1 diabetic rats for at least 6 hours.


Assuntos
Betaína/análogos & derivados , Glicemia/metabolismo , Ácidos Borônicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hiperglicemia , Nanoestruturas , Animais , Betaína/síntese química , Betaína/química , Betaína/farmacologia , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Géis , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Masculino , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Ratos , Ratos Sprague-Dawley
9.
Org Biomol Chem ; 17(24): 5908-5912, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31145403

RESUMO

We describe the biocompatible conjugation of the Tris base to 2-formyl and 2-acetylphenylboronic acid (abbreviated as 2-FPBA and 2-APBA respectively), which have emerged as a versatile chemotype for fast biocompatible conjugation reactions. Tris base was found to react with 2-FPBA/APBA to give oxazolidinoboronate (OzB) complexes, analogous to the thiazolidinoboronate (TzB) and imidazolidinoboronate (IzB) complex formation that we recently reported. The Tris conjugations proceed well in complex biological media, and in contrast to the TzB/IzB complexes, the Tris conjugates exhibit superior kinetic stability (dissociation over days) as well as chemical stability against oxidation. We demonstrate the utility of such conjugation chemistries via a small molecule-induced peptide cyclization in blood serum.


Assuntos
Materiais Biocompatíveis/química , Ácidos Borônicos/síntese química , Trometamina/química , Ácidos Borônicos/química , Cinética , Estrutura Molecular
10.
Nat Commun ; 10(1): 1263, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894535

RESUMO

Stereocontrolled Csp3 cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp3 cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp3 boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp3 boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp3 boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp3 stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp3 cross-coupling.


Assuntos
Ácidos Borônicos/síntese química , Técnicas de Química Sintética , Ácidos Graxos Monoinsaturados/síntese química , Paládio/química , Catálise , Humanos , Ligantes , Estrutura Molecular , Estereoisomerismo
11.
ACS Sens ; 4(1): 134-142, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30624896

RESUMO

Fluorenylboronate ester chromophore-based thin films were investigated for the detection of triacetone triperoxide (TATP) vapors via the decomposition product, hydrogen peroxide. Sensing with a high level of sensitivity was achieved using a fluorescence "turn-on" mechanism based on the significant shifts in the absorption and photoluminescence spectra that occurs when the boronate esters were converted to phenoxides by hydrogen peroxide under basic conditions. The addition of an organic base was found to be critical for achieving fast conversion reactions and the formation of the phenoxide anions. Addition of a nitrile group to the fluorenyl boronate ester moiety improved the stability of the material to photooxidation, increased the photoluminescence quantum yields, and enhanced the absorption and emission shifts to longer wavelengths. In real-time sensing measurements, films comprising the cyanofluorenyl boronate ester moiety and tetra- n-butylammonium hydroxide had a response time to acid-decomposed TATP vapor of seconds and a limit of detection of 40 ppb in 60 s.


Assuntos
Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/análise , Peróxido de Hidrogênio/análise , Peróxidos/análise , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Substâncias Explosivas/análise , Substâncias Explosivas/química , Fluorenos/síntese química , Fluorenos/química , Fluorescência , Corantes Fluorescentes/síntese química , Fluorometria/métodos , Compostos Heterocíclicos com 1 Anel/química , Peróxido de Hidrogênio/química , Limite de Detecção , Oxirredução , Peróxidos/química
12.
Chem Res Toxicol ; 32(1): 100-112, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30560658

RESUMO

Stimulus-responsive cleavage reactions have found broad use to direct drug release at a particular target disease area. Increased levels of reactive oxygen species (ROS) have been associated with the development and progression of cancer and several other disease states, motivating the development of drug conjugates that can undergo a chemoselective ROS-triggered release. Melatonin (MLT) and the reactive electrophile p-benzoquinone methide ( p-QM) have evidenced either cytoprotective or cytotoxic effects in biological systems, depending on the dose, cellular targets, and time of exposure. In this study, we report the synthesis and biological activity of two MLT derivatives linked to ROS-responsive arylboronate triggers (P1 and P2), which can be activated by endogenously generated hydrogen peroxide (H2O2) to release MLT, or 5-methoxytryptamine (5-MeOT), and p-QM-intermediates. Their H2O2-induced activation mechanism was studied by HPLC-DAD-MS. P1, which rapidly releases MLT and p-QM, was able to strongly induce the Nrf2 antioxidant signaling pathway, but was ineffective to provide protection against H2O2-mediated oxidative damage. By contrast, P1 exhibited strong toxic effects in HeLa cancer cells, without causing significant toxicity to normal NCTC-2544 cells. Similar, although more limited, effects were exerted by P2. In both cases, cytotoxicity was accompanied by depletion of cellular glutathione (GSH), probably as a consequence of p-QM release, and increased ROS levels. A role for MLT in toxicity was also observed, suggesting that the P1 released products, MLT and p-QM, contributed additively to promote cell death.


Assuntos
Ácidos Borônicos/farmacologia , Desenho de Drogas , Peróxido de Hidrogênio/farmacologia , Melatonina/farmacologia , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células HeLa , Humanos , Peróxido de Hidrogênio/síntese química , Peróxido de Hidrogênio/química , Melatonina/síntese química , Melatonina/química , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
13.
J Am Chem Soc ; 140(46): 15621-15625, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30411878

RESUMO

A catalytic, enantioselective method for the preparation of chiral, non-racemic, alkylboronic esters bearing two vicinal stereogenic centers is described. The reaction proceeds via a 1,2-migration of a zwitterionic thiiranium-boronate complex to give exclusively anti carbosulfenylation products. A broad scope of aryl groups migrate with good yield and excellent enantioselectivity (up to 99:1 e.r.). Similarly, a range of di- and trisubstituted alkenylboronic esters are competent reaction partners. This method provides access to both secondary and tertiary chiral alkylboronic esters.


Assuntos
Ácidos Borônicos/síntese química , Bases de Lewis/química , Ácidos Sulfênicos/química , Ácidos Borônicos/química , Catálise , Estrutura Molecular , Estereoisomerismo
14.
J Am Chem Soc ; 140(42): 13634-13639, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30289691

RESUMO

Substituted 1,3-dienes are valuable synthetic intermediates used in myriad catalytic transformations, yet modern catalytic methods for their preparation in a highly modular fashion using simple precursors are relatively few. We report here an aerobic boron Heck reaction with cyclobutene that forms exclusively linear 1-aryl-1,3-dienes using (hetero)arylboronic acids, or 1,3,5-trienes using alkenylboronic acids, rather than typical Heck products (i.e., substituted cyclobutenes). Experimental and computational mechanistic data support a pericyclic mechanism for C-C bond cleavage that enables the cycloalkene to circumvent established limitations associated with diene reagents in Heck-type reactions.


Assuntos
Alcenos/síntese química , Ácidos Borônicos/química , Alcenos/química , Ácidos Borônicos/síntese química , Técnicas de Química Sintética , Ciclobutanos/síntese química , Ciclobutanos/química , Oxigênio/química , Estereoisomerismo
15.
Anal Chem ; 90(21): 12553-12558, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30295464

RESUMO

Real-time monitoring of the distribution of energy released during oxidative phosphorylation (OXPHOS) in living cells would advance the understanding of metabolic pathways and cell biology. However, the relationship between intracellular temperature and ATP fluctuation during the OXPHOS process is rarely studied due to the limitation of the sensing approach. Novel fluorescent polymer probes were developed for accurate simultaneous measurements of intracellular temperature and ATP. Utilizing the fluorescence imaging techniques, it was demonstrated for the first time that the temperature in mitochondria increased 2.4 °C and the ATP fluctuation level simultaneously decreased 75% within 2 min during the OXPHOS process. Moreover, the resultant fluorescent polymer probes had good performance and properties for mitochondrial targeting, providing an effective way for investigating mechanisms by which energy is released during the OXPHOS process.


Assuntos
Trifosfato de Adenosina/análise , Ácidos Borônicos/química , Cumarínicos/química , Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Compostos Organofosforados/química , Resinas Acrílicas/síntese química , Resinas Acrílicas/química , Resinas Acrílicas/toxicidade , Trifosfato de Adenosina/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Cumarínicos/síntese química , Cumarínicos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Microscopia Confocal/métodos , Compostos Organofosforados/síntese química , Compostos Organofosforados/toxicidade , Fosforilação Oxidativa , Temperatura Ambiente , Termogênese
16.
Bioconjug Chem ; 29(11): 3841-3846, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30339361

RESUMO

DNA-encoded chemical libraries (DELs) are a cost-effective technology for the discovery of novel chemical probes and drug candidates. A major limiting factor in assembling productive DELs is the availability of DNA-compatible chemical reactions in aqueous media. In an effort to increase the chemical accessibility and structural diversity of small molecules displayed by DELs, we developed a robust Suzuki-Miyaura reaction protocol that is compatible with the DNA structures. By employing a water-soluble Pd-precatalyst, we developed conditions that allow efficient coupling of DNA-linked aryl halides with a wide variety of boronic acids/esters including heteroaryl boronates.


Assuntos
Ácidos Borônicos/química , DNA/química , Hidrocarbonetos Aromáticos/química , Bibliotecas de Moléculas Pequenas/química , Água/química , Ácidos Borônicos/síntese química , Catálise , DNA/síntese química , Ésteres/síntese química , Ésteres/química , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Halogenados/síntese química , Hidrocarbonetos Halogenados/química , Paládio/química , Bibliotecas de Moléculas Pequenas/síntese química
17.
Langmuir ; 34(40): 12116-12125, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30212220

RESUMO

Insulin plays a significant role in diabetes treatment. Although a huge number of insulin-loaded, glucose-responsive nanocarriers have been developed in past decades, most of them showed a lower loading capacity and efficiency due to the weak interaction between insulin and nanocarriers. In this work, a novel insulin-encapsulated glucose-responsive polymeric complex micelle (CM) is devised, showing (i) enhanced insulin-loading efficiency owing to the zinc ions' chelation by nitrilotriacetic acid (NTA) groups of NTA-functioned glycopolymer and the histidine imidazole of insulin, (ii) the glucose-triggered pulse release of insulin, and (iii) long stability under physiological conditions. This CM was fabricated by the self-assembly of block copolymer PEG- b-P(Asp- co-AspPBA) and glycopolymer P(Asp- co-AspGA- co-AspNTA), resulting in complex micelles with a PEG shell and a cross-linked core composed of phenylboronic acid (PBA)/glucose complexations. Notably, the modified nitrilotriacetic acid (NTA) groups of CM could specifically bind insulin via chelated zinc ions, thus enhancing the loading efficacy of insulin compared to that of nonmodified CM. The dynamic PBA/glucose complexation core of CM dissociates under the trigger of high glucose concentration (>2 g/L) while being quite stable in low glucose concentrations (<2 g/L), as demonstrated by the pulse release of insulin in vitro. Finally, in a murine model of type 1 diabetes, NTA-modified complex micelles loading an insulin (NTA-CM-INS) group exhibited a long hypoglycemic effect which is superior to that of free insulin in the PBS (PBS-INS) group and insulin-loaded complex micelles without an NTA modification (CM-INS) group. This long-term effect benefited from Zn(II) chelation by NTA-modified complex micelles and could avoid hypoglycemia caused by the burst release of insulin. Taken together, this constitutes a highly effective way to encapsulate insulin and release insulin via an on-demand manner for blood glucose control in diabetes.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Portadores de Fármacos/química , Glucose/química , Insulina/uso terapêutico , Micelas , Ácido Nitrilotriacético/química , Animais , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Ácidos Borônicos/toxicidade , Quelantes/síntese química , Quelantes/química , Quelantes/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Camundongos , Células NIH 3T3 , Ácido Nitrilotriacético/síntese química , Ácido Nitrilotriacético/toxicidade , Peptídeos/síntese química , Peptídeos/química , Peptídeos/toxicidade , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/toxicidade , Zinco/química
18.
Analyst ; 143(20): 4936-4943, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30215639

RESUMO

Riboflavin (vitamin B2), a cis-diol-containing compound, is an essential vitamin for maintaining human health mainly in energy metabolism and is a critical component of enzyme cofactors and flavoproteins. Thus, the determination of riboflavin in food products is essential in riboflavin-fortified foods. However, analysis of riboflavin at natural levels in foods or biological samples is difficult because of its very low concentration level and the presence of undesirable matrix effects which could interfere with the measuring system. Thus, it is essential to develop efficient and selective enrichment approaches for riboflavin. Molecularly imprinted polymers can be well used for riboflavin extraction and pre-concentration from food samples. In this study, we present riboflavin-imprinted magnetic nanoparticles as an ideal sorbent for the selective enrichment of riboflavin followed by direct fluorometric determination. The riboflavin-imprinted magnetic nanoparticles were prepared according to a newly reported strategy, called boronate affinity-based surface initiated imprinting. Magnetic nanoparticles and vinylphenylboronic acid were used as supporting materials and a functional monomer, respectively. The prepared riboflavin-imprinted magnetic nanoparticles exhibited several significant advantages, such as excellent selectivity, high binding affinity and low binding pH toward riboflavin, which made the molecularly imprinted material become an ideal sorbent for the selective enrichment of riboflavin. The prepared riboflavin-imprinted magnetic nanoparticles were successfully applied to the analysis of riboflavin in milk.


Assuntos
Ácidos Borônicos/química , Nanopartículas de Magnetita/química , Impressão Molecular , Riboflavina/análise , Animais , Ácidos Borônicos/síntese química , Análise de Alimentos , Concentração de Íons de Hidrogênio , Leite/química , Reprodutibilidade dos Testes , Riboflavina/química
19.
Inorg Chem ; 57(16): 10128-10136, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30091913

RESUMO

The first boronic acid functionalized Hf-based UiO-66 (UiO = University of Oslo) metal-organic framework (MOF) having the ability to detect both extracellular and intracellular peroxynitrite is presented. The Hf-UiO-66-B(OH)2 material (1) was synthesized under solvothermal conditions from a mixture of HfCl4 and 2-borono-1,4-benzenedicarboxylic acid [H2BDC-B(OH)2] ligand in DMF in the presence of formic acid (modulator) at 130 °C for 48 h. The desolvated material (1') was utilized as a fluorescent turn-on probe for the rapid sensing of extracellular peroxynitrite (ONOO-) under conditions mimicking those of biological medium (10 mM HEPES buffer, pH 7.4). Selective sensing of ONOO- over other ROS/RNS was also achieved by 1'. The oxidative cleavage of attached boronic acid groups forming corresponding hydroxy-functionalized ligands can be accounted for the fluorescent increment phenomenon in the presence of ONOO-. The probe showed extraordinary sensitivity (detection limit = 9.0 nM) toward ONOO- in 10 mM HEPES buffer at pH 7.4. Probe-loaded cells did not exhibit cytotoxicity and morphological deformities. It is remarkable that the probe inside the cells responded toward the peroxynitrite solution to give an intense blue fluorescent signal. The fluorescence microscopy study with J774A.1 macrophage cells unambiguously demonstrated that probe 1' is suitable to image peroxynitrite in living cells.


Assuntos
Ácidos Borônicos/química , Corantes Fluorescentes/química , Estruturas Metalorgânicas/química , Ácido Peroxinitroso/análise , Animais , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Linhagem Celular , Estabilidade de Medicamentos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Limite de Detecção , Macrófagos/efeitos dos fármacos , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/toxicidade , Camundongos , Microscopia de Fluorescência/métodos , Oxirredução , Temperatura Ambiente
20.
Chembiochem ; 19(15): 1648-1652, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29806887

RESUMO

Bioorthogonal chemistry can be used for the selective modification of biomolecules without interfering with any other functionality that might be present. Recent developments in the field include orthogonal bioorthogonal reactions to modify multiple biomolecules simultaneously. During our research, we observed that the reaction rates for the bioorthogonal inverse-electron-demand Diels-Alder (iEDDA) reactions between nonstrained vinylboronic acids (VBAs) and dipyridyl-s-tetrazines were exceptionally higher than those between VBAs and tetrazines bearing a methyl or phenyl substituent. As VBAs are mild Lewis acids, we hypothesised that coordination of the pyridyl nitrogen atom to the boronic acid promoted tetrazine ligation. Herein, we explore the molecular basis and scope of VBA-tetrazine ligation in more detail and benefit from its unique reactivity in the simultaneous orthogonal tetrazine labelling of two proteins modified with VBA and norbornene, a widely used strained alkene. We further show that the two orthogonal iEDDA reactions can be performed in living cells by labelling the proteasome by using a nonselective probe equipped with a VBA and a subunit-selective VBA bearing a norbornene moiety.


Assuntos
Alcenos/química , Ácidos Borônicos/química , Reação de Cicloadição/métodos , Norbornanos/química , Proteínas/química , Compostos de Vinila/química , Alcenos/síntese química , Ácidos Borônicos/síntese química , Proteínas de Fluorescência Verde/síntese química , Proteínas de Fluorescência Verde/química , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Norbornanos/síntese química , Proteínas/síntese química , Albumina Sérica Humana/síntese química , Albumina Sérica Humana/química , Compostos de Vinila/síntese química
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