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1.
Pharm Res ; 37(4): 70, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32185516

RESUMO

PURPOSE: While including amorphous solid dispersion (ASD) in tablet formulations is increasingly common, tablets containing high ASD loading are associated with slow disintegration, which presents a challenge to control pill burden for less potent compounds. METHODS: We use a model ASD, composed of a hydrophobic drug with copovidone and a non-ionic surfactant, to explore formulation options that can prevent slow disintegration. RESULTS: In addition to the ASD loading, the pH of the disintegration medium and the inclusion of inorganic salts in the tablet also have an impact on the tablet disintegration time. Certain kosmotropic salts, when added in the formulation, can significantly accelerate tablet disintegration, though the rank order in their effectiveness does not exactly follow the Hofmeister series at pH 1.8. The particle size and dissolution rate of the salt can contribute to its overall effectiveness. CONCLUSION: We provided a mechanistic explanation of the disintegration process: fast-dissolving kosmotropic salt results in a concentrated salt solution inside the restrained tablet matrix, thus inhibiting the dissolution of copovidone and preventing polymer gelling which is the main cause leading the slow disintegration. The outcome of this study has enabled the design of a higher ASD loading platform formulation for copovidone based ASD. Graphical Abstract MicroCT aids the mechanistic understanding of the role of inorganic salt in the tablet disintegration of amorphous solid dispersion based formulation.


Assuntos
Pirrolidinas/química , Sais/química , Comprimidos/química , Compostos de Vinila/química , Química Farmacêutica , Excipientes/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Osmolar , Tamanho da Partícula , Solubilidade
2.
Nat Commun ; 11(1): 446, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974383

RESUMO

Afterglow luminescent probes with high signal-to-background ratio show promise for in vivo imaging; however, such probes that can be selectively delivered into target sites and switch on afterglow luminescence remain limited. We optimize an organic electrochromic material and integrate it into near-infrared (NIR) photosensitizer (silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) and (poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene]) containing nanoparticles, developing an H2S-activatable NIR afterglow probe (F12+-ANP). F12+-ANP displays a fast reaction rate (1563 ± 141 M-1 s-1) and large afterglow turn-on ratio (~122-fold) toward H2S, enabling high-sensitivity and -specificity measurement of H2S concentration in bloods from healthy persons, hepatic or colorectal cancer patients. We further construct a hepatic-tumor-targeting and H2S-activatable afterglow probe (F12+-ANP-Gal) for noninvasive, real-time imaging of tiny subcutaneous HepG2 tumors (<3 mm in diameter) and orthotopic liver tumors in mice. Strikingly, F12+-ANP-Gal accurately delineates tumor margins in excised hepatic cancer specimens, which may facilitate intraoperative guidance of hepatic cancer surgery.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Sulfeto de Hidrogênio/análise , Neoplasias Hepáticas/diagnóstico por imagem , Substâncias Luminescentes/química , Imagem Molecular/métodos , Animais , Neoplasias Colorretais/sangue , Cistationina beta-Sintase/análise , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/análise , Cistationina gama-Liase/metabolismo , Células Hep G2 , Humanos , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/química , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Substâncias Luminescentes/síntese química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Compostos de Vinila/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Chemosphere ; 239: 124732, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31499304

RESUMO

A polar modified post-cross-linked poly (divinylbenzene-co-ethyleneglycol-dimethacrylate) (PCL-PDE) resin was synthesized by suspension polymerization of ethylene glycol dimethacrylate (EGDMA) and divinylbenzene (DVB), and a post-cross-linked reaction. After characterization, the adsorption behaviors of 5-hydroxymethylfurfural (5-HMF) on PCL-PDE resin were determined in comparison with the starting copolymers PDE resin. The equilibrium adsorption capacity of 5-HMF on PCL-PDE resin was much larger than PDE resin and the increase rate was greater than 52.6%. The equilibrium data of 5-HMF onto PCL-PDE resin were found to be better fitted by the Langmuir isotherm model. The kinetic data shows that the adsorption reached equilibrium in a short time (less than 20 min) can be fitted by the pore diffusion model (PDM) at various operating conditions. The effective pore diffusion coefficient was dependent upon adsorption temperature, and were 6.706 × 10-10, 8.958 × 10-10, 1.136 × 10-9 and 1.429 × 10-9 m2 s-1 at 288, 298, 308 and 318 K, respectively. Furthermore, the effects of feed flow rate (Qf = 0.6, 1.5, 3.0 and 6.0 mL min-1) and initial 5-HMF concentration (cf = 0.52, 1.02, 2.00 and 4.96 g L-1) on the adsorption were investigated systematically. Besides, a general rate model (GRM) was used to predict adsorption breakthrough curves of 5-HMF. The simulation results are highly consistent with the experimental data, indicating that the GRM can successfully simulate this process. In the desorption process, the desorption capacity reaches 99.6% of adsorbed capacity, suggesting that the PCL-PDE resin exhibited good reusability. Therefore, it could be suggested that the PCL-PDE resin has a potential application in the separation and purification of 5-HMF.


Assuntos
Resinas Acrílicas/química , Furaldeído/análogos & derivados , Resinas Acrílicas/síntese química , Adsorção , Reagentes para Ligações Cruzadas/química , Difusão , Furaldeído/química , Furaldeído/isolamento & purificação , Cinética , Metacrilatos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Compostos de Vinila/química
4.
Artigo em Inglês | MEDLINE | ID: mdl-31610481

RESUMO

Traditional chromatographic techniques used in downstream processes of biomolecule manufacturing are often time-consuming and expensive. In this study, a cost-effective microporous micro-capillary film (MMCF) composed of ethylenevinyl alcohol (EVOH) was evaluated for its potential application in immunoadsorption with high process efficiency. A peptide ligand Ac-Phe-Tyr-His-Glu (Ac-FYHE) was immobilized on the inner surface of MMCF for selective binding of human immunoglobulin (hIgG). The porous structure and chemical properties of the prepared MMCF were confirmed by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). hIgG (2 mg/ml) adsorption studies demonstrated that the binding process followed a Langmuir isotherm with equilibrium adsorption capacities of 9.31 and 3.47 mg/ml adsorbent under static and dynamic conditions, respectively. Moreover, the membrane showed good flowrate tolerance when studied under flowrates of 0.5 ml/min to 10 ml/min. hIgG purity was 88.2% when obtained from an hIgG (2 mg/ml) and HSA (8 mg/ml) mixture and the purity remained over 80.0% when hIgG concentrations increased in the mixtures. Moreover, purity of 82.3% was achieved when removing hIgG directly from human serum. The MMCF-Ac-FYHE affinity column is expected to selectively remove hIgG from blood for the treatment of autoimmune diseases with high efficiency and cost effectiveness.


Assuntos
Cromatografia de Afinidade/métodos , Imunoglobulina G/isolamento & purificação , Peptídeos/química , Adsorção , Humanos , Cinética , Ligantes , Estrutura Molecular , Porosidade , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Propriedades de Superfície , Compostos de Vinila/química
5.
Eur J Med Chem ; 184: 111767, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622854

RESUMO

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ±â€¯19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.


Assuntos
Descoberta de Drogas , Ácido Palmítico/antagonistas & inibidores , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Compostos de Vinila/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HEK293 , Humanos , Estrutura Molecular , Ácido Palmítico/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Fatores de Transcrição/metabolismo , Compostos de Vinila/síntese química , Compostos de Vinila/química
6.
Eur J Med Chem ; 184: 111733, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604163

RESUMO

Norovirus (NV), is the most common cause of acute gastroenteritis worldwide. To date, there is no specific anti-NV drug or vaccine to treat NV infections. In this study, we evaluated the inhibitory effect of different stilbene-based analogs on RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23). Initial screening of our in-house chemical library against NV led to the identification of a hit containing stilbene scaffold 5 which on initial optimization gave us a vinyl stilbene compound 16c (EC50 = 4.4 µM). Herein we report our structure-activity relationship study of the novel series of vinyl stilbene analogs that inhibits viral RNA genome replication in a human NV-specific manner. Among these newly synthesized compounds, several amide derivatives of vinyl stilbenes exhibited potent anti-NV activity with EC50 values ranging from 1 to 2 µM. A trans-vinyl stilbenoid with an appended substituted piperazine amide (18k), exhibited potent anti-NV activity and also displayed favorable metabolic stability. Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral mechanism.


Assuntos
Antivirais/farmacologia , Norovirus/efeitos dos fármacos , Estilbenos/farmacologia , Compostos de Vinila/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos/efeitos dos fármacos , Microssomos/microbiologia , Estrutura Molecular , Células RAW 264.7 , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Estilbenos/química , Relação Estrutura-Atividade , Compostos de Vinila/química , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
7.
Eur J Pharm Biopharm ; 144: 79-90, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499162

RESUMO

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (i.e. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydroxypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes.


Assuntos
Portadores de Fármacos/química , Poliaminas/química , Solubilidade/efeitos dos fármacos , Química Farmacêutica/métodos , Cristalização/métodos , Dessecação/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Derivados da Hipromelose/química , Polímeros/química , Povidona/química , Pirrolidinas/química , Compostos de Vinila/química
8.
Chem Pharm Bull (Tokyo) ; 67(8): 877-883, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366836

RESUMO

The 4-vinylpyrimidin-2-one nucleoside (T-vinyl) forms a cross-link with the RNA containing uracil at the complementary site at a high reaction rate. To obtain the stable T-vinyl derivative so that its reactivity is protected until it access to the target site, several derivatives were investigated, and the 2-thiopyridinyl- and 2-thiopyrimidinyl T-vinyl derivatives were determined to be good candidates. The 2-thiopyrimidinyl T-vinyl derivative was found to more efficiently cross-link with mRNA albeit having a better stability than the 2-thiopyridinyl T-vinyl derivative. The investigation using the luciferase (Luc) mRNA, the synthetic mRNA and non-cellular translation system revealed that the translation is terminated at the end of the cross-linked duplex between the mRNA and the oligoribonucleotide (ORN). Thus, the 2-thiopyrimidinyl T-vinyl derivative has successfully demonstrated both a good stability and high efficiency for the cross-linking reaction, and expanded its applicability in biological applications.


Assuntos
Reagentes para Ligações Cruzadas/química , Nucleosídeos/química , Oligorribonucleotídeos/química , RNA Mensageiro/química , Compostos de Vinila/química , Reagentes para Ligações Cruzadas/síntese química , Estrutura Molecular , Nucleosídeos/síntese química , Compostos de Vinila/síntese química
9.
J Mater Sci Mater Med ; 30(8): 96, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414231

RESUMO

Critical size bone defects that do not heal spontaneously are among the major reasons for the disability in majority of people with locomotor disabilities. Tissue engineering has become a promising approach for repairing such large tissue injuries including critical size bone defects. Three-dimension (3D) porous scaffolds based on piezoelectric polymers like poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) have received a lot of attention in bone tissue engineering due to their favorable osteogenic properties. Owing to the favourable redox properties, titanium dioxide (TiO2) nanostructures have gained a great deal of attention in bone tissue engineering. In this paper, tissue engineering scaffolds based on P(VDF-TrFE) loaded with TiO2 nanowires (TNW) were developed and evaluated for bone tissue engineering. Wet-chemical method was used for the synthesis of TNW. Obtained TNW were thoroughly characterized for the physicochemical and morphological properties using techniques such as X-Ray diffraction (XRD) analysis and transmission electron microscopy (TEM). Electrospinning was used to produce TNW incorporated P(VDF-TrFE) scaffolds. Developed scaffolds were characterized by state of art techniques such as Scanning Electron Microscopy (SEM), XRD and Differential scanning calorimetry (DSC) analyses. TEM analysis revealed that the obtained TiO2 nanostructures possess nanofibrous morphology with an average diameter of 26 ± 4 nm. Results of characterization of nanocomposite scaffolds confirmed the effective loading of TNW in P(VDF-TrFE) matrix. Fabricated P(VDF-TrFE)/TNW scaffolds possessed good mechanical strength and cytocompatibility. Osteoblast like cells showed higher adhesion and proliferation on the nanocomposite scaffolds. This investigation revealed that the developed P(VDF-TrFE) scaffolds containing TNW can be used as potential scaffolds for bone tissue engineering applications.


Assuntos
Osso e Ossos/citologia , Nanofios/química , Polivinil/química , Engenharia Tecidual , Tecidos Suporte/química , Titânio/química , Compostos de Vinila/química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Hidrocarbonetos Fluorados/química , Teste de Materiais , Camundongos , Nanocompostos/química , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Ratos , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos
10.
J Chromatogr A ; 1605: 360341, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395356

RESUMO

A novel strategy for the analysis of 20 organochlorine pesticides (OCPs) monitoring in marine surface waters through ethylenevinyl acetate (EVA) passive samplers was developed and validated. The approach is based on the coupled of ultrasound-assisted solvent extraction (UASE) and headspace solid-phase microextraction (HS-SPME) as extraction method for OCPs from EVA samplers. The UASE-HS-SPME method was optimized with a 27-4 Plackett-Burman design, while the significant factors (salting out, temperature and extraction time) were optimized using a central composite design (CCD) combined with desirability function (DF). The OCPs detection was performed using multiple reaction monitoring (MRM) by gas chromatography-tandem mass spectrometry (GC-MS/MS). The optimum experimental conditions comprised: salting out: 23% wv-1 NaCl, temperature: 75°C and extraction time: 55 min. The optimized method was validated in terms of linearity (R2>0.9946), recovery (>61%) and inter-day and intra-day reproducibility (<19%) for 20 OCPs studied. The limits of detection (LODs) were ranging from 0.01 ng for α-hexachlorocyclohexane and 0.27 ng for endrin aldehyde. Finally, the methodology was tested in marine surface seawater of Southern Chile using EVA samplers, where twelve OCPs were detected at ultra-trace levels (ngL-1).


Assuntos
Monitoramento Ambiental/métodos , Cromatografia Gasosa-Espectrometria de Massas , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Microextração em Fase Sólida , Chile , Etilenos/análise , Limite de Detecção , Reprodutibilidade dos Testes , Solventes/química , Espectrometria de Massas em Tandem , Temperatura , Compostos de Vinila/química , Poluentes Químicos da Água/análise
11.
Eur J Pharm Biopharm ; 143: 8-17, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398439

RESUMO

In this paper, we employed Broadband Dielectric Spectroscopy (BDS) in order to determine the effect of the high pressure on the solubility limits of the amorphous flutamide within Kollidon VA64 matrix. In order to achieve this goal, drug-polymer systems have been examined: (i) at ambient pressure and both isothermal and nonisothermal conditions by means of BDS as well as Differential Scanning Calorimetry (DSC), to validate proposed method; (ii) at high pressure conditions (20 and 50 MPa) and elevated temperatures (343 K, 353 K and 363 K) by means of dielectric spectroscopy. Our studies revealed that regardless of applied pressure the solubility of the flutamide within the co-polymer matrix increases with increasing temperature at isobar conditions. Moreover, our results clearly indicate that with increasing pressure the solubility of the drug within the polymer matrix is decreasing at isothermal conditions. Therefore, during the solubility limit studies one should consider the situation in which by increasing the pressure (at constant temperature) would achieve an effect similar to the lowering of the temperature (at constant pressure).


Assuntos
Flutamida/química , Polímeros/química , Varredura Diferencial de Calorimetria/métodos , Espectroscopia Dielétrica/métodos , Pressão , Pirrolidinas/química , Solubilidade , Temperatura , Compostos de Vinila/química
12.
J Chromatogr A ; 1608: 460405, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31378530

RESUMO

Temperature effect on the adsorption enthalpy of polyphenols was analyzed with van't Hoff plots using the distribution coefficient, K, determined with isocratic and gradient elution chromatography. Catechin and epigallocatechin gallate (EGCG) were used as model polyphenols. The stationary phase was polystyrene-divinylbenzene (PS-DVB) resin particles and the mobile phase was an ethanol-water mixture. The values of adsorption enthalpy determined by chromatography and isothermal titration calorimetry were obtained in the temperature range of 283 and 318 K. The results obtained by van't Hoff plots were consistent with the ones obtained with the isothermal titration calorimetry (ITC). The interaction between PS-DVB particles and the polyphenols was found to be exothermic with negative values of enthalpy, -30.1 and -37.7 kJ/mol for catechin and EGCG, respectively.


Assuntos
Calorimetria , Cromatografia , Polímeros/química , Polifenóis/análise , Termodinâmica , Adsorção , Polifenóis/metabolismo , Poliestirenos/química , Compostos de Vinila/química , Água/química
13.
Macromol Rapid Commun ; 40(16): e1900168, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31206971

RESUMO

Porous organic polymers (POPs) have enormous applications in various fields and thus have received a lot of research attention in recent decades. Numerous synthetic methods have been developed, but mild synthesis conditions and fast polymerization rate are highly desired. Herein, high porous POPs with high surface areas from aromatic vinyl monomers by using acid catalysis method is reported. The polymerization is ultrafast and could be accomplished even in 5 min at room temperature. Furthermore, the surface area can be tuned by using various acid catalysts and controlling the reaction time. Due to the high surface area, these POPs show promising adsorption of carbon dioxide and hydrogen, respectively. Furthermore, the large π-system of the building block and high surface area of the POPs also make them show potential applications in photocatalytic hydrogen evolution as well as promising catalyst support for metal nanoparticles.


Assuntos
Hidrocarbonetos Aromáticos/química , Polímeros/química , Compostos de Vinila/química , Catálise , Concentração de Íons de Hidrogênio , Estrutura Molecular , Tamanho da Partícula , Polimerização , Porosidade , Propriedades de Superfície
14.
Nucleic Acids Res ; 47(13): 6578-6589, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31188442

RESUMO

Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.


Assuntos
Alquilantes/farmacologia , DNA/efeitos dos fármacos , Conformação de Ácido Nucleico/efeitos dos fármacos , Alquilantes/síntese química , Alquilantes/química , Alquilação , Pareamento de Bases , DNA/química , DNA de Cadeia Simples/química , DNA de Cadeia Simples/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Purinas/química , Purinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Compostos de Vinila/química , Compostos de Vinila/farmacologia
15.
Macromol Rapid Commun ; 40(16): e1900139, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31188503

RESUMO

The radical polymerization of 2-vinylfluorenol, an alcohol derivative of vinylfluorene, gives poly(vinylfluorenol), which quantitatively releases hydrogen gas (≈110 mL per gram polymer at standard temperature and pressure) by simply warming at 100 °C with an iridium catalyst. A high population of fluorenol units in the polymer accomplishes a large formula-weight-based theoretical hydrogen density (1.0 wt%). The dehydrogenated ketone derivative, poly(vinylfluorenone), exhibits reversible negative-charge storage with a high density of 260 mAh g-1 . The electrolytically reduced poly(vinylfluorenone) is momentarily hydrogenated in the presence of an electrolyte with water as the hydrogen source to be converted to the original poly(vinylfluorenol). The formed poly(vinylfluorenol) almost quantitatively evolves hydrogen gas similar to the starting poly(vinylfluorenol). Both hydrogen and charge storage with the organic fluorenol/fluorenone polymer suggest a new type of energy-storage configuration.


Assuntos
Técnicas Eletroquímicas , Hidrogênio/química , Irídio/química , Compostos de Vinila/química , Catálise , Hidrogenação , Estrutura Molecular , Compostos de Vinila/síntese química
16.
Eur J Pharm Biopharm ; 141: 149-160, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132400

RESUMO

The aim of this work was to investigate the relationship between formulation material properties, process parameters and process performance for the manufacturing of amorphous solid dispersions via hot-melt extrusion (HME) using experimentation coupled with process modeling. Specifically, we evaluated the impact of the matrix copovidone melt rheology with and without the addition of a plasticizing surfactant, polysorbate 80, while also varying the process parameters, barrel temperature and screw speed, and keeping fill volume constant. To correlate the process performance to a critical quality attribute, we used telmisartan as an indicator substance by processing at temperatures below its solubility temperature in the polymeric matrix. We observed a broader design space of HME processes for the plasticized formulation with respect to screw speed than for the copovidone-only matrix formulation. This observation was determined by the range of observed melt temperatures in the extruder, both measured and simulated. The reason was not primarily linked to a reduced shear-thinning behavior, characterized by the power law index, n, but instead more to an overall reduced melt viscosity during extrusion and zero-shear rate viscosity, η0, accordingly. We also found that the amount of residual crystallinity of telmisartan correlated with the simulated maximum melt temperature in the extruder barrel. This finding confirmed the applicability of the temperature-dependent API-matrix solubility phase diagram for HME to process development. Given the complex inter-dependent relationships between material properties, process and performance, process modeling combined with reduced laboratory experimentation was established as a holistic approach for the evaluation of Quality-by-Design-based HME process design spaces.


Assuntos
Polímeros/química , Povidona/química , Telmisartan/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Temperatura Alta , Ciência dos Materiais/métodos , Polissorbatos/química , Pirrolidinas/química , Reologia , Solubilidade/efeitos dos fármacos , Compostos de Vinila/química , Viscosidade/efeitos dos fármacos
17.
Talanta ; 201: 496-502, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122456

RESUMO

According to the molecular properties of non-steroidal anti-inflammatory drugs (NSADs), a new adsorbent for magnetic solid phase extraction (MSPE) was designed and synthesized. Triethyl-(4-vinylbenzyl)aminium chloride and 4-vinylbenzeneboronic acid were utilized as dual functional monomers to copolymerize with divinylbenzene on the surface of pre-modified Fe3O4 nanoparticles. The prepared magnetic adsorbent (Fe3O4@TCVA) was characterized by elemental analysis, Fourier transform infrared, scanning electron microscopy, transmission electron microscopy and vibrating sample magnetometer. Due to the abundant boronic acid, quaternary amine and phenyl groups, the Fe3O4@TCVA displayed satisfactory extraction performance for target NSADs (diclofenac acid, ibuprofen and mefenamic acid) by means of B-N coordination, anion-exchange, π-π and hydrophobic interactions. Under the optimized conditions, the Fe3O4@TCVA/MSPE was combined with high-performance liquid chromatography with diode array detection (HPLC-DAD) to sensitively analyze NSADs in water and human urine samples. Results indicated that the limits of detection for water and urine samples were in the ranges of 0.014-0.031 µg/L and 0.029-0.11 µg/L, respectively. The relative standard deviations for the intra-day and inter-day assay variability were below 10%. The applicability of the proposed Fe3O4@TCVA/MSPE-HPLC-DAD method was demonstrated by the successful extraction and quantification of trace levels of NSADs in real water and human urine samples. Satisfactory spiked recovery and reproducibility were achieved.


Assuntos
Anti-Inflamatórios não Esteroides/urina , Diclofenaco/urina , Ibuprofeno/urina , Ácido Mefenâmico/urina , Extração em Fase Sólida/métodos , Compostos de Vinila/química , Adsorção , Água Potável/análise , Humanos , Lagos/análise , Limite de Detecção , Nanopartículas de Magnetita/química , Polimerização , Polivinil/síntese química , Polivinil/química , Reprodutibilidade dos Testes , Cloreto de Sódio/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise
18.
Curr Drug Deliv ; 16(7): 663-671, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038065

RESUMO

BACKGROUND: Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism. OBJECTIVE: The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution. METHODS: Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH. RESULTS: The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR. CONCLUSION: The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.


Assuntos
Antibacterianos/química , Portadores de Fármacos/química , Imunossupressores/química , Sirolimo/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Oxirredução , Polietilenoglicóis/química , Polivinil/química , Pirrolidinas/química , Compostos de Vinila/química
19.
Nanoscale ; 11(19): 9362-9368, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31038517

RESUMO

Boron-titanate monolayer nanosheets were prepared through a scalable step by step intercalation approach for anchoring 3-mercaptopropyltriethoxysilane (MPTS) on the surface. MPTS provides clickable sites with 4-vinylphenylboronic acid (VPBA) via a thiol-ene (TE) click reaction to obtain monolayer titanate nanosheets with boronic acid ligands immobilized on the surface. The nanosheets obtained are denoted as VPBA-MPTS-TiNSs, with a lateral dimension of a few dozen nanometers and with a thickness of ca. 3.5 nm. The nanosheets exhibit a superior adsorption capacity of 1669.7 mg g-1 and favorable selectivity for the adsorption of glycoproteins by employing immunoglobulin G (IgG) as the protein model. The adsorbed IgG is thereafter readily collected by using 0.1% (m/v) cetane trimethyl ammonium bromide (CTAB) as the eluent. The practical applications of VPBA-MPTS-TiNSs are further demonstrated by the selective adsorption/purification of IgG from human serum.


Assuntos
Ácidos Borônicos/química , Imunoglobulina G/química , Nanoestruturas/química , Titânio/química , Compostos de Vinila/química , Adsorção , Humanos , Concentração de Íons de Hidrogênio , Imunoglobulina G/sangue , Imunoglobulina G/isolamento & purificação , Silanos/química
20.
Org Lett ; 21(10): 3606-3609, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31046296

RESUMO

Skipped polyenes featuring high ( E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern.


Assuntos
Níquel/química , Polienos/síntese química , Compostos de Vinila/química , Catálise , Estrutura Molecular , Polienos/química
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