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1.
Photochem Photobiol Sci ; 19(1): 105-113, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31930262

RESUMO

We report on the light-switch behaviour of two head-to-tail expanded bipyridinium species as a function of their interaction with calf thymus DNA and polynucleotides. In particular, both DNA and polynucleotides containing exclusively adenine or guanine moieties quench the luminescence of the fused expanded bipyridinium species. This behaviour has been rationalized demonstrating that a reductive photoinduced electron transfer process takes place involving both adenine or guanine moieties. The charge separated state so produced recombines in the tens of picoseconds. These results could help in designing new organic substrates for application in DNA probing technology and lab on chip-based sensing systems.


Assuntos
Sondas de DNA/química , DNA/análise , Corantes Fluorescentes/química , Imagem Óptica , Compostos de Piridínio/química , Animais , Bovinos , Sondas de DNA/síntese química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Oxirredução , Compostos de Piridínio/síntese química , Espectroscopia de Luz Próxima ao Infravermelho , Raios Ultravioleta
2.
Environ Toxicol Pharmacol ; 71: 103218, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302432

RESUMO

A novel panel of oximes were synthesized, which have displayed varying degree of reactivation ability towards different organophosphorus (OP) modified cholinesterases. In the present article, we report a comparative reactivation profile of a series of quaternary pyridinium-oximes for electric eel acetylcholinesterase (EEAChE) inhibited by the organophosphorus (OP) inhibitors methyl paraoxon (MePOX), ethyl paraoxon (POX; paraoxon) and diisopropyl fluorophosphate (DFP) that are distinguishable as dimethoxyphosphoryl, diethoxyphosphoryl and diisopropoxyphosphoryl AChE-OP-adducts. Most of the 59-oximes tested led to faster and more extensive reactivation of MePOX- and POX-inhibited EEAChE as compared to DFP-modified EEAChE. All were effective reactivators of three OP-modified EEAChE conjugates showing 18-21% reactivation for DFP-inhibited AChE and ≥45% reactivation for MePOX- and POX-inhibited EEAChE. Oximes 7 and 8 showed kr values better than pralidoxime (1) for DFP-inhibited EEAChE. Reactivation rates determined at different inhibition times showed no significant change in kr values during 0-90 min incubation with three OPs. However, a 34-72% decrease in kr for MePOX and POX and > 95% decrease in kr for DFP-inhibited EEAChE was observed after 24 h of OP-exposure (aging).


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Compostos Organofosforados/química , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Animais , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/química , Desenho de Fármacos , Electrophorus , Simulação de Acoplamento Molecular , Estrutura Molecular , Agentes Neurotóxicos/química , Intoxicação por Organofosfatos/enzimologia , Intoxicação por Organofosfatos/prevenção & controle , Oximas/síntese química , Oximas/química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química
3.
Molecules ; 24(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242559

RESUMO

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated ß-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N'-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated ß-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson's. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it.


Assuntos
Técnicas de Química Sintética , Compostos de Piridínio/síntese química , Fenômenos Químicos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos de Piridínio/química , Compostos de Piridínio/isolamento & purificação
4.
Colloids Surf B Biointerfaces ; 181: 814-821, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247406

RESUMO

A series of novel gemini pyridinium surfactants with different alkyl chains were synthesized and characterized. The surface properties and aggregation behavior of the gemini surfactants in solution were studied. The gemini pyridinium salts exhibit higher surface activity than quaternary ammonium salts and can form vesicles above critical micellization concentration (CMC). The antimicrobial performance of these surfactants against E. coli was investigated and compared with those of quaternary ammonium salts. Alkyl chain length has a significant effect on the antimicrobial activity of the gemini surfactants, and the surfactant with decyl group showed more effective antimicrobial activity than quaternary ammonium salts. The high cationic charge density on the polar head group and the strong adsorption tendency confer relatively high antimicrobial of the gemini surfactants.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Tensoativos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Escherichia coli/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tamanho da Partícula , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Propriedades de Superfície , Tensoativos/síntese química , Tensoativos/química
5.
Talanta ; 201: 330-334, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122431

RESUMO

A novel ratiometric fluorescence probe for hypochlorous acid was constructed by coumarin and pyridinium fluorophore based on the Forster resonance energy transfer (FRET) and intramolecular charge transfer (ICT) platform. In this ICT/FRET system, the energy transfer efficiency is high to 94.3%. Moreover, the probe could respond to hypochlorous acid with high selectivity and sensitivity, and exhibited a large Stokes shift. It was interesting to find that the probe could recognize hypochlorous acid via a new mechanism, in which the α-position of carbonyl group was oxidized to form a diketone derivative. More importantly, the probe was successfully applied to the ratiometric imaging of both exogenous and endogenous hypochlorous acid in living RAW 264.7 cells, with low toxicity and high photo-stability.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Ácido Hipocloroso/metabolismo , Compostos de Piridínio/química , Animais , Cumarínicos/síntese química , Cumarínicos/efeitos da radiação , Desenho de Fármacos , Fluorescência , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Concentração de Íons de Hidrogênio , Luz , Limite de Detecção , Camundongos , Imagem Óptica/métodos , Compostos de Piridínio/síntese química , Compostos de Piridínio/efeitos da radiação , Células RAW 264.7
6.
Talanta ; 199: 140-146, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952238

RESUMO

Small molecules emitting in the NIR for tracking mitochondrial pH alteration with super-resolution are expected to play an essential role in biomedical applications. Herein, two small molecules based on pyridinium salt (P1 and P2) have been synthesized and systematically investigated. It was found that pyridinium salts P1 and P2 emitted in the NIR (about 610 nm), which could detect pH changes from 2.0 to 11.0 with good linearity and high sensitivity. Importantly, P2 could precisely target cellular mitochondria in a real-time manner under stimulated emission depletion (STED). These results implied a chemical strategy with a potential application in super-resolution imaging and mitochondrial pH determination.


Assuntos
Mitocôndrias/química , Compostos de Piridínio/química , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Microscopia de Fluorescência , Modelos Moleculares , Estrutura Molecular , Compostos de Piridínio/síntese química , Teoria Quântica , Bibliotecas de Moléculas Pequenas/síntese química
7.
Colloids Surf B Biointerfaces ; 176: 325-333, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30641304

RESUMO

The diblock copolymer polystyrene-block-poly(N-methyl 4-vinylpyridine iodide) (PS-b-P4VPQ) with the molecular weight of PS 3.5 × 103 g/mol and P4VPQ 11.6 × 103 g/mol forms core-shell polymer micelles in aqueous solution. The cationic brush shell of the polymer micelle can be used to accommodate hydrophilic drugs and biomolecules, such as DNA, for biomedical applications. It is essential to understand how biomolecules are adsorbed within the brush layer. Here we investigated the interaction of the cationic brush of the polymer micelle with DNA by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). It is found when adding only relatively small amounts of on average 30 base pairs (bp) DNA, at 19.6 and 39.2 µM for 0.1 mM PS-b-P4VPQ, most of the polymer micelle/DNA complexes remain well dispersed. The brush layer of the polymer micelles are slightly swelled due to the adsorption of DNA within the brush layer. When the DNA concentration is increased to 58.8 µM or higher, the polymer micelle/DNA complexes form closely packed agglomerates. At high DNA concentrations, some adsorbed DNA will start to build up at the edge or surface of the brush layer which could induce aggregation of the polymer micelle/DNA complexes. This means that it is possible to prepare mostly dispersed polymer/DNA complexes by keeping the DNA concentration below the aggregation concentration. The well dispersed polymer micelle/DNA complexes are advantageous for many DNA related biomedical applications.


Assuntos
DNA/química , Micelas , Poliestirenos/química , Compostos de Piridínio/química , Adsorção , Cátions , Poliestirenos/síntese química , Compostos de Piridínio/síntese química , Espalhamento a Baixo Ângulo , Difração de Raios X
8.
Anal Chim Acta ; 1048: 96-104, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30598162

RESUMO

Enzymatic 18O exchange, the well-established approach in comparative proteomics, has some disadvantages such as back exchange of labeled oxygen and overlapping the peak of a labeled peptide with isotopic peaks of an unlabeled one. Herein we demonstrated a simple procedure in which samples digested with a trypsin (with and without H218O) were reacted with unlabeled and quadrupled 13C-labeled pyrylium salt respectively which results in formation of pyridinium cations. Thus, each isobarically labeled peptide containing zero or four 13C atoms in the mass reporter group, during tandem MS/MS forms an unique reporter ion useful for a relative quantitation. Such a sample treatment improves the signal to noise ratio, reduces overlapping of the isotopic peaks and completely eliminates the back exchange problem.


Assuntos
Marcação por Isótopo/métodos , Oligopeptídeos/química , Fragmentos de Peptídeos/química , Proteômica/métodos , Piranos/química , Espectrometria de Massas em Tandem/métodos , Proteínas Sanguíneas/síntese química , Proteínas Sanguíneas/química , Isótopos de Carbono/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas de Membrana/síntese química , Proteínas de Membrana/química , Oligopeptídeos/síntese química , Isótopos de Oxigênio/química , Fragmentos de Peptídeos/síntese química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Albumina Sérica Humana/síntese química , Albumina Sérica Humana/química , Tripsina/química
9.
Talanta ; 192: 212-219, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348380

RESUMO

Nucleus imaging is of great importance for understanding cellular processes of genetic expression, proliferation and growth, etc. Although many nucleic-acid selective dyes for nucleus staining are available, few of them meet multiple standards. Herein, we report a cationic fluorescence dye FTI that possesses visible light excitation (436 nm), orange emission (571 nm) and a large Stokes shift (~135 nm) for nucleic-acid staining. FTI displays an obvious and sensitive fluorescent response to DNA in vitro with a 6.4-fold quantum yield increasing. Co-staining and nucleic acid digest experiments in live cells demonstrate that FTI exhibits an unexpected selectivity for the nucleolus of the cells due to the stronger affinity to RNA than DNA. Because of good photostability and low cytotoxicity, FTI can accomplish a promising stain for DNA recognition in vitro and nucleolus-specific imaging in cancer cells.


Assuntos
Nucléolo Celular/metabolismo , DNA/metabolismo , Fluorenos/química , Corantes Fluorescentes/química , Compostos de Piridínio/química , Estabilidade de Medicamentos , Fluorenos/síntese química , Fluorenos/efeitos da radiação , Fluorenos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/efeitos da radiação , Substâncias Intercalantes/toxicidade , Luz , Microscopia Confocal , Microscopia de Fluorescência , Compostos de Piridínio/síntese química , Compostos de Piridínio/efeitos da radiação , Compostos de Piridínio/toxicidade
10.
Anticancer Agents Med Chem ; 19(2): 265-275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30179142

RESUMO

BACKGROUND: This paper reports synthesis, cytotoxic activity, and apoptosis inducing effect of a novel series of styrylimidazo[1,2-a]pyridine derivatives. OBJECTIVE: In this study, anti-cancer activity of novel styrylimidazo[1,2-a]pyridines was evaluated. METHODS: Styrylimidazo[1,2-a]pyridine derivatives 4a-o were synthesized through a one-pot three-component reaction of 2-aminopyridines, cinnamaldehydes, and isocyanides in high yield. All synthesized compounds 4a-o were evaluated against breast cancer cell lines including MDA-MB-231, MCF-7, and T-47D using MTT assay. Apoptosis was evaluated by acridine orange/ethidium bromide staining, cell cycle analysis, and TUNEL assay as the mechanism of cell death. RESULTS: Most of the synthesized compounds exhibited more potent cytotoxicity than standard drug, etoposide. Induction of apoptosis by the most cytotoxic compounds 4f, 4g, 4j, 4n, and 4m was confirmed through mentioned methods. CONCLUSION: In conclusion, these results confirmed the potency of styrylimidazo[1,2-a]pyridines for further drug discovery developments in the field of anti-cancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Imidazóis/farmacologia , Compostos de Piridínio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Relação Estrutura-Atividade
11.
Bioorg Chem ; 83: 559-568, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471578

RESUMO

A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aß self-aggregation as well as AChE-induced Aß aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer's disease.


Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos de Piridínio/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Desenho de Fármacos , Electrophorus , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/metabolismo , Compostos Heterocíclicos com 2 Anéis/toxicidade , Cavalos , Humanos , Peróxido de Hidrogênio/farmacologia , Cinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Multimerização Proteica/efeitos dos fármacos , Compostos de Piridínio/síntese química , Compostos de Piridínio/metabolismo , Compostos de Piridínio/toxicidade , Ratos , Torpedo
12.
Bioorg Chem ; 82: 74-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30273836

RESUMO

A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.


Assuntos
Antineoplásicos/farmacologia , Glicosaminoglicanos/metabolismo , Indóis/farmacologia , Compostos de Piridínio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/metabolismo , Benzotiazóis/farmacologia , Células CHO , Linhagem Celular Tumoral , Cricetulus , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Ligantes , Estrutura Molecular , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Compostos de Piridínio/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 211: 260-271, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30557843

RESUMO

Two cationic δ,δ'­diazacarbazoles, 1­Methyl­5H­pyrrolo[3,2­b:4,5­b']dipyridinium iodide (MPDPI) and 1,5­Dimethyl­5H­pyrrolo[3,2­b:4,5­b']dipyridinium iodide (DPDPI), were devised and synthesized. Through characterizations of the interactions between DNA and the two δ,δ'­diazacarbazoles by various spectroscopy means, the strong interactions between the two compounds and double-strand DNA have been observed and the interaction types and mechanisms were explored. UV-Vis and fluorescent data have shown the big changes of DNA in the presence of either of the two compounds, demonstrating that both of the δ,δ'­diazacarbazoles can bind to DNA tightly, and high ionic strength decreased the intercalative interactions. The UV-Vis and fluorescence of dsDNA in the presence of DPDPI showed more profound changes than those in the presence of MPDPI, due to CH3 (in the structure of DPDPI) taking place of H (in the structure of MPDPI) at the position of 5­NH. And the circular dichroism (CD) spectra of CT-DNA and atomic force microscopy (AFM) results indicated more compacted conformation of DNA in the presence of DPDPI than MPDPI, implying that DPDPI has a more significant effect on DNA conformations than MPDPI. Most interestingly, fluorescence enhancement of cationic δ,δ'­diazacarbazoles occurred in the presence of DNA. With ionic strength increasing, the intercalative interactions between δ,δ'­diazacarbazoles and DNA were weakened, but δ,δ'­diazacarbazoles-DNA complexes showed enhanced fluorescence, which indicated that there are other interactions present at high ionic strength. Furthermore, laser confocal fluorescence microscopy results proved that DPDPI was membrane-permeable and stained living cells.


Assuntos
Carbazóis/química , DNA/metabolismo , Corantes Fluorescentes/metabolismo , Compostos de Piridínio/metabolismo , Pirróis/metabolismo , Cátions , Permeabilidade da Membrana Celular , Dicroísmo Circular , DNA/química , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Masculino , Microscopia de Força Atômica , Microscopia Confocal/métodos , Conformação de Ácido Nucleico , Concentração Osmolar , Células PC-3 , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Pirróis/síntese química , Pirróis/química , Espectrofotometria Ultravioleta
14.
J Am Chem Soc ; 140(50): 17691-17701, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30452256

RESUMO

Multi-triggered DNA/bipyridinium dithienylethene (DTE) hybrid carboxymethyl cellulose (CMC)-based hydrogels are introduced. DTE exhibits cyclic and reversible photoisomerization properties, switching between the closed state (DTEc), the electron acceptor, and the open isomer (DTEo) that lacks electron acceptor properties. One system introduces a dual stimuli-responsive hydrogel containing CMC chains modified with electron donor dopamine sites and self-complementary nucleic acids. In the presence of DTEc and the CMC scaffold, a stiff hydrogel is formed, cooperatively stabilized by dopamine/DTEc donor-acceptor interactions and by duplex nucleic acids. The cyclic and reversible formation and dissociation of the supramolecular donor-acceptor interactions, through light-induced photoisomerization of DTE, or via oxidation and subsequent reduction of the dopamine sites, leads to hydrogels of switchable stiffness. Another system introduces a stimuli-responsive hydrogel triggered by one of three alternative signals. The stiff, multi-triggered hydrogel consists of CMC chains cross-linked by dopamine/DTEc donor-acceptor interactions, and by supramolecular K+-stabilized G-quadruplexes. The G-quadruplexes are reversibly separated in the presence of 18-crown-6 ether and reformed upon the addition of K+. The stiff hydrogel undergoes reversible transitions between high-stiffness and low-stiffness states triggered by light, redox agents, or K+/crown ether. The hybrid donor-acceptor/G-quadruplex cross-linked hydrogel shows shape-memory and self-healing features. By using three different triggers and two alternative memory-codes, e.g., the dopamine/DTEc or the K+-stabilized G-quadruplexes, the guided shape-memory function of the hydrogel matrices is demonstrated.


Assuntos
DNA Complementar/química , Hidrogéis/química , Compostos de Piridínio/química , Carboximetilcelulose Sódica/síntese química , Carboximetilcelulose Sódica/química , Éteres de Coroa/química , DNA Complementar/síntese química , DNA Complementar/genética , Dopamina/síntese química , Dopamina/química , Quadruplex G , Hidrogéis/síntese química , Isomerismo , Hibridização de Ácido Nucleico , Oxirredução , Fenômenos Físicos , Compostos de Piridínio/síntese química , Compostos de Piridínio/efeitos da radiação , Raios Ultravioleta
15.
ACS Sens ; 3(12): 2621-2628, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30474375

RESUMO

Voltage sensitive dyes (VSDs) are used for in vitro drug screening and for imaging of patterns of electrical activity in tissue. Wide application of this technology depends on the availability of sensors with high sensitivity (percent change of fluorescence per 100 mV), high fluorescence quantum yield, and fast response kinetics. A promising approach uses a two-component system consisting of anionic membrane permeable quenchers with fluorophores labeling one side of the membrane; this produces voltage-dependent fluorescence quenching. However, the quencher must be kept at low concentrations to minimize pharmacological effects, thus limiting sensitivity. By developing tethered bichromophoric fluorophore quencher (TBFQ) dyes, where the fluorophore and quencher are covalently connected by a long hydrophobic chain, the sensitivity is maximized and is independent of VSD concentration. A series of 13 TBFQ dyes based on the aminonaphthylethenylpyridinium (ANEP) fluorophore and the dipicrylamine anion (DPA) quencher have been synthesized and tested in an artificial lipid bilayer apparatus. The best of these, TBFQ1, shows a 2.5-fold change in fluorescence per 100 mV change in membrane potential, and the response kinetics is in the 10-20 ms range. This sensitivity is an order of magnitude better than that of commonly used VSDs. However, the fluorescence quantum yield is only 1.6%, which may make this first generation of TBFQ VSDs impractical for in vivo electrical imaging. Nevertheless, the design principles established here can serve as foundation for improved TBFQ VSDs. We believe this approach promises to greatly enhance our ability to monitor electrical activity in cells and tissues.


Assuntos
Corantes Fluorescentes/química , Picratos/química , Compostos de Piridínio/química , Técnicas Eletroquímicas/métodos , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/síntese química , Bicamadas Lipídicas/química , Potenciais da Membrana , Estrutura Molecular , Compostos de Piridínio/síntese química
16.
ChemMedChem ; 13(24): 2653-2663, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30362667

RESUMO

The current standard therapy to counteract organophosphate intoxication is not effective in equal measure against all types of organophosphorus compounds (OPCs), as the outcome of oxime-induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state. As a consequence, neurotransmission is irreversibly disrupted at the neuromuscular junction. Previous electrophysiological studies identified the symmetric bispyridinium compound 1,1'-(propane-1,3-diyl)bis[4-(tert-butyl)pyridin-1-ium] diiodide (MB327) as a re-sensitizer of the desensitized nAChR. MB327 is thereby capable of restoring the functional activity. Very recently, in silico modeling studies suggested non-symmetric derivatives of MB327 as potential re-sensitizers with enhanced binding affinity and thus possible enhanced efficacy. In this study, 26 novel non-symmetric bispyridinium compounds and related derivatives were synthesized. For the synthesis of the highly polar target compounds in sufficient quantities, newly developed and highly efficient two-step procedures were used. Compounds were characterized in terms of their binding affinity toward the MB327 binding site at the nAChR using recently developed mass spectrometry (MS) Binding Assays. Regarding structure-affinity relationships at the MB327 binding site, the presence of two quaternary aromatic nitrogen centers as well as pyridinium systems with a tert-butyl group at the 4-position or a NMe2 group at the 3- or 4-positions appeared to be beneficial for high binding affinities.


Assuntos
Compostos de Piridínio/síntese química , Compostos de Piridínio/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Torpedo
17.
Bioorg Med Chem Lett ; 28(23-24): 3784-3786, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30301674

RESUMO

First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2-C7) were prepared (Scheme 1, 5a-f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 µM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 µM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n = 2-5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 µM concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79 kcal⋅mol-1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Tacrina/química , Tacrina/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/síntese química , Electrophorus , Simulação de Acoplamento Molecular , Paraoxon/farmacologia , Compostos de Piridínio/síntese química , Tacrina/síntese química
18.
Chem Commun (Camb) ; 54(75): 10610-10613, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30175822

RESUMO

A novel pyridine-based organic conjugated molecule (NCPy) has been successfully synthesized and converted into an organic pyridinium salt (NCPy-salt). Highly oriented organic nanofibers and high-quality films were obtained by transforming the molecule to a salt form. This transformation also resulted in a unique ternary resistive switching memory behavior.


Assuntos
Carbazóis/química , Nanofibras/química , Naftalimidas/química , Compostos de Piridínio/química , Sais/química , Carbazóis/síntese química , Condutividade Elétrica , Modelos Químicos , Naftalimidas/síntese química , Compostos de Piridínio/síntese química , Teoria Quântica , Sais/síntese química
19.
Analyst ; 143(20): 5054-5060, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30238115

RESUMO

A mitochondrial-targeted pH fluorescent probe 4-(2-(6-hydroxynaphthalen-2-yl)vinyl)-1-methylpyridin-1-ium was facilely synthesized via the carbon-carbon double bond bridging of 6-hydroxy-2-naphthaldehyde and 1,4-dimethylpyridinium iodide salt. The probe exhibited remarkable pH-dependent behavior in the linear range of 7.60-10.00, with a pKa value of 8.85 ± 0.04 near mitochondrial pH. A significantly large Stokes shift of 196 nm was obtained, which reduces the interference of excitation light. Application of the probe in live HepG2 cells indicated that the probe had excellent mitochondrial targeting ability and was successfully used to visualize mitochondrial pH fluctuations in live cells.


Assuntos
Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Naftalenos/química , Compostos de Piridínio/química , Estabilidade de Medicamentos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Luz , Microscopia Confocal , Microscopia de Fluorescência , Naftalenos/síntese química , Naftalenos/efeitos da radiação , Naftalenos/toxicidade , Compostos de Piridínio/síntese química , Compostos de Piridínio/efeitos da radiação , Compostos de Piridínio/toxicidade
20.
ChemMedChem ; 13(17): 1806-1816, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-29974635

RESUMO

A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pKi =4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pKi value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.


Assuntos
Compostos de Piridínio/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Intoxicação por Organofosfatos/tratamento farmacológico , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Receptores Nicotínicos/química , Relação Estrutura-Atividade , Torpedo
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