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1.
Org Biomol Chem ; 18(3): 431-440, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31850445

RESUMO

Amines are ubiquitous in the chemical industry and are present in a wide range of biological processes, motivating the development of amine-sensitive sensors. There are many turn-on amine sensors, however there are no examples of turn-on sensors that utilize the amine's ability to react by single electron transfer (SET). We investigated a new turn-on amine probe with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophore. BODIPY fluorescence is first preprogrammed into an off state by internal photoinduced electron transfer (PET) to an electron-deficient quinolinium ring, resulting in fluorescence quenching. At low concentrations of aliphatic amine (0 to 10 mM), this PET pathway is shut down by external SET from the amine to the photoexcited charge-transfer state of the probe and the fluorescence is turned on. At high concentrations of amine (50 mM to 1 M), we observed collisional quenching of the BODIPY fluorescence. The probe is selective for aliphatic amines over aromatic amines, and aliphatic thiols or alcohols. The three molecular processes modulate the BODIPY fluorescence in a multi-mechanistic way with two of them producing a direct response to amine concentrations. The totality of the three molecular processes produced the first example of a multi-state and dose-responsive amine sensor.


Assuntos
Aminas/análise , Compostos de Boro/química , Corantes Fluorescentes/química , Compostos de Quinolínio/química , Compostos de Boro/síntese química , Teoria da Densidade Funcional , Fluorescência , Corantes Fluorescentes/síntese química , Modelos Químicos , Compostos de Quinolínio/síntese química , Espectrometria de Fluorescência/métodos
2.
Analyst ; 144(22): 6570-6577, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31591613

RESUMO

A fluorescent probe based on a triphenylamine benzopyridine platform for hydrogen sulfide (H2S) assaying has been designed and synthesized. As a result of the H2S-triggered cleavage reaction, the disappearance of the quenching effect of dinitrophenyl and the increased hydrophobicity in a poor solvent lead to the aggregation-induced emission (AIE) effect; consequently an obvious 'turn-on' fluorescence signal can be observed in this process. The probe TPANF features high selectivity towards H2S, low detection limit (0.17 µM), and good photostability and biocompatibility. Moreover, it has been successfully utilized to monitor H2S in food samples to distinguish the extent of food deterioration and to identify the H2S concentration variation in living cells. In addition, endogenous H2S in HCT-116 xenograft tumor tissues was imaged by using this probe. The approach could provide useful insight for the development of other activatable AIE-based probes that are potentially helpful for specific assaying in food chemistry and biological systems.


Assuntos
Compostos de Anilina/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Compostos de Quinolínio/química , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Animais , Galinhas , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Contaminação de Alimentos/análise , Células HCT116 , Humanos , Limite de Detecção , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência/métodos , Carne de Porco/análise , Produtos Avícolas/análise , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/toxicidade , Suínos
3.
Bioorg Med Chem ; 27(3): 552-559, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611633

RESUMO

Selective and sensitive detection of G-quadruplex DNA structures is an important issue and attracts extensive interest. To this end, numerous small molecular fluorescent probes have been designed. Here, we present a series of N-alkylated styrylquinolinium dyes named Ls-1, Ls-2 and Ls-3 with varying side groups at the chain end. We found that these dyes exhibited different binding behaviors to DNAs, and Ls-2 with a sulfonato group at the chain end displayed sensitivity and selectivity to G-quadruplex DNA structures in vitro. The characteristics of this dye and its interaction with G-quadruplex DNA were comprehensively investigated by means of UV-vis spectrophotometry, fluorescence, circular dichroism and molecular docking. Furthermore, confocal fluorescence images and MTT assays indicated dye Ls-2 could pass through membrane and enter the living HepG2 cells with low cytotoxicity.


Assuntos
DNA/análise , Corantes Fluorescentes/química , Compostos de Quinolínio/química , Estirenos/química , Alquilação , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Quadruplex G , Células Hep G2 , Humanos , Estrutura Molecular , Imagem Óptica , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/farmacologia
4.
J Am Chem Soc ; 140(41): 13171-13175, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30272972

RESUMO

Artificial metalloenzymes (ArMs), which combine an abiotic metal cofactor with a protein scaffold, catalyze various synthetically useful transformations. To complement the natural enzymes' repertoire, effective optimization protocols to improve ArM's performance are required. Here we report on our efforts to optimize the activity of an artificial transfer hydrogenase (ATHase) using Escherichia coli whole cells. For this purpose, we rely on a self-immolative quinolinium substrate which, upon reduction, releases fluorescent umbelliferone, thus allowing efficient screening. Introduction of a loop in the immediate proximity of the Ir-cofactor afforded an ArM with up to 5-fold increase in transfer hydrogenation activity compared to the wild-type ATHase using purified mutants.


Assuntos
Hidrogenase/química , Metaloproteínas/química , Engenharia de Proteínas/métodos , Compostos de Quinolínio/química , Umbeliferonas/química , Sequência de Aminoácidos , Sequência de Bases , Evolução Molecular Direcionada/métodos , Escherichia coli/metabolismo , Hidrogenase/genética , Hidrogenação , Metaloproteínas/genética , Oxirredução , Periplasma/metabolismo , Compostos de Quinolínio/síntese química , Umbeliferonas/síntese química
5.
Chemistry ; 24(59): 15840-15851, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30088300

RESUMO

Three new polyether-tethered bisquinolinium dimers (3 a-c) were synthesized, and their binding affinities, selectivities, and thermal stabilization towards dimeric G-quadruplex DNA (G2T1) in human telomeric regions were studied. The bisquinolinium dimer with a medium-length polyether linker (3 b) showed 30-425-fold higher binding affinity and selectivity towards antiparallel G2T1 than towards monomeric quadruplexes, which included human telomeric monomeric G-quadruplexes (G1), c-kit 1, c-kit 2, and c-myc. In addition, compound 3 b induced the formation of quadruplexes and displayed the highest level of thermal stabilization (ΔTm >28.1 °C) among all reported multimeric G-quadruplex binders. Compound 3 b also displayed a higher selectivity towards antiparallel G2T1 than monomer 360 A and bisquinolinium dimers 3 a and c. In contrast with our recent research on the analogous berberine dimer 1 b and dinickel-salphen complex 2 c, polyether linkers and their monomeric G-quadruplex binders in these dimeric G-quadruplex binders play a crucial role in regulating the binding affinities, selectivities, and thermal stabilization towards G2T1. More interestingly, these dimeric G-quadruplex compounds bind through end-stacking with the two adjacent G-quadruplex units in G2T1, and they showed high selectivity towards antiparallel G2T1 rather than mixed-type G2T1. In addition, compound 3 b, which displayed high selectivity towards antiparallel G2T1, showed strong telomerase inhibition and potent anticancer activities against HeLa and MCF-7 cells.


Assuntos
Antineoplásicos/síntese química , Quadruplex G , Compostos de Quinolínio/síntese química , Telômero/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sequência de Bases , Berberina/química , Dimerização , Éteres/química , Células HeLa , Humanos , Células MCF-7 , Conformação de Ácido Nucleico , Fenilenodiaminas/química , Polímeros/química , Compostos de Quinolínio/metabolismo , Compostos de Quinolínio/farmacologia , Relação Estrutura-Atividade , Telômero/metabolismo , Termodinâmica
6.
Future Med Chem ; 10(15): 1769-1786, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30043647

RESUMO

AIM: Choline kinase α inhibitors represent one of the newest classes of cytotoxic drugs for cancer treatment, since aberrant choline metabolism is a characteristic shared by many human cancers. RESULTS: Here, we present a new class of asymmetrical pyridinium/quinolinium derivatives developed and designed based on drug optimization. CONCLUSION: Among all compounds described here, compound 8, bearing a 7-chloro-4N-methyl-p-chloroaniline quinolinium moiety, exhibited the greatest inhibitory activity at the enzyme (IC50 = 0.29 µM) and antiproliferative activity in cellular assays (GI50 = 0.29-0.92 µM). Specifically, compound 8 strongly induces a cell-cycle arrest in G1 phase, but it does not significantly induce apoptosis while causing senescence in the MDA-MB-231 cell line.


Assuntos
Antineoplásicos/farmacologia , Colina Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Compostos de Piridínio/farmacologia , Compostos de Quinolínio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colina Quinase/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Relação Estrutura-Atividade
7.
Chem Asian J ; 13(18): 2611-2618, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-29963750

RESUMO

The development of effective bioanalytical methods for rapid, sensitive and specific detection of HOCl in vitro and in vivo plays a key role for better understanding the roles of this molecule in normal and diseased conditions, but remains challenging due to the highly reactive nature of HOCl and the complicated biological conditions. In this work, a new fluorescence probe, PQI, was developed for monitoring of the HOCl level in biological samples. PQI was easily synthesized by a one-step condensation reaction. Upon addition of HOCl, significant changes in the absorption spectra and the color of the solution were noticed, facilitating the "naked eye" detection of HOCl in PBS buffer. The fluorescence of PQI was found to be significantly increased within a few seconds, leading to "OFF-ON" fluorescence response towards HOCl. The sensing mechanism, oxidation of thioether by HOCl, was confirmed by HRMS titration analysis. PQI features a large Stokes shift, high sensitivity and selectivity, and rapid fluorescence response towards HOCl. Quantitative detection of HOCl in single live cells was demonstrated through fluorescence imaging and flow cytometry analysis. PQI was then successfully used in visualisation of HOCl in live zebrafish and nude mice.


Assuntos
Corantes Fluorescentes/farmacologia , Ácido Hipocloroso/análise , Fenotiazinas/farmacologia , Compostos de Quinolínio/farmacologia , Animais , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Humanos , Concentração de Íons de Hidrogênio , Ácido Hipocloroso/química , Luz , Limite de Detecção , Células MCF-7 , Camundongos Nus , Imagem Óptica/métodos , Oxirredução , Fenotiazinas/síntese química , Fenotiazinas/química , Fenotiazinas/efeitos da radiação , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Compostos de Quinolínio/efeitos da radiação , Peixe-Zebra
8.
Chemistry ; 24(48): 12638-12651, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-29878408

RESUMO

Six novel probes were prepared by covalent attachment of a G4-DNA ligand (bis(quinolinium) pyridodicarboxamide; PDC) to various coumarin or pyrene fluorophores. In the absence of DNA, the fluorescence of all probes is quenched due to intramolecular photoinduced electron transfer (PET), as evidenced by photophysical and electrochemical studies, molecular modeling, and DFT calculations. All probes demonstrate similarly high thermal stabilization of various G4-DNA substrates belonging to different folding topologies, as assessed by fluorescence melting experiments; however, their fluorimetric response is strongly heterogeneous with respect to the structures of the probes and G4-DNA targets. Thus, the probes containing the 7-diethylaminocoumarin fluorophore demonstrate significant fluorescence enhancement in the presence of G4-DNA, with the strongest "light-up" response (20- to 180-fold) observed for antiparallel G4 structures as well as for hybrid G4 structures, formed by the variants of human telomeric sequence and capable of a conformation change to the antiparallel isoform. These results shed light on the influence of the linker and electronic properties of fluorophores on the efficiency of G4-DNA "light-up" probes operating via PET.


Assuntos
DNA/química , Corantes Fluorescentes/química , Quadruplex G , Amidas/química , Cumarínicos/síntese química , Cumarínicos/química , Transporte de Elétrons , Corantes Fluorescentes/síntese química , Humanos , Isomerismo , Ligantes , Luz , Simulação de Dinâmica Molecular , Pirenos/síntese química , Pirenos/química , Piridinas/química , Teoria Quântica , Quinolinas/química , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Telômero/química
9.
Eur J Med Chem ; 155: 171-182, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29886321

RESUMO

Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 µM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.


Assuntos
Acetilcolinesterase/metabolismo , Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Pró-Fármacos/farmacologia , Compostos de Quinolínio/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Células CACO-2 , Carbamatos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Pró-Fármacos/síntese química , Pró-Fármacos/química , Agregados Proteicos/efeitos dos fármacos , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Relação Estrutura-Atividade
10.
Org Lett ; 20(14): 4281-4284, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29952573

RESUMO

Total syntheses of the antibacterial alkaloids berberine, coptisine, and jatrorrhizine have been achieved in four steps through a unified route. The key step of this strategy is an efficient intramolecular Friedel-Crafts alkoxyalkylation which, following oxidation, establishes the isoquinolinium core of these natural products. Herein, the design and development of this synthetic strategy, which has enabled the shortest and most efficient syntheses of these alkaloids reported to date, is described.


Assuntos
Antibacterianos/síntese química , Berberina/análogos & derivados , Compostos de Quinolínio/síntese química , Alquilação , Berberina/síntese química , Produtos Biológicos , Descoberta de Drogas , Humanos , Estrutura Molecular , Oxirredução , Estereoisomerismo
11.
Molecules ; 23(1)2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29361678

RESUMO

A novel method for cleavage of the dithiine ring in 5,12-(dimethyl)-thioqinantrenium bis-chloride 1 "via" reaction with sodium hydrosulfide leads to 1-methyl-3-mercaptoquinoline-4(1H)-thione 2. Further transformation of thiol and thione functions of compound 2 leads to a series of sulfide and disulfide derivatives of quinolinium salts 4 and 6. 1-Methyl-4-chloro-3-benzylthioquinoline chloride 8 was obtained by N-alkylating 4-chloro-3-benzylthioquinoline using dimethyl sulfate. Antimicrobial activity of the obtained compounds was investigated using six Gram-positive and six Gram-negative bacterial strains, as well as Candida albicans yeast. Greater activity was demonstrated towards Gram-positive strains. MIC values for compounds and with benzylthio 4d and benzoylthio 4f substituents in 3-quinoline position were found to be in the 0.5-1 µg/mL range, at a level similar to that of ciprofloxacin (reference). Compounds 4d and 4f also demonstrated interesting antifungal properties (MIC = 1).


Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Compostos de Quinolínio/síntese química , Compostos de Enxofre/síntese química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Descoberta de Drogas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Compostos de Quinolínio/farmacologia , Relação Estrutura-Atividade , Compostos de Enxofre/farmacologia
12.
Bioorg Med Chem Lett ; 26(13): 3115-3118, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27165853

RESUMO

A novel molecule, TatBim-Alexa, consisting of the HIV1 Tat cell-penetrating peptide, the Bim apoptosis-inducing peptide, and Alexa Fluor 546 was synthesized for photoinducion of apoptosis. The Alexa Fluor 546 was used as a photosensitizer and covalently attached at the C-terminus of TatBim peptide by the thiol-maleimide reaction. Photo-dependent cytosolic internalization of TatBim-Alexa and photo-dependent apoptosis using TatBim-Alexa were demonstrated in several kinds of mammalian cells including human cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Corantes Fluorescentes/farmacologia , Peptídeos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Compostos de Quinolínio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Células HeLa , Humanos , Estrutura Molecular , Peptídeos/química , Processos Fotoquímicos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Relação Estrutura-Atividade
13.
Sci Rep ; 6: 23793, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27029499

RESUMO

A novel family of compounds derivative of 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or -bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.92 µM, respectively, in a range similar to that of the previously reported biscationic compounds MN58b and RSM932A. Our compounds show greater antiproliferative activities than do the reference compounds, with unprecedented values of GI50 in the nanomolar range for several of the cancer-cell lines assayed, and more importantly they present low toxicity in non-tumoral cell lines, suggesting a cancer-cell-selective antiproliferative activity. Docking studies predict that the compounds interact with the choline-binding site in agreement with the binding mode of most previously reported biscationic compounds. Moreover, the crystal structure of ChoKα1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before.


Assuntos
Antineoplásicos/química , Colina Quinase/antagonistas & inibidores , Inibidores Enzimáticos/química , Compostos de Piridínio/química , Compostos de Quinolínio/química , Antineoplásicos/síntese química , Sítios de Ligação , Butanos/química , Cátions , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colina Quinase/química , Cristalização , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Simulação de Acoplamento Molecular , Especificidade de Órgãos , Ligação Proteica , Compostos de Piridínio/síntese química , Relação Quantitativa Estrutura-Atividade , Compostos de Quinolínio/síntese química
14.
J Biol Chem ; 291(9): 4356-73, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26679998

RESUMO

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Ciclofilinas/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Esclerose Múltipla/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Compostos de Quinolínio/uso terapêutico , Substituição de Aminoácidos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Ciclofilina D , Ciclofilinas/genética , Ciclofilinas/metabolismo , Ciclosporinas/efeitos adversos , Ciclosporinas/síntese química , Ciclosporinas/farmacologia , Ciclosporinas/uso terapêutico , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Mutação , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Compostos de Quinolínio/efeitos adversos , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , Distribuição Aleatória , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia
15.
Org Lett ; 17(11): 2828-31, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-26008226

RESUMO

Rhodium-catalyzed annulation reactions between triazoles and internal alkynes, leading to various mesoionic isoquinoliums, are described. The reaction involves sequential triazole-directed C-H activation and C-C, C-N, and C-O bond formation processes in a one-pot manner. The starting materials and catalysts are easily available. The reaction offers a facile and practical approach to mesoionic isoquinolium derivatives.


Assuntos
Alquinos/química , Compostos de Quinolínio/síntese química , Ródio/química , Triazóis/química , Catálise , Estrutura Molecular , Compostos de Quinolínio/química
16.
J Med Chem ; 58(9): 3875-91, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25822852

RESUMO

Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of ß-amyloid (Aß) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aß40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.


Assuntos
Regiões 5' não Traduzidas , Proteínas ADAM/biossíntese , Secretases da Proteína Precursora do Amiloide/biossíntese , Carbazóis/química , Quadruplex G , Proteínas de Membrana/biossíntese , Compostos de Quinolínio/química , RNA Mensageiro/metabolismo , Proteínas ADAM/genética , Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide/genética , Carbazóis/síntese química , Carbazóis/farmacologia , Células HEK293 , Células HeLa , Humanos , Proteínas de Membrana/genética , Biossíntese de Proteínas , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , RNA Mensageiro/genética , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Agric Food Chem ; 63(7): 1906-14, 2015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25645055

RESUMO

Thirty-four new 2-aryl-6-chloro-3,4-dihydroisoquinolin-2-ium bromides were synthesized, and their structures were elucidated by spectroscopic analysis. Antifungal activities against Alternaria alternate, Curvularia lunata and Valsa mali were evaluated by the mycelium linear growth rate method. SAR was discussed also. All compounds showed some activity against each of the fungi at 25 µg/mL. Compared to azoxystrobin, a commercial fungicide, 31 out of 34 test compounds showed higher inhibition rates against C. lunata and 10 were more effective against A. alternate and V. mali. Compounds 5-4, 5-2 and 5-34 showed the highest activity against A. alternate (EC50 = 10.3 µg/mL), C. lunata (EC50 = 4.6 µg/mL) and V. mali (EC50 = 3.9 µg/mL), respectively, superior to azoxystrobin (EC50 = 12.8, 71.9, 37.2 µg/mL). Compound 5-4 displayed good activities against each of the fungi with EC50 of 10.3, 4.7, and 18.0 µg/mL while 5-34 displayed excellent activities against V. mali (EC50 = 3.9 µg/mL) and C. lunata (EC50 = 5.8 µg/mL). The SAR showed that the type and position of substituents on the C-ring had significant effects on the activity. Generally, the presence of 2'-F, 4'-F or 2'-CH3 could significantly improve the activities, whereas OH, OMe, NO2 or CF3 groups decreased the activities. Thus, it was concluded that the present research provided a new series of 2-aryl-6-chloro-3,4-dihydroisoquinolin-2-iums with excellent antifungal potency, and the results were of importance for the structure optimization design, synthesis and development of more potent isoquinoline antifungal agents.


Assuntos
Ascomicetos/efeitos dos fármacos , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Doenças das Plantas/prevenção & controle , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/farmacologia , Ascomicetos/crescimento & desenvolvimento , Fungicidas Industriais/química , Estrutura Molecular , Doenças das Plantas/microbiologia , Compostos de Quinolínio/química , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 24(22): 5238-41, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25442318

RESUMO

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C10 to C18) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos de Quinolínio/química , Compostos de Quinolínio/síntese química , Animais , Anti-Infecciosos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Testes de Sensibilidade Microbiana , Compostos de Amônio Quaternário/química , Compostos de Quinolínio/farmacologia , Compostos de Quinolínio/toxicidade , Sais/química
19.
20.
Bioorg Med Chem ; 21(22): 7194-201, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24080102

RESUMO

The 3-dimensional quantitative structure-activity relationship (3D-QSAR) molecular modeling technique or comparative molecular field analysis (CoMFA) has been used to design analogs of the natural product cryptolepine (1). Twenty-three compounds with their in vitro biological activities (IC50 values) against Crytococcus neoformans were used to generate the training set database of compounds for the CoMFA studies. The cross-validated q(2), noncross-validated r(2), and partial least squares (PLS) analysis results were used to predict the biological activity of 11 newly designed test set compounds. The best CoMFA model produced a q(2) of 0.815 and an r(2) of 0.976 indicating high statistical significance as a predictive model. The steric and electrostatic contributions from the contour map were interpreted from the color-coded contour plots generated from the PLS model and the active structural components for potency against C. neoformans were determined and validated in the test set compounds. The 3-substituted benzylthio quinolinium salts (4) that make up the test set were synthesized and evaluated based on the predicted activity from the CoMFA model and the results produced a good correlation between the predicted and experimental activity (R=0.82). Thus, CoMFA has served as an effective tool to aid the design of new analogs and in this case, it has aided the identification of compounds equipotent with amphotericin B, the gold standard in antifungal drug design.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Cryptococcus/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Compostos de Quinolínio/química , Compostos de Quinolínio/farmacologia , Compostos de Sulfidrila/química , Animais , Basidiomycota/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Alcaloides Indólicos/química , Análise dos Mínimos Quadrados , Quinolinas/química , Compostos de Quinolínio/síntese química , Reprodutibilidade dos Testes , Células Vero
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