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1.
Chemistry ; 26(3): 729-734, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31729089

RESUMO

The psychotropic effects of Psilocybe "magic" mushrooms are caused by the l-tryptophan-derived alkaloid psilocybin. Despite their significance, the secondary metabolome of these fungi is poorly understood in general. Our analysis of four Psilocybe species identified harmane, harmine, and a range of other l-tryptophan-derived ß-carbolines as their natural products, which was confirmed by 1D and 2D NMR spectroscopy. Stable-isotope labeling with 13 C11 -l-tryptophan verified the ß-carbolines as biosynthetic products of these fungi. In addition, MALDI-MS imaging showed that ß-carbolines accumulate toward the hyphal apices. As potent inhibitors of monoamine oxidases, ß-carbolines are neuroactive compounds and interfere with psilocybin degradation. Therefore, our findings represent an unprecedented scenario of natural product pathways that diverge from the same building block and produce dissimilar compounds, yet contribute directly or indirectly to the same pharmacological effects.


Assuntos
Agaricales/metabolismo , Alcaloides/química , Carbolinas/química , Inibidores da Monoaminoxidase/química , Monoaminoxidase/metabolismo , Psilocibina/química , Triptofano/química , Agaricales/química , Monoaminoxidase/química
2.
J Photochem Photobiol B ; 199: 111600, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473429

RESUMO

Full-aromatic and partially hydrogenated ß-carboline (ßC) derivatives constitute a group of alkaloids widely distributed in a great variety of living systems. In plants and bacteria, tetrahydro-ßCs are the primary product of the Pictet-Spengler enzymatically catalyzed condensation. Tetrahydro-ßC skeleton is further modified giving rise to the formation of a vast set of derivatives including dihydro- and full-aromatic ßCs. However, in most of the cases, the later processes still remain unclear and other sources, such as photo-triggered reactions, deserve to be explored. In this context, the photophysic and photochemistry of 7-methoxy-1-methyl-3,4-dihydro-2H-pyrido[3,4-b]indole or harmaline (Hlina) in aqueous solution is reported herein. UV-visible absorption and fluorescence emission spectroscopy coupled with multivariate data analysis (PARAFAC), HPLC and HRESI-MS techniques were used for both quantitative and qualitative analysis. The formation singlet oxygen and hydrogen peroxide reactive oxygen species (ROS) was quantified and their role together with the influence of pH and oxygen partial pressure on the photochemical degradation of HlinaH+ was assessed. We report herein the first study on photochemical full-aromatization of a dihydro-ßC derivative. These results can shed some light on the ßCs biosynthesis and role in living systems.


Assuntos
Alcaloides/química , Carbolinas/química , Indóis/química , Oxigênio/química , Processos Fotoquímicos , Harmalina/química , Harmina/química , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Hidroxilação , Luz , Análise Multivariada , Pressão Parcial , Espécies Reativas de Oxigênio/química , Oxigênio Singlete/química , Relação Estrutura-Atividade
3.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416271

RESUMO

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent ß-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin-murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 µM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent ß-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbolinas/síntese química , Carbolinas/farmacologia , Desenho de Drogas , Hidrazonas/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Carbolinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Embrião de Galinha , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 181: 111567, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401535

RESUMO

Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25-46 with 9-substituted ß-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Cobre/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carbolinas/química , Carbolinas/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Cobre/química , Cobre/uso terapêutico , Feminino , Humanos , Masculino , Camundongos Nus , Modelos Moleculares , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia
5.
Int J Nanomedicine ; 14: 4817-4831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308660

RESUMO

Background: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. Methods: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. Results: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. Conclusion: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.


Assuntos
Coagulação Sanguínea , Carbolinas/química , Carbolinas/uso terapêutico , Nanopartículas/química , Peptídeos/uso terapêutico , Trombose/sangue , Trombose/tratamento farmacológico , Administração Oral , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carbolinas/administração & dosagem , Eritrócitos/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Peptídeos/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
6.
Org Biomol Chem ; 17(27): 6687-6698, 2019 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-31232413

RESUMO

The Pictet-Spengler reaction of tryptophan esters and aldehydes has been widely applied in natural product synthesis and medicinal chemistry. To date, the trans- or cis-configuration of 1,3-disubstituted tetrahydro-ß-carbolines (THßCs) formed in this reaction has most often been assigned based on the relative 13C chemical shifts of C1 and C3 in the diastereomers. Although the upfield shifts of C1 and C3 in trans-THßCs relative to cis-THßCs has been attributed to steric compression associated with the "γ-gauche" effect, we show that this effect is not borne out experimentally for other carbons that should suffer this same compression. Thus we developed a robust alternative method for stereochemical assignment based on 1H NMR coupling constants (31 examples) and supported by extensive DFT-based conformational analysis and calculation of 1H-1H coupling constants. DFT calculations of 13C NMR chemical shifts also cast doubt upon the role of the "γ-gauche" effect on C1 and C3 chemical shifts in trans-THßCs.


Assuntos
Carbolinas/química , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Teoria Quântica , Estereoisomerismo
7.
Molecules ; 24(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252565

RESUMO

The emission properties of three 4-azafluorenone and five new α-carboline fluorophores in both solution and thin solid films were investigated. Fluorescence of the azafluorenone is clearly enhanced in thin solid films due to the presence of phenyl/biphenyl rotors, and these derivatives can be classified as green Aggregation-Induced Emission luminogens (AIEgens) with a non-emissive heteroaromatic core structure. Compared to azafluorenones, emission of α-carbolines is hypsochromically shifted to the blue region of the electromagnetic spectrum, and most of these derivatives exhibit strong violet-blue fluorescence in both solution and thin solid film layers. Further, the effective mobility and electroluminescence of new α-carbolines were investigated in prepared organic field-effect transistors and organic light-emitting diodes, respectively.


Assuntos
Carbolinas/síntese química , Fluorenos/síntese química , Corantes Fluorescentes/síntese química , Carbolinas/química , Fluorenos/química , Corantes Fluorescentes/química , Estrutura Molecular , Soluções
8.
Fitoterapia ; 137: 104180, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150766

RESUMO

Effect-directed isolation of free radical scavengers from the methanol extract of the freeze-dried fruiting bodies of the cultivated basidiomycetous mushroom, black poplar (Cyclocybe cylindracea), yielded a ß-carboline alkaloid. Its structure was determined based on ESI-TOF-MS/MS, NMR and circular dichroism spectra by comparison with published data. The compound, identified as the C1-S diastereomer of brunnein B, exhibited explicit radical scavenging activity (EC50 = 119.1 ±â€¯1.2 µg/mL). The quantity of the active component was determined with HPLC-MS in the fruiting body (36.2 ±â€¯2.8 ng/g DW, dry weight) and its different tissues such as peel (94.7 ±â€¯1.9 ng/g DW), inner cap (90.5 ±â€¯1.3 ng/g DW), gills (71.5 ±â€¯0.6 ng/g DW), and stipe (162.2 ±â€¯1.7 ng/g DW). It is a ß-carboline alkaloid that was not reported previously.


Assuntos
Agaricales/química , Alcaloides/química , Carbolinas/química , Depuradores de Radicais Livres/química , Alcaloides/isolamento & purificação , Carbolinas/isolamento & purificação , Depuradores de Radicais Livres/isolamento & purificação , Hungria , Estrutura Molecular
9.
Chem Commun (Camb) ; 55(51): 7327-7330, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31168530

RESUMO

Autofluorescing carboline-fluors were efficiently and rationally developed via a Pictet-Spengler involved one-pot multi-component reaction. The carboline-fluors demonstrate specific targeting towards the endoplasmic reticulum in living cells, and superior sensitivity to commercial ER-Trackers. Importantly, they were also successfully used to visualize changes in the ER during cell apoptosis and ER stress.


Assuntos
Carbolinas/química , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/química , Apoptose , Sobrevivência Celular , Células HeLa , Humanos , Imagem Individual de Molécula
10.
Eur J Med Chem ; 179: 123-132, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247374

RESUMO

The synthesis and in vitro anticancer activity of novel ß-carbolines is reported. New tryptamines have been prepared via hetero-Diels-Alder reaction of nitrosoalkenes with indoles and used to prepare functionalized ß-carbolines by the Pictet-Spengler approach. These included 6-substituted-ß-carboline-3-carboxylates and 3-(1H-tetrazol-5-yl)-ß-carbolines, whose synthesis is reported for the first time. Carboline-3-carboxylates derived from l-tryptophan methyl ester were also prepared. The structural diversity that was achieved allowed the discovery of impressive activities against a range cancer cell lines with the selectivity depending on the type of substitution pattern of the ß-carboline core. We have identified at least one ß-carboline derivative with GI50 ≤ 1  µM for each of the following human tumor cell lines: glioblastoma (U251), melanona (UACC-61), breast (MCF-7), ovarian expressing multiple-drug-resistance phenotype 4 (NCI-ADR/RES), renal (786-0), lung (NCI-H460), ovarian cancer (OVCAR-3), leukemia (K-562) and colon (HT29). These results demonstrated that the new ß-carboline derivatives are very promising anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Ácidos Carboxílicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbolinas/síntese química , Carbolinas/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
11.
J Mass Spectrom ; 54(7): 643-654, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31113009

RESUMO

Cinnamic acid derivatives, particularly α-cyano-4-hydroxycinnamic acid (E-α-cyano-4-hydroxycinnamic acid or (E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate; CHCA), have been extensively used especially for protein and peptide analysis. Together with the introduction of ionic liquid MALDI matrix (ILM) started the study of applications of IL prepared with CHCA and a counter organic base (ie, aliphatic amines) in which CHCA moiety is the chromophore responsible of UV-laser absorption. Despite the extensive studies of norharmane (9H-pyrido[3,4-b]indole; nHo) applications as matrix and its peculiar basic properties in the ground and electronic excited state, nHo containing ILM was never tested in MALDI-MS experiments. This pyrido-indole compound was introduced as MALDI matrix 22 years ago for different applications including low molecular weight (LMW) carbohydrates (neutral, acidic, and basic carbohydrates). These facts encouraged us to use it as a base, for the first time, for ILM preparation. As a rational design of new IL MALDI matrices, E-α-cyanocinnamic acid.nHo and E-cinnamic acid.nHo were prepared and their properties as matrices studied. Their performance was compared with that of (a) the corresponding IL prepared with butylamine as basic component, (b) the corresponding crystalline E-α-cyanocinnamic and E-cinnamic acid, and (c) the classical crystalline matrices (2,5-dihydroxybenzoic acid, DHB; nHo) used in the analysis of neutral/sulfated carbohydrates. The IL DHB.nHo was tested, too. Herein, we demonstrate the outstanding performance for the IL CHCA.nHo for LMW carbohydrate in positive and negative ion mode (linear and reflectron modes). Sulfated oligosaccharides were detected in negative ion mode, and although the dissociation of sulfate groups was not completely suppressed the relative intensity (RI) of [M - Na]- peak was quite high. Additionally, to better understand the quite different performance of each IL tested as matrix, the physical and morphological properties in solid state were studied (optical image; MS image).


Assuntos
Carbolinas/química , Ácidos Cumáricos/química , Líquidos Iônicos/química , Oligossacarídeos/análise , Gentisatos/química , Íons , Limite de Detecção , Peso Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Estereoisomerismo
12.
Int J Nanomedicine ; 14: 3027-3041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118620

RESUMO

Background: In the discovery of DNA intercalators, ß-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-ß-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity. Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models. Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 µmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice. Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral ß-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.


Assuntos
Carbolinas/farmacologia , Nanopartículas/química , Neoplasias/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Creatinina/sangue , DNA/metabolismo , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 220: 117099, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141766

RESUMO

A novel ß-carboline-based chemosensor, having an acidic NH proton that leads to fluoride-induced deprotonation involving a vivid color change from colorless to yellow is described. The absorption spectrum of the chemosensor in acetonitrile has a peak at 375 nm, which changes to 428 nm with the gradual addition of only fluoride in the solution with a clear isosbestic points at 357 nm and 392 nm. More interestingly, the chemosensor gives a turn-on type of fluorescence at 554 nm in the presence of fluoride. Further it was found that the sensor is highly selective towards fluoride over other anions including chloride, bromide, iodide, nitrate, borate, perchlorate and can quantitatively detect fluoride at ppb level with a limit of detection of 0.02 mg/ L or 20 ppb. The chemosensor was successfully demonstrated to assess the fluoride concentration in the tap water.


Assuntos
Carbolinas/química , Corantes Fluorescentes/química , Fluoretos/análise , Água Doce/análise , Limite de Detecção , Espectroscopia de Ressonância Magnética , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , Poluentes Químicos da Água/análise
14.
Chem Biol Interact ; 308: 224-234, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100279

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multitarget studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the NMDA subtype of the glutamate receptor was conducted as an additional indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and calcium-induced swelling as indicators of mitochondrial permeability transition. Antioxidant potential was measured to evaluate the tendency to prevent oxidative stress. Potential for disease modification was gauged by the ability to stimulate microtubule assembly. Finally, binding modes of conjugates to AChE and BChE were studied using quantum mechanical-assisted molecular docking. We found selective BChE inhibitors (conjugates of γ-carbolines and phenothiazine I, γ-carbolines and carbazoles II, and aminoadamantanes and carbazoles III) as well as inhibitors of both cholinesterases (conjugates of γ-carbolines and methylene blue IV and bis-γ-carbolines with ditriazole-containing spacers V). These compounds combined potentials for cognition enhancement, neuroprotection, and disease modification. None of the conjugates exhibited high potency against CaE, thereby precluding potential drug-drug interactions from CaE inhibition. Thus, the studied compounds exhibited positive characteristics of multitarget drugs, indicating their potential for the next generation of AD therapeutics.


Assuntos
Adamantano/química , Carbazóis/química , Carbolinas/química , Inibidores da Colinesterase/química , Fenotiazinas/química , Adamantano/metabolismo , Adamantano/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Carbazóis/metabolismo , Carbazóis/uso terapêutico , Carbolinas/metabolismo , Carbolinas/uso terapêutico , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Colinesterases/química , Colinesterases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Fenotiazinas/metabolismo , Fenotiazinas/uso terapêutico
15.
Arch Pharm (Weinheim) ; 352(6): e1900026, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31056792

RESUMO

Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti-inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat-100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat-100. Here, we present the enantioselective synthesis of small-molecule compounds based on the tetrahydro-ß-carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S-derivative S-21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by Ki values in the range of 0.5-2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac-tubulin as surrogate parameter.


Assuntos
Carbolinas/química , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Acetilação , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Solubilidade , Estereoisomerismo
16.
Eur J Med Chem ; 171: 434-461, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928713

RESUMO

γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled receptors. Each class of GABA receptor has distinct pharmacology and physiology. GABAA receptors are heteropentameric transmembrane protein complexes made up of α1-6, ß1-3, γ1-3, δ, ε, θ, π subunits, giving rise to numerous allosteric binding sites and have thus attracted much attention targets for the treatment of conditions such as epilepsy, anxiety and sleep disorders. The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.


Assuntos
Moduladores GABAérgicos/farmacologia , Receptores de GABA/metabolismo , Sítio Alostérico/efeitos dos fármacos , Carbolinas/química , Carbolinas/farmacologia , Etomidato/química , Etomidato/farmacologia , Moduladores GABAérgicos/química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Ligantes , Estrutura Molecular , Propofol/química , Propofol/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Esteroides/química , Esteroides/farmacologia
17.
Dokl Biochem Biophys ; 484(1): 1-5, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012000

RESUMO

The synthesized new binary conjugates of tetrahydro-γ-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of ß-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.


Assuntos
Antioxidantes/química , Carbolinas/química , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/uso terapêutico , Carbolinas/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Indóis/química , Indóis/uso terapêutico
18.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010183

RESUMO

BACKGROUND: Based on our previous work, we found that 10-methoxycanthin-6-one displayed potential antibacterial activity and quaternization was an available method for increasing the antibacterial activity. Here, we explored the antibacterial activity of quaternized 10-methoxy canthin-6-one derivatives. METHODS AND RESULTS: Twenty-two new 3-N-benzylated 10-methoxy canthin-6-ones were designed and synthesized through quaternization reaction. The in vitro antibacterial activity against three bacteria was evaluated by the double dilution method. Moreover, the structure-activity relationships (SARs) were carefully summarized in order to guide the development of antibacterial canthin-6-one agents. Two highly active compounds (6p and 6t) displayed 8-fold superiority (MIC = 3.91 µg/mL) against agricultural pathogenic bacteria R. solanacearum and P. syringae compared to agrochemical streptomycin sulfate, and showed potential activity against B. cereus. Moreover, these two compounds exhibited good "drug-like" properties, low cytotoxicity, and no inhibition on seed germination. CONCLUSIONS: This work provides two new effective quaternized canthin-6-one derivatives as candidate bactericide, promoting the development of natural-sourced bactericides and preservatives.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carbolinas/química , Alcaloides Indólicos/química , Testes de Sensibilidade Microbiana , Pseudomonas syringae/efeitos dos fármacos , Ralstonia solanacearum/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 20(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934601

RESUMO

Harmine is a natural ß-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.


Assuntos
Carbolinas/química , Carbolinas/síntese química , Carbolinas/administração & dosagem , Carbolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Conformação Molecular , Solubilidade , Termodinâmica
20.
Planta Med ; 85(8): 648-656, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30974464

RESUMO

Four pairs of ß-carboline enantiomers (1A: /1B: -4A: /4B: ), 2 ß-carboline derivatives (5:  - 6: ) with a single enantiomeric configuration, together with 2 known achiral congeners (7:  - 8: ) were isolated from the stems of Picrasma quassioides. Their structures were elucidated on the basis of extensive spectroscopic analyses and quantum mechanical calculations. Compound 5: possesses a 4,5-seco ß-carboline framework and represents the first example of this type of ß-carboline alkaloids from nature. A possible biosynthetic pathway is proposed to generate the racemate 4: and the enantiomerically pure compounds 5: and 6: . All isolates were screened for their cytotoxicity against hepatocellular carcinoma Hep3B and HepG2 cells, which revealed that enantiomeric compounds 4A: and 4B: had distinctive effects in HepG2 cells. Further investigation showed that 4B: could induce apoptosis in HepG2 cells.


Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Carbolinas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Picrasma/química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Cromatografia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Estereoisomerismo
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