Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.366
Filtrar
1.
J Agric Food Chem ; 67(46): 12844-12853, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31668063

RESUMO

Flazin is a ß-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC50 < 500 µM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.


Assuntos
Carbolinas/farmacologia , Furanos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos
2.
Fitoterapia ; 139: 104375, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629050

RESUMO

Picrasamide A (1), a new cinnamamide derivative, together with two new ß-carboline alkaloids (2 and 3) and five known ß-carboline alkaloids (4-8) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated by detailed analyses of UV, IR, HRESIMS, and NMR data. Compound 1 was the first case of cinnamamide derivative from genus Picrasma. The AChE inhibitory activity and the antimicrobial activity of 1-8 were assessed. In addition, preliminary structure-activity relationships of these ß-carboline alkaloids on the AChE inhibitory activity and antimicrobial activity were proposed.


Assuntos
Antibacterianos/farmacologia , Inibidores da Colinesterase/farmacologia , Cinamatos/farmacologia , Picrasma/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , China , Inibidores da Colinesterase/isolamento & purificação , Cinamatos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/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.
BMC Neurol ; 19(1): 211, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464590

RESUMO

BACKGROUND: THK5351 and flortaucipir tau ligands have high affinity for paired helical filament tau, yet diverse off-target bindings have been reported. Recent data support the hypothesis that THK5351 binds to monoamine oxidase B (MAO-B) expressed from reactive astrocytes and that flortaucipir has an affinity toward MAO-A and B; however, pathological evidence is lacking. We performed a head-to-head comparison of the two tau ligands in a sporadic Creutzfeldt-Jakob disease (CJD) patient and performed an imaging-pathological correlation study. CASE PRESENTATION: A 67-year-old man visited our clinic a history of 6 months of rapidly progressive dementia, visual disturbance, and akinetic mutism. Diffusion-weighted imaging showed cortical diffusion restrictions in the left temporo-parieto-occipital regions. 18F-THK5351 PET, but not 18F-flortaucipir PET showed high uptake in the left temporo-parieto-occipital regions, largely overlapping with the diffusion restricted areas. Cerebrospinal fluid analysis was weakly positive for 14-3-3 protein and pathogenic prion protein was found. The patient showed rapid cognitive decline along with myoclonic seizures and died 13 months after his first visit. A post-mortem study revealed immunoreactivity for PrPsc, no evidence of neurofibrillary tangles, and abundant astrocytosis which was reactive for MAO-B antibody. CONCLUSIONS: Our findings add pathological evidence that increased THK5351 uptake in sporadic CJD patients might be caused by an off-target binding driven by its high affinity for MAO-B.


Assuntos
Aminopiridinas/farmacologia , Carbolinas/farmacologia , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Síndrome de Creutzfeldt-Jakob/patologia , Tomografia por Emissão de Pósitrons/métodos , Quinolinas/farmacologia , Idoso , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Masculino , Monoaminoxidase/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas tau/metabolismo
6.
J Ethnopharmacol ; 243: 112096, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31323300

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Arenaria kansuensis is used in traditional medicine to treat lung inflammation for a long time. However, the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of this plant have not been studied extensively. AIM OF THE STUDY: The purpose of this study was to investigate the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of A. kansuensis and its possible mechanism. MATERIALS AND METHODS: In vivo experiment, the anti-pulmonary fibrosis effects of the fraction (Part1) enriched from ethyl acetate extracts of the whole plant A. kansuensis were evaluated through bleomycin (BLM)-induced pulmonary fibrosis mice (five groups, n = 10) daily at doses of 50, 100 and 150 mg/kg for 15 days. In vitro experiment, the anti-inflammation and reversed epithelial-mesenchymal transition (EMT) effect of 12 ß-carboline alkaloids isolated from Part1 were evaluated through lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cell model and TGF-ß1 induced A549 cell model. RESULTS: In this study, a fraction named Part1 extracted from Arenaria kansuensis presented strong anti-pulmonary fibrosis effect at the dose of 150 mg/kg. Vivo experiments showed that the survival rate and body weight of mice significantly increased after Part1 treatment. Part1 could significantly inhibit the initial of inflammation, deposition of collagen and expression of TGF-ß1 and α-SMA, moreover, the expression of E-cadherin was significantly elevated after administration of Part1. All the cure effects of Part1 were in dose dependent manner. A total of 12 ß-carboline alkaloids were identified in Part1 and they all showed suppressive effect on inflammatory cytokines including MCP-1, TNF-α, IL-6 and IL-1ß through inhibition of NF-kb/p65 phosphorylation, and that epithelial-mesenchymal transition (EMT) process was reversed by different compounds in different levels. The expression of indicators of EMT including α-SMA, vimentin and E-cadherin was significantly improved after given different ß-carboline alkaloids. CONCLUSIONS: This study showed that antifibrogenic effect of ß-carboline alkaloids was due to inhibiting the initial of inflammation through NF-kb/p65 pathway and reversing the process of EMT.


Assuntos
Alcaloides , Anti-Inflamatórios , Arenaria (Planta) , Carbolinas , Extratos Vegetais , Fibrose Pulmonar/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Bleomicina , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/metabolismo
7.
Fitoterapia ; 137: 104196, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175948

RESUMO

Depressive disorders remain a current public health problem whose prevalence has increased in the past decades. In the constant search for new therapeutic alternatives, ß-carboline alkaloids have been identified as good candidates for new antidepressant drugs. In this systematic review, we summarized all pre-clinical investigations involving the use of natural or semisynthetic ß-carboline in depression models. A literature search was conducted in August 2018, using PubMed, Scopus and Science Direct databases. All reports were carefully analyzed, and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. The entire systematic review was performed according to PRISMA statement. From a total of 373 articles, 26 met all inclusion criteria. In vitro and in vivo studies have evaluated a wide variety of ß-carbolines through enzymatic and binding assays, and acute or chronic animal models. Most of the in vivo and in vitro studies is concentrated on two molecules: harman and harmine. They have been investigated in several animal models and some mechanisms of action have been proposed for their antidepressant activity. In general, ß-carbolines modulate 5-HT and GABA systems, promote neurogenesis, induce neuroendocrine response and restore astrocytic function, being effective when administrated acutely or chronically in different animal models, including chronic mild stress protocols. In short, ß-carbolines are multi-target antidepressant compounds and may be useful in the treatment of depressive disorders.


Assuntos
Alcaloides/farmacologia , Antidepressivos/farmacologia , Carbolinas/farmacologia , Depressão/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Harmina/análogos & derivados , Harmina/farmacologia
8.
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
9.
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
10.
Acta Pharmacol Sin ; 40(10): 1334-1342, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31036877

RESUMO

Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.


Assuntos
/efeitos dos fármacos , Peroxirredoxina VI/metabolismo , Células A549 , Carbolinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Humanos , Lipídeos/biossíntese , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
11.
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
12.
Toxins (Basel) ; 11(4)2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003411

RESUMO

Picrasma quassioides (D. Don) Benn, a medical plant, is used in clinic to treat inflammation, pain, sore throat, and eczema. The alkaloids are the main active components in P. quassioides. In this study, we examined the analgesic effect of dehydrocrenatidine (DHCT), a ß-carboline alkaloid abundantly found in P. quassioides in a neuropathic pain rat model of a sciatic nerve chronic constriction injury. DHCT dose-dependently attenuated the mechanic allodynia. In acutely isolated dorsal root ganglion, DHCT completely suppressed the action potential firing. Further electrophysiological characterization demonstrated that DHCT suppressed both tetrodotoxin-resistant (TTX-R) and sensitive (TTX-S) voltage-gated sodium channel (VGSC) currents with IC50 values of 12.36 µM and 4.87 µM, respectively. DHCT shifted half-maximal voltage (V1/2) of inactivation to hyperpolarizing direction by ~16.7 mV in TTX-S VGSCs. In TTX-R VGSCs, DHCT shifted V1/2 of inactivation voltage to hyperpolarizing direction and V1/2 of activation voltage to more depolarizing potential by ~23.9 mV and ~12.2 mV, respectively. DHCT preferred to interact with an inactivated state of VGSCs and prolonged the repriming time in both TTX-S and TTX-R VGSCs, transiting the channels into a slow inactivated state from a fast inactivated state. Considered together, these data demonstrated that the analgesic effect of DHCT was likely though the inhibition of neuronal excitability.


Assuntos
Carbolinas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Carbolinas/farmacologia , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Hiperalgesia/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio Disparados por Voltagem/fisiologia
13.
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
14.
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
15.
Nutrients ; 11(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978920

RESUMO

Harman and norharman, two neuroactive ß-carbolines, are present in several plants and in thermally processed foods. They exhibited a wide spectrum of biological and pharmacological effects, including antioxidant, neuroprotective, and anti-inflammatory effects. In this article, we review the progress of recent research on the presence of these compounds in food, as well as their various biological and neuroactive properties. Our findings strongly suggest that some foods, especially coffee, can act as a rich source of ß-carbolines, which may possibly be associated with a reduced risk for serious neurodegenerative diseases, such as Parkinson's and Alzheimer's.


Assuntos
Carbolinas/análise , Alimentos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Química Encefálica , Carbolinas/administração & dosagem , Carbolinas/química , Carbolinas/farmacologia , Tremor Essencial/induzido quimicamente , Tremor Essencial/metabolismo , Manipulação de Alimentos , Harmina/administração & dosagem , Harmina/análogos & derivados , Harmina/análise , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Extratos Vegetais/química
16.
Zhongguo Zhong Yao Za Zhi ; 44(1): 119-124, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30868822

RESUMO

To explore the mechanism of ß-carboline alkaloids inhibiting the migration and invasion of SGC-7901 cells and its correlation with FAK gene expression,CCK-8 method was used to determine the inhibitory rate of ß-carboline alkaloids on the proliferation of gastric cancer SGC-7901 cells under different concentrations.The effect of ß-carboline alkaloids on the migration and invasion of SGC-7901 cells was used by Transwell compartment.Detection of mRNA and protein expression of FAK genes were used by qRT-PCR and Western blot.Then si-FAK-1051 recombinant plasmid was transfected into SGC-7901 cells.FAK gene silencing effect was identified by qRT-PCR and Western blot technique again.Finally,the effects of FAK gene silencing on proliferation and migration of gastric cancer SGC-7901 cells were detected by CCK-8 kit and Transwell chamber assay respectively.With the increase of the concentration ofß-carboline alkaloids,the inhibitory rate of SGC-7901 cells in human gastric cancer cells increased gradually,with IC5013.364 mg·L-1.The number of SGC-7901 cells of Transwell compartment in the positive experimental group(5-FU,5 mg·L-1) and the ß-carboline alkaloids group decreased significantly(P<0.01) and the number of SGC-7901 cells in the ß-carboline alkaloids group was significantly lower than that in the positive experimental group(P<0.01).Compared with the blank control group,the mRNA and protein expression level of FAK genes in the positive experimental group was significantly lower than that in the experimental group of ß-carboline alkaloids(P<0.05).After transfection of si-FAK-1051 into gastric cancer SGC-7901 cells,the expression of mRNA and protein of FAK gene was significantly down regulated(P<0.05).SGC-7901 cell proliferation and cell migration ability also decreased significantly(P<0.05).ß-carboline alkaloids are more effective than 5-FU in inhibiting migration and invasion of gastric cancer SGC-7901 cells,and the mechanism may be related to the inhibition of mRNA and protein expression of FAK gene by ß-carboline alkaloids.


Assuntos
Alcaloides/farmacologia , Carbolinas/farmacologia , Movimento Celular/efeitos dos fármacos , Invasividade Neoplásica , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Neoplasias Gástricas/tratamento farmacológico
17.
Dalton Trans ; 48(13): 4398-4404, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30864598

RESUMO

Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing ß-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carbolinas/farmacologia , Complexos de Coordenação/farmacologia , Lisossomos/efeitos dos fármacos , Rênio/química , Células A549 , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Complexos de Coordenação/síntese química , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Camundongos Nus , Relação Estrutura-Atividade
18.
PLoS One ; 14(3): e0214250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921410

RESUMO

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.


Assuntos
Carbolinas/farmacologia , Epilepsia/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Ubiquinona/análogos & derivados , Araquidonato 15-Lipoxigenase/metabolismo , Linhagem Celular , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Ubiquinona/farmacologia
19.
Eur J Med Chem ; 168: 293-300, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826506

RESUMO

Pityriacitrin is a marine alkaloid with typical ß-carboline scaffold, and which has been proven to exhibit diverse biological functions. During the course of our research for highly active compounds from natural products, the pityriacitrin have also been isolated and identified from a Chinese Burkholderia sp. NBF227. So, in order to explore the potential functional molecules, a series of ß-carboline analogues derived from pityriacitrin were designed and synthesized, and their in vitro cytotoxic activities against SGC-7901, A875, HepG2, and MARC145 cell lines were evaluated. The results demonstrated that some of these ß-carboline derivatives exhibited moderate to good cytotoxic activities, especially, compound 9o with a special sulfonyl group presented the highest inhibitory activities against all tested cell lines with the IC50 values of 6.82 ±â€¯0.98, 8.43 ±â€¯1.93, 7.69 ±â€¯2.17, 7.19 ±â€¯1.43 µM, respectively, which might be used as lead compound for discovery of novel cytotoxic agents.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Carbolinas/farmacologia , Alcaloides/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Burkholderia/química , Carbolinas/síntese química , Carbolinas/química , Linhagem Celular , 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
20.
Eur J Med Chem ; 168: 515-526, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851694

RESUMO

In an effort to develop anticancer agents that may overcome drug resistance, the number one reason in caner death, we have developed a series of novel hybrids of ß-carboline and N-hydroxycinnamamide as histone deacetylase (HDAC) inhibitors. Most of the hybrids 13a-p showed strong antiproliferative effects with low-micromolar IC50 values against four human cancer cells. The most potent compound of series 13p exhibited high HDAC1/6 inhibitory effects, and also increased the acetylation levels of histone H3, H4 and α-tubulin. Importantly, 13p demonstrated high anticancer potency against drug-sensitive HepG2 and Bel7402 cells and drug-resistant Bel7402/5FU cells. Hybrid 13p triggered significant apoptosis by regulating apoptotic relative proteins expression in these Bel7402/5FU cells. Finally, 13p induced a substantial amount of autophagic flux activity by the accretion of the expression of LC3-II and the degeneration of expression of p62 and LC3-I in Bel7402/5FU cells. Overall, 13p is a novel ß-carboline/N-hydroxycinnamamide hybrid with significant anticancer potency that warrants further evaluation for the treatment of drug-resistant hepatocellular carcinoma.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cinamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carbolinas/química , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cinamatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/patologia , Estrutura Molecular , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA