Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.129
Filtrar
1.
Anticancer Res ; 39(11): 6107-6114, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704838

RESUMO

AIM: The present investigation aimed to examine the therapeutic potential of the new coumarin derivative bis(4-hydroxy-2H-chromen-2-one) coumarin (4HC) against breast cancer. MATERIALS AND METHODS: For this purpose, the effects of 4HC treatment on the proliferation of MCF-7 breast cancer cells and on MCF-10a non-cancerous cells were evaluated using a fluorescent assay. Cell cycle distribution and apoptosis were measured by image cytometry. The expression level of aromatase (CYP19A1) and apoptosis-related genes were determined by real-time PCR. RESULTS: MCF-7 mammary cancer cell proliferation was significantly decreased within 24 h after treatment with 4HC at 50 µM, while no effect was observed on the viability of MCF-10a non-cancerous mammary cells. 4HC also increased the percentage of the cells in the G2/M phase, inducing apoptosis. Real-time PCR revealed that 4HC induced MCF-7 mortality through an up-regulation of Bax and a down-regulation of Bcl-2, resulting in an increase in caspase-3 gene expression. The increased expression of apoptosis-related genes was accompanied by a decrease in CYP19A1 gene expression. CONCLUSION: 4HC selectively inhibits proliferation of MCF-7cells in vitro. Moreover, 4HC has inhibitory effects on aromatase gene expression and promoting effects on apoptosis, in MCF-7 cells.


Assuntos
Apoptose/efeitos dos fármacos , Aromatase/química , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Cromonas/química , Cumarínicos/química , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Aromatase/genética , Aromatase/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células Tumorais Cultivadas
2.
J Enzyme Inhib Med Chem ; 34(1): 1489-1497, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31416364

RESUMO

MAO-B leads to an increase in the levels of hydrogen peroxide and oxidative free radicals, which contribute to the aetiology of the AD. Thus, both iron ion chelators and MAO-B inhibitors can be used to treat AD. Taking the coumarin derivatives and hydroxypyridinones as the lead compounds, a series of dual-target hybrids were designed and synthesised by Click Chemistry. The compounds were biologically evaluated for their iron ion chelating and MAO-B inhibitory activity. Most of the compounds displayed excellent iron ion chelating activity and moderate to good anti-MAO-B activity. Compounds 27b and 27j exhibited the most potent MAO-B inhibitory activity, with IC50 values of 0.68 and 0.86 µM, respectively. In summary, these dual-target compounds have the potential anti-AD activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/farmacologia , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridonas/farmacologia , Doença de Alzheimer/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 181: 111587, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404864

RESUMO

Cancer is the second leading cause of death worldwide, and it results in around 9 million deaths annually. The anticancer agents play an intriguing role in the treatment of cancers, while the severe anticancer scenario and the emergence of drug-resistant especially multidrug-resistant cancers create a huge demand for novel anticancer drugs with different mechanisms of action. The coumarin scaffold is ubiquitous in nature and is a highly privileged motif for the development of novel drugs due to its biodiversity and versatility. Coumarin derivatives can exert diverse antiproliferative mechanisms, and some of them such as Irosustat are under clinical trials for the treatment of various cancers, revealing their potential as putative anticancer drugs. Hybridization of coumarin moiety with other anticancer pharmacophores is a promising strategy to reduce side effects, overcome the drug resistance, and may provide valuable therapeutic intervention for the treatment of cancers. Thus, coumarin-containing hybrids occupy an important position in the development of novel anticancer agents. This review aims to summarize the recent advances made towards the development of coumarin-containing hybrids as potential anticancer agents, covering articles published between 2015 and 2019, and the structure-activity relationship together with mechanisms of action are also discussed.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Desenho de Drogas , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade
4.
Anticancer Res ; 39(8): 4179-4184, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366503

RESUMO

BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2. MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells. RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 µM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 µM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells. CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.


Assuntos
Cumarínicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Código das Histonas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Metilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/genética
5.
Chem Pharm Bull (Tokyo) ; 67(7): 640-647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257319

RESUMO

Neuroinflammation manifested by over-activation of microglial cells plays an essential role in neurodegenerative diseases. Short-term activation of microglia can be beneficial, but chronically activated microglia can aggravate neuronal dysfunction possibly by secreting potentially cytotoxic substances such as tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO), which can result in dysfunction and death of neurons. Therefore inhibiting over-activation of microglia and the production of cytotoxic intermediates may become an effective therapeutic approach for neuroinflammation. In this paper, we review our continuous research on natural inhibitors of over-activated microglia from traditional herbals, including flavonoids, lignans, sesquiterpene coumarins, and stilbenes.


Assuntos
Produtos Biológicos/química , Microglia/metabolismo , Animais , Produtos Biológicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Lignanas/química , Lignanas/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/biossíntese , Estilbenos/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
6.
Eur J Med Chem ; 179: 779-790, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31288127

RESUMO

Azole antifungals inhibit the biosynthesis of ergosterol, the fungal equivalent of cholesterol in mammalian cells. Here we report an investigation of the activity of coumarin-substituted azole antifungals. Screening against a panel of Candida pathogens, including a mutant lacking CYP51, the target of antifungal azoles, revealed that this enzyme is inhibited by triazole-based antifungals, whereas imidazole-based derivatives have more than one mode of action. The imidazole-bearing antifungals more effectively reduced trailing growth associated with persistence and/or recurrence of fungal infections than triazole-based derivatives. The imidazole derivatives were more toxic to mammalian cells and more potently inhibited the activity of CYP3A4, which is one of the main causes of azole toxicity. Using live cell imaging, we showed that regardless of the type of azole ring fluorescent 7-diethylaminocoumarin-based azoles localized to the endoplasmic reticulum, the organelle that harbors CYP51. This study suggests that the coumarin is a promising scaffold for development of novel azole-based antifungals that effectively localize to the fungal cell endoplasmic reticulum.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Cumarínicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Azóis/síntese química , Azóis/química , Candida/citologia , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Imagem Óptica , Relação Estrutura-Atividade
7.
Curr Top Med Chem ; 19(13): 1121-1128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210111

RESUMO

BACKGROUND: The discovery of novel potent molecules for both cancer prevention and treatment has been continuing over the past decade. In recent years, identification of new, potent, and safe anticancer agents through drug repurposing has been regarded as an expeditious alternative to traditional drug development. The cyclooxygenase-2 is known to be over-expressed in several types of human cancer. For this reason cyclooxygenase-2 inhibition may be useful tool for cancer chemotherapy. OBJECTIVE: The first aim of the study was to develop a validated linear model to predict antitumor activity. Subsequently, applicability of the model for repurposing these cyclooxygenase-2 inhibitors as antitumor compounds to abridge drug development process. METHODS: We performed a quantitative structure-toxicity relationship (QSTR) study on a set of coumarin derivatives using a large set of molecular descriptors. A linear model predicting growth inhibition on leukemia CCRF cell lines was developed and consequently validated internally and externally. Accordingly, the model was applied on a set of 143 cyclooxygenase-2 inhibitor coumarin derivatives to explore their antitumor activity. RESULTS: The results indicated that the developed QSAR model would be useful for estimating inhibitory activity of coumarin derivatives on leukemia cell lines. Electronegativity was found to be a prominent property of the molecules in describing antitumor activity. The applicability domain of the developed model highlighted the potential antitumor compounds. CONCLUSION: The promising results revealed that applied integrated in silico approach for repurposing by combining both the biological activity similarity and the molecular similarity via the computational method could be efficiently used to screen potential antitumor compounds among cyclooxygenase-2 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Reposicionamento de Medicamentos , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Reprodutibilidade dos Testes
8.
Chem Biol Interact ; 309: 108708, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31199928

RESUMO

Colon cancer is one of the most lethal cancers worldwide even with the significant progress made in screening techniques and therapeutic agents. Genetic mutations in tumors complicated the treatments, and the survival rate remains low for patients at late or metastatic stages. KRAS gene mutation which leads to failure of the EGFR targeted therapies stands for an example of the challenges in clinical sites. Therefore, development of novel agents for colon cancer treatment is in need. Natural and synthetic coumarin derivatives have been suggested with various biological activities with pharmacologic potential including anti-cancer capacity. Here in this study, five coumarin derivatives, include trifluoromethyl-, dimethoxy-, and/or nitro-substitutions at different positions, were synthesized. Their cancer inhibition potential was investigated in various cancer cell lines. Our data demonstrated that one nitro-coumarin derivate, 5,7-Dimethoxy-4-methyl-6-nitro-chromen-2-one, exhibits cytotoxicity specifically towards colon cancer cells under competitive EC50. Our results showed that this compound can effectively suppress colon cancer cells harboring either wild type or mutant KRAS genes, and that it could inhibit short-term proliferation, long term proliferation, and migration capacities of cancer cells. Finally, we demonstrated that this coumarin derivate facilitates cancer cell death through activation of apoptosis pathway. Our results suggest that this coumarin derivate is a promising lead drug worth further investigation and development for future cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Dióxido de Nitrogênio/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mutação
9.
Fitoterapia ; 137: 104239, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201886

RESUMO

In the search for bioactive natural products from the African flora, three previously undescribed compounds including one stilbene-coumarin derivative (1), one coumarin-carbinol (2) and one fatty glycoside (3) were isolated from the stem bark and leaves of Monotes kerstingii, together with sixteen known compounds (4-19). The structures of the isolated compounds were elucidated based on their NMR and MS spectroscopic data and by comparison of these data with those previously reported in the literature. Compounds 1-19 were screened for anthelmintic and antimicrobial activity. None of the compounds exhibited significant anthelmintic activity. However, compounds 4, 5, 8 and 14 displayed interesting antibacterial activity against B. subtilis at a concentration of 100 µM with respective inhibition percentages of 99, 79, 71 and 100%, respectively, compared to erythromycin used as positive control. In addition, at the same concentration, compound 6 showed remarkable antifungal activity against Septoria tritici with 93.6% growth inhibition and was found to be more active than the positive controls epoconazole and terbinafine displaying 76.6 and 84.3%, respectively .


Assuntos
Anti-Helmínticos/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Dipterocarpaceae/química , Anti-Helmínticos/isolamento & purificação , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Camarões , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Folhas de Planta/química
10.
Eur J Med Chem ; 174: 236-251, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048139

RESUMO

STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Tiofenos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Descoberta de Drogas , Fluorescência , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/química , Serina/química , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia , Tirosina/química
11.
J Enzyme Inhib Med Chem ; 34(1): 1083-1092, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117844

RESUMO

The work is focused on the design of drugs that prevent and treat Alzheimer's disease (AD) and its complications. A series of 3-(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 µM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 µM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Cloreto de Alumínio/farmacologia , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Peixe-Zebra
12.
Biochimie ; 163: 21-32, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075282

RESUMO

Huntington's diseases (HD) is a very devastating disease caused by r(CAG) expansion in HTT gene, encoding the huntingtin protein. r(CAG) expansion causes disease via multiple pathways including, 1) loss of normal protein function like sequestration of RNA binding protein such as Muscleblind-like (MBNL) and nucleolin, 2) Gain of function for mutant proteins and 3) repeat-associated non-ATG (RAN) translation; in which expanded r(CAG) translates into toxic poly glu, poly ser, or poly ala without the use of any canonical start codon. Herein, we have rationally designed and synthesized a unique class of pyridocoumarin derivatives that target the r(CAG)exp involved in HD and spinocerebellar ataxia (SCA) pathogenesis. Notably, compounds 3 and 15 showed higher affinity (nanomolar Kd) and selectivity for diseased r(CAG)exp RNA compared to regular duplex AU-paired RNA. Interestingly, both scaffolds are cell permeable, exhibit low toxicity to healthy fibroblast cells and are also capable of reducing the level of poly Q aggregation in cellular models. Indeed, our current study offers promising facet for selectively targeting repeats containing RNAs that cause severe diseases like HD and SCAs.


Assuntos
Cumarínicos/química , Doença de Huntington/tratamento farmacológico , Proteínas Mutantes/genética , RNA Mensageiro/química , Ataxias Espinocerebelares/tratamento farmacológico , Células Cultivadas , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Desenho de Drogas , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Cinética , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , RNA Mensageiro/efeitos dos fármacos , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos
13.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035404

RESUMO

Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the treatment of cancer, but also for reducing CRF level of cancer patients. In this study, total-thirty new Dihydroartemisinin-Coumarin hybrids (DCH) were designed and synthesized. The in vitro cytotoxicity against cancer cell lines (HT-29, MDA-MB-231, HCT-116, and A549) was evaluated. Simultaneously, we also tested the anti-neuroinflammatory activity of DCH. DCH could inhibit the activated microglia N9 release of NO, TNF-α, and IL-6. The docking analysis was shown that MD-2, the coreceptor of TLR4, might be one of the targets of DCH.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Anti-Inflamatórios/síntese química , Artemisininas/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Cell Physiol Biochem ; 52(6): 1255-1266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31026389

RESUMO

BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear. METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells. RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation. CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Células HeLa , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , NF-kappa B/metabolismo , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetato de Tetradecanoilforbol , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
15.
Phytochemistry ; 162: 224-231, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953909

RESUMO

Seven previously undescribed coumarin derivatives, panitins A‒G, an ethoxylated artifact, and 34 known analogues, were isolated from the roots of Murraya paniculata. Their structures were elucidated on the basis of comprehensive analysis of 1D and 2D NMR and HRMS spectroscopic data, and comparison with the data reported in literature. The absolute configurations of undescribed compounds were assigned via comparison of the specific rotation, Mosher's method, exciton chiral method, and comparison of calculated and experimental ECD data. Panitin D, trans-dehydroosthol, and exotimarin I showed potent inhibition against LPS-induced NO production in BV-2 microglial cells with IC50 values of 19.6 ±â€¯2.3, 12.4 ±â€¯0.9, and 26.9 ±â€¯0.8 µM, respectively.


Assuntos
Cumarínicos/farmacologia , Murraya/química , Óxido Nítrico/antagonistas & inibidores , Linhagem Celular , Cumarínicos/química , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/biossíntese , Raízes de Plantas/química
16.
Eur J Med Chem ; 173: 203-212, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31005056

RESUMO

Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.


Assuntos
Cumarínicos/farmacologia , Inflamação/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Inflamação/metabolismo , Masculino , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Doença de Parkinson/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
17.
Life Sci ; 225: 117-131, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951743

RESUMO

AIM: Alzheimer's disease (AD) is a slowly progressing neurodegenerative disorder that attributed to the increase of amyloid precursor protein (APP). Recently, evidence indicates that microRNA alterations are involved in the development of AD. In this paper, we demonstrated whether osthole could delay the occurrence of AD by regulating miRNA. METHODS: Microarray was used to discover differential miRNAs in AD. The target genes regulated by miRNA were predicted by databases; The protective effects of osthole on APP/PS1 mice were determined by Morris Water Maze, H&E and Nissl staining; The APP-SH-SY5Y cells were transfected with miRNA-101a-3p inhibitor, the expression of miRNA-101a-3p and APP mRNA in APP/PS1 mice and APP-SH-SY5Y cells were detected by RT-PCR; And western blot and ICC staining were used to detect the APP and Aß proteins expression. KEY FINDINGS: MiRNA-101a-3p was the osthole-mediated miRNA in AD and APP is the target gene. Osthole could increase the learning and memory ability in APP/PS1 mice and inhibit APP mRNA/protein expression by up-regulating miRNA-101a-3p. For exploring the underlying mechanism, miR-101a-3p inhibitor was transfected into the APP-SH-SY5Y cells. We can know that osthole had a protective effect on APP-SH-SY5Y cells, and it could raise miRNA-101a-3p expression and inhibit APP mRNA/protein expression, the formation of Aß protein was inhibited too. SIGNIFICANCE: These results emphasized that osthole had a protective effect on APP/PS1 mice and APP-SH-SY5Y cells. The main cause was due to osthole could inhibit APP expression by up-regulating miRNA-101a-3p so as to help delay the occurrence of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Precursor de Proteína beta-Amiloide/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cumarínicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Humanos , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Presenilina-1/metabolismo , Células Tumorais Cultivadas , Regulação para Cima
18.
Chem Biodivers ; 16(5): e1800436, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957958

RESUMO

Two series of novel coumarin derivatives, substituted at 3 and 7 positions with aminoalkoxy groups, are synthesized, characterized, and screened. The effect of amine substituents and the length of cross-linker are investigated in acetyl- and butyrylcholinesterase (AChE and BuChE) inhibition. Target compounds show moderate to potent inhibitory activities against AChE and BuChE. 3-(3,4-Dichlorophenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one (4y) is identified as the most potent compound against AChE (IC50 =0.27 µm). Kinetic and molecular modeling studies affirmed that compound 4y works in a mixed-type way and interacts simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, compound 4y blocks ß-amyloid (Aß) self-aggregation with a ratio of 44.11 % at 100 µm and significantly protects PC12 cells from H2 O2 -damage in a dose-dependent manner.


Assuntos
Cumarínicos/química , Ligantes , Fármacos Neuroprotetores/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Humanos , Peróxido de Hidrogênio/toxicidade , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ratos , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987181

RESUMO

(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.


Assuntos
Envelhecimento/patologia , Isquemia Encefálica/tratamento farmacológico , Quimiocinas/metabolismo , Cumarínicos/uso terapêutico , Inflamação/patologia , Pulmão/patologia , Proteínas com Domínio MARVEL/metabolismo , Miocárdio/patologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Isquemia Encefálica/complicações , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacologia , Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações
20.
Eur J Pharm Sci ; 135: 103-112, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034983

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis has been one of the primal afflictions to human, and owing to the current scenario of drug resistance, newer drugs, and alternate targets are required to mitigate the disease. FtsZ is a GTP hydrolyzing protein, conserved in prokaryotes that plays a central role in Z-ring formation during cell division cytokinesis stage. This study employs the use of pharmacophore models derived from two different datasets based on Mtb-FtsZ GTPase inhibition and whole cell antibacterial activity, to virtually screen and shortlist novel compounds from In-house small molecule library as Mtb-FtsZ inhibitors and evaluate their in-vitro and ex-vivo activity. The results revealed Piperine (IC50 = 21.2 ±â€¯0.7 µM), 4-Bromo di-methoxy coumarin (IC50 = 13.0 ±â€¯1.6 µM) and Di-ethyl amino methyl coumarin (IC50 = 19.4 ±â€¯1.1) as potent Mtb-FtsZ GTPase inhibitors which showed considerable antibacterial activity (84.0 ±â€¯2.6 µM, 56.0 ±â€¯4.3 µM and 108 ±â€¯7.1 µM respectively) against M. smegmatis. They appear to be bacteriostatic, as well as treatment with these compounds led to a 3× increase in cell length of M. smegmatis. Further these molecules also altered the FtsZ gene expression by 3-fold when compared to untreated. In addition compound Aloin, an Aloe exudate showed potent Mtb-FtsZ inhibition (IC50 = 16.7 ±â€¯0.4 µM) but exhibited poor anti-mycobacterial activity (>500 µM).


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas do Citoesqueleto/metabolismo , Mycobacterium smegmatis/efeitos dos fármacos , Alcaloides/farmacologia , Proteínas de Bactérias/genética , Benzodioxóis/farmacologia , Divisão Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Citocinese , Proteínas do Citoesqueleto/genética , Bases de Dados de Compostos Químicos , Avaliação Pré-Clínica de Medicamentos/métodos , GTP Fosfo-Hidrolases/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Mycobacterium smegmatis/citologia , Mycobacterium tuberculosis/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA