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1.
Life Sci ; 242: 117211, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891720

RESUMO

Ventricular hypertrophy is a risk factors for arrhythmias, ischemia and sudden death. It involves cellular modifications leading to a pathological remodeling and is associated with heart failure. The activation of the G protein-coupled estrogen receptor (GPER) mediates beneficial actions in the cardiovascular system. Our goal was to prevent and regress the hypertrophy by the activation of GPER in neonatal cardiac myocytes (NRCM) and SHR male rats. Aldosterone increased the neonatal cardiomyocytes cell surface area after 48 h of incubation. The aldo-induced hypertrophy was blocked by the mineralocorticoid receptor (MR) inhibitor Eplererone or the reduction of MR expression by siRNA. The activation of GPER by the agonist G-1 totally prevented the increase surface area by Ald. The transfection of neonatal rat cardiac myocytes with a siRNA against GPER or the incubation with GPER blockers G-15 and G-36 inhibited the protection of G-1. The significant increase of cell surface area after 48 h of incubation with Ald was totally regressed in 24 h by the presence of G-1, indicating that the activation of GPER not only prevent the hypertrophy but also regress the hypertrophy when it is already established. In the in vivo model, G-1 or Vehicle was constantly infused via the minipump to SHR. The reduction of the hypertrophy by G-1 was evident by the cross-sectional area, BNP and ANP markers and by echocardiography. In this studied we demonstrated that the activation of GPER prevented and regressed the hypertrophy induced by Ald in NRCM and regressed hypertrophy in SHR rats.


Assuntos
Cardiomegalia/prevenção & controle , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Cardiomegalia/diagnóstico por imagem , Células Cultivadas , Ciclopentanos/farmacologia , Ecocardiografia , Eplerenona/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Quinolinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/fisiologia
2.
J Enzyme Inhib Med Chem ; 35(1): 584-597, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31992093

RESUMO

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to 1.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Quinolinas/síntese química , Quinolinas/química , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
3.
Fitoterapia ; 140: 104406, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31698061

RESUMO

One new quinoline alkaloid (1), two new bisabolane-type sesquiterpene derivatives (2 and 3), and a new natural product (4) along with ten known compounds (514) were isolated from the deep sea-derived fungus Aspergillus sp. SCSIO06786 which cultured on solid rice medium. Three new structures were elucidated by analysis of 1D/2D NMR data and HR-ESI-MS. The absolute configurations of 2 and 3 were established by comparison of the experimental and reported ECD values. Compounds 11-13 exhibited moderate selective inhibitory activities against the tested pathogenic bacteria with MIC values among 3.13-12.5 µg/mL.


Assuntos
Alcaloides/isolamento & purificação , Aspergillus/química , Quinolinas/isolamento & purificação , Água do Mar/microbiologia , Sesquiterpenos/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Sedimentos Geológicos/microbiologia , Oceano Índico , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/farmacologia , Sesquiterpenos/farmacologia
4.
Biosci Biotechnol Biochem ; 84(1): 187-197, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31566092

RESUMO

Walnut is a nutritious food material, but only a few studies have been conducted on the mechanisms of its functions and the technique for quality evaluation. Therefore, we analyzed the components in aqueous methanol extract of walnut, and characterized 30 components, including three new compounds, glansreginin C, ellagic acid 4-O-(3'-O-galloyl)-ß-D-xyloside, and platycaryanin A methyl ester. We analyzed the extracts of other nuts using HPLC and clarified that a characteristic peak corresponding to glansreginin A was mainly observed in walnut. These results suggested that glansreginin A might be an indicator component of the quality of walnut. We then examined whether glansreginin A has neuroprotective effect, using lipopolysaccharide (LPS)-induced inflammatory model mice. The results revealed that oral administration of glansreginin A prevented LPS-induced abnormal behavior and LPS-induced hyper-activation of microglia in the hippocampus. These results suggested that glansreginin A has the ability to exert neuroprotective effect via anti-inflammation in the brain.


Assuntos
Anti-Inflamatórios/farmacologia , Juglans/química , Fármacos Neuroprotetores/farmacologia , Valor Nutritivo , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Quinolonas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Ácido Elágico/farmacologia , Hipocampo/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Lipopolissacarídeos/farmacologia , Masculino , Metanol/química , Éteres Metílicos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Quinolinas/uso terapêutico
5.
Anticancer Res ; 39(11): 5973-5982, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704822

RESUMO

BACKGROUND/AIM: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. MATERIALS AND METHODS: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 µM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. RESULTS: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. CONCLUSION: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 10(1): 4349, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554791

RESUMO

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFß receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFß signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFß receptor stabilisation. This upregulation of the TGFß pathway by HGF leads to TGFß-mediated EMT and invasion. In vivo we show that TGFß receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFß and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias da Bexiga Urinária/genética , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Chem Biodivers ; 16(11): e1900349, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515922

RESUMO

In this work, the antifouling activity of five alkaloids, isolated from trees of the Atlantic rainforest, was studied. The tested alkaloids were olivacine (1), uleine (2) and N-methyltetrahydroellipticine (3) from Aspidosperma australe ('yellow guatambú') and the furoquinoline alkaloids kokusaginine (4) and flindersiamine (5) from Balfourodendron riedelianum ('white guatambú'). All these compounds can be isolated from their natural sources in high yields in a sustainable way. The five compounds were subjected to laboratory tests (attachment test of the mussel Mytilus edulis platensis) and field trials, by incorporation into soluble matrix paints, and 45 days of exposure of the painted panels in the sea. The results show that compound 3 is a very potent antifoulant, and that compounds 4 and 5 are also very active, while compounds 1 and 2 did not show any significant antifouling activity. These results open the way for the development of environmentally friendly antifouling agents, based on abundant and easy-to-purify compounds that can be obtained in a sustainable way.


Assuntos
Aspidosperma/química , Incrustação Biológica/prevenção & controle , Alcaloides Indólicos/farmacologia , Quinolinas/farmacologia , Rutaceae/química , Animais , Bivalves , Brasil , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Quinolinas/química , Quinolinas/isolamento & purificação
8.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547465

RESUMO

The aim is to explore the mechanism of the apoptosis signal-regulating kinase-1 (ASK-1) signaling pathway and the involvement of the thioredoxin (Trx) system during testicular ischemia reperfusion injury (tIRI) by using ASK-1 specific inhibitor, NQDI-1. Male Sprague-Dawley rats (n = 36, 250-300 g) were equally divided into 3 groups: sham, tIRI, and tIRI + NQDI-1 (10 mg/kg, i.p, pre-reperfusion). For tIRI induction, the testicular cord and artery were occluded for 1 h followed by 4 h of reperfusion. Histological analyses, protein immunoexpression, biochemical assays, and real-time PCR were used to evaluate spermatogenesis, ASK-1/Trx axis expression, enzyme activities, and relative mRNA expression, respectively. During tIRI, ipsilateral testes underwent oxidative stress indicated by low levels of superoxide dismutase (SOD) and Glutathione (GSH), increased oxidative damage to lipids and DNA, and spermatogenic damage. This was associated with induced mRNA expression of pro-apoptosis genes, downregulation of antiapoptosis genes, increased caspase 3 activity and activation of the ASK-1/JNK/p38/survivin apoptosis pathway. In parallel, the expression of Trx, Trx reductase were significantly reduced, while the expression of Trx interacting protein (TXNIP) and the NADP+/ nicotinamide Adenine Dinucleotide phosphate (NADPH) ratio were increased. These modulations were attenuated by NQDI-1 treatment. In conclusion, the Trx system is regulated by the ASK-1/Trx/TXNIP axis to maintain cellular redox homeostasis and is linked to tIRI-induced germ cell apoptosis via the ASK-1/JNK/p38/survivin apoptosis pathway.


Assuntos
Aporfinas/farmacologia , MAP Quinase Quinase Quinase 5/metabolismo , Quinolinas/farmacologia , Traumatismo por Reperfusão/metabolismo , Espermatozoides/metabolismo , Tiorredoxinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas de Ciclo Celular/metabolismo , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Survivina/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
J Agric Food Chem ; 67(41): 11340-11353, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532201

RESUMO

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives (3a-f) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC50 = 0.41 µg/mL) and 3f-28 (EC50 = 0.55 µg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum. Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.


Assuntos
Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Quinina/farmacologia , Quinolinas/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/química , Desenho de Drogas , Fungicidas Industriais/química , Estrutura Molecular , Quinina/química , Quinolinas/química , Relação Estrutura-Atividade
10.
Arch Pharm (Weinheim) ; 352(9): e1900101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414521

RESUMO

Based on the cabozantinib scaffold, novel c-Met inhibitors were rationalized from the limited knowledge of structure-activity relationships for the quinoline 6-position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c-Met active site. In addition, ortho-fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c-Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6-position, while the ortho-fluorinations performed were shown to give considerable reductions in the c-Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the para-amino substituted 15b and 18b.


Assuntos
Anilidas/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/química , Quinolinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Desenho de Drogas , Humanos , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/química , Quinolinas/farmacologia
11.
Breast Cancer Res ; 21(1): 94, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409375

RESUMO

BACKGROUND: Human epidermal growth factor receptor-2 (HER2)-targeted therapies prolong survival in HER2-positive breast cancer patients. Benefit stems primarily from improved control of systemic disease, but up to 50% of patients progress to incurable brain metastases due to acquired resistance and/or limited permeability of inhibitors across the blood-brain barrier. Neratinib, a potent irreversible pan-tyrosine kinase inhibitor, prolongs disease-free survival in the extended adjuvant setting, and several trials evaluating its efficacy alone or combination with other inhibitors in early and advanced HER2-positive breast cancer patients are ongoing. However, its efficacy as a first-line therapy against HER2-positive breast cancer brain metastasis has not been fully explored, in part due to the lack of relevant pre-clinical models that faithfully recapitulate this disease. Here, we describe the development and characterisation of a novel syngeneic model of spontaneous HER2-positive breast cancer brain metastasis (TBCP-1) and its use to evaluate the efficacy and mechanism of action of neratinib. METHODS: TBCP-1 cells were derived from a spontaneous BALB/C mouse mammary tumour and characterised for hormone receptors and HER2 expression by flow cytometry, immunoblotting and immunohistochemistry. Neratinib was evaluated in vitro and in vivo in the metastatic and neoadjuvant setting. Its mechanism of action was examined by transcriptomic profiling, function inhibition assays and immunoblotting. RESULTS: TBCP-1 cells naturally express high levels of HER2 but lack expression of hormone receptors. TBCP-1 tumours maintain a HER2-positive phenotype in vivo and give rise to a high incidence of spontaneous and experimental metastases in the brain and other organs. Cell proliferation/viability in vitro is inhibited by neratinib and by other HER2 inhibitors, but not by anti-oestrogens, indicating phenotypic and functional similarities to human HER2-positive breast cancer. Mechanistically, neratinib promotes a non-apoptotic form of cell death termed ferroptosis. Importantly, metastasis assays demonstrate that neratinib potently inhibits tumour growth and metastasis, including to the brain, and prolongs survival, particularly when used as a neoadjuvant therapy. CONCLUSIONS: The TBCP-1 model recapitulates the spontaneous spread of HER2-positive breast cancer to the brain seen in patients and provides a unique tool to identify novel therapeutics and biomarkers. Neratinib-induced ferroptosis provides new opportunities for therapeutic intervention. Further evaluation of neratinib neoadjuvant therapy is warranted.


Assuntos
Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quinolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Biologia Computacional/métodos , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Isoenxertos , Camundongos , Terapia de Alvo Molecular , Terapia Neoadjuvante , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
12.
Eur J Med Chem ; 182: 111592, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421632

RESUMO

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Quinolinas/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/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 , Células MCF-7 , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Viscosidade
13.
Biomed Khim ; 65(4): 331-338, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31436175

RESUMO

The effect of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of hepatocytes cytolysis (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase), parameters reflecting the state of oxidative status (intensity of biochemical luminescence and the content of diene conjugates), and the activity of oxidative metabolism enzymes (aconitate hydratase, glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) was studied in rats with CCl4-induced liver injury. The results obtained in the course of the work demonstrated the ability of the test compound to reduce the severity of oxidative stress and liver cells damage, as well as to change the activity of aconitate hydratase and NADP-generating enzymes in the direction of control values. 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline was more effective in normalizing CCl4-induced changes of the analyzed parameters that Carsil used as a reference compound. The tendency to normalize the state of oxidative status and enzyme activity of oxidative metabolism can attributed to hepatoprotective and antioxidant properties of the tested compound.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse Oxidativo , Quinolinas/farmacologia , Animais , Antioxidantes/farmacologia , Radicais Livres , Fígado/enzimologia , Ratos
14.
Eur J Med Chem ; 181: 111520, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404863

RESUMO

A series of novel triazole nucleobase analogues containing steroidal/coumarin/quinoline moieties have been synthesized based on copper-catalyzed azide-alkyne cycloaddition (CuAAC). The anti-cancer activity of the new triazole nucleobase analogues was studied in gastric cancer cell lines (MGC-803, SGC-7901) and normal gastric epithelial cells (GES-1) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells. Among the tested compounds, compound 20c demonstrated good anti-proliferation activity against MGC-803 cells (IC50 = 1.48 µM) and SGC-7901 (IC50 = 2.28 µM) cells as well as the best selectivity between the cancer and normal cells. Further mechanistic studies indicated that compound 20c could down-regulate the expression of TGF ß1 both in the tested gastric cancer cell lines and inhibit the cell migration and invasion. The results of the study indicate that compound 20c could be used as a promising skeleton for anti-gastric cancer agents with improved efficacy and less side effects.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Quinolinas/farmacologia , Esteroides/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinolinas/química , Esteroides/química , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
15.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
16.
Malar J ; 18(1): 285, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443646

RESUMO

Mutations in the propeller domain of Plasmodium falciparum kelch 13 (Pfk13) gene are associated with artemisinin resistance in Southeast Asia. Artemisinin resistance is defined by increased ring survival rate and delayed parasite clearance half-life in patients. Additionally, an amplification of the Plasmodium falciparum plasmepsin II gene (pfpm2), encoding a protease involved in hemoglobin degradation, has been found to be associated with reduced in vitro susceptibility to piperaquine in Cambodian P. falciparum parasites and with dihydroartemisinin-piperaquine failures in Cambodia. The World Health Organization (WHO) has recommended the use of these two genes to track the emergence and the spread of the resistance to dihydroartemisinin-piperaquine in malaria endemic areas. Although the resistance to dihydroartemisinin-piperaquine has not yet emerged in Africa, few reports on clinical failures suggest that k13 and pfpm2 would not be the only genes involved in artemisinin and piperaquine resistance. It is imperative to identify molecular markers or drug resistance genes that associate with artemisinin and piperaquine in Africa. K13 polymorphisms and Pfpm2 copy number variation analysis may not be sufficient for monitoring the emergence of dihydroartemisinin-piperaquine resistance in Africa. But, these markers should not be ruled out for tracking the emergence of resistance.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Ácido Aspártico Endopeptidases/genética , Resistência a Medicamentos/genética , Malária Falciparum/prevenção & controle , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Quinolinas/farmacologia , África , Ácido Aspártico Endopeptidases/metabolismo , Humanos , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo
17.
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
18.
Chem Biodivers ; 16(9): e1900333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365785

RESUMO

In the current study, the ethanol extracts of flower, stem, and root parts of two endemic Turkish species, e. g., Haplophyllum sahinii O. Tugay & D. Ulukus and H. vulcanicum Boiss. & Heldr., were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) associated with Alzheimer's disease as well as tyrosinase (TYR) linked to Parkinson's disease using ELISA microplate assay at 200 µg/mL. Among the extracts, the highest inhibition was caused by the stem extract of H. sahinii against BChE (IC50 =64.93±1.38 µg/mL). Consistently, all of the extracts were found to exert a selective inhibition towards BChE to some extent. It was only the root extract of H. vulcanicum that could inhibit AChE at low level (IC50 =203.18±5.33 µg/mL). None of the extracts displayed an inhibition over 50 % against TYR. Metabolite profiling of the extracts was achieved by a highly hyphenated liquid chromatographic mass spectrometric technique (HPLC-DAD-ESI-Q-TOF-MS/MS), which revealed the presence of furoquinoline (ß-fagarine, γ-fagarine) and amide (tubasenicine, tubacetine) alkaloids; furano- (rutamarin), pyrano- (xanthyletine), and geranyloxy coumarins; phenylpropanoid (secoisolariciresinol), arylnaphthalene (mono-O-acetyldiphyllin apioside), and dibenzylbutyrolactone (kusunokinin, haplomyrfolin) lignans. Several important differences were observed between the extracts analyzed. ß-Fagarine was the major alkaloid in H. vulcanicum, whereas γ-fagarine was present only in the roots of both Haplophyllum species; moreover, secoisolariciresinol and secoisolariciresinol dimethyl ether were the main lignans in the stems and flowers. This is the first study identifying ChE and TYR inhibitory effect and metabolic profiles of H. vulcanicum and H. sahinii.


Assuntos
Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Lignanas/farmacologia , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Rutaceae/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Cumarínicos/metabolismo , Humanos , Lignanas/química , Lignanas/metabolismo , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Rutaceae/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Turquia
19.
Artigo em Inglês | MEDLINE | ID: mdl-31330406

RESUMO

As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin in human plasma and adefovir in urine was developed and successfully validated. Plasma samples were processed by protein precipitation using methanol with a subsequent concentrating step. Urine samples were diluted using 0.1% formic acid. Separation was achieved on a Synergy Polar-RP reversed phase column (50 × 4.6 mm, 2.5 µm) in gradient elution using a mobile phase composed of water and 0.1% formic acid and a mixture of methanol and acetonitrile (50:50, v/v) containing 0.1% formic acid at a flow rate of 1.0 mL/min. The linear range covered concentrations from 0.273 to 52.6 ng/mL for adefovir and from 0.539 to 104.2 ng/mL for pitavastatin in human plasma, respectively. The calibration curve for adefovir in urine ranged from 0.104 to 10.0 µg/mL. The weighted linear regression (1/conc2) implied excellent linearity with correlation coefficients ≥0.999.


Assuntos
Adenina/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Organofosfonatos/sangue , Organofosfonatos/urina , Quinolinas/sangue , Quinolinas/urina , Espectrometria de Massas em Tandem/métodos , Adenina/sangue , Adenina/farmacologia , Adenina/urina , Humanos , Organofosfonatos/farmacologia , Plasma/química , Quinolinas/farmacologia
20.
Eur J Med Chem ; 180: 449-456, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330446

RESUMO

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 µM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 µM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Movimento Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/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 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
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