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1.
Int J Cancer ; 146(6): 1631-1642, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304590

RESUMO

Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-ß) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.


Assuntos
Encéfalo/metabolismo , Pirazóis/farmacocinética , Quinolinas/farmacocinética , Fator de Crescimento Transformador beta/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Cães , Feminino , Interações Ervas-Drogas , Humanos , Células Madin Darby de Rim Canino , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Pirazóis/sangue , Pirazóis/farmacologia , Quinolinas/sangue , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Distribuição Tecidual
2.
Life Sci ; 243: 117237, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887302

RESUMO

AIMS: Dauricine has been found that has significant neuroprotective effect on Alzheimer's disease (AD), but the mechanism is unclear, so we further investigated the possible mechanism of dauricine on AD. MAIN METHODS: Cell counting kit-8 (CCK8) was applied to measure the cytotoxicity of dauricine on SH-SY5Y cells that overexpress the Swedish mutant form of human ß-amyloid precursor protein (APPsw) and control cells (Neo). We used the Cu2+ to induce oxidative damage on APPsw cells, then tested the effect of dauricine on the damage and relative factors including reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) activity. The secretion level of amyloid beta 1-42(Aß1-42), protein expression of apoptosis-related factors and the components of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were determined by western blotting. Aß1-42-transgenic Caenorhabditis elegans GMC101, a model of AD, was applied to evaluate the neuroprotective effect of dauricine through the behavioral experiment and relative anti-oxidative tests. KEY FINDINGS: In vitro, dauricine decreased the secretion level of Aß1-42, significantly reduced the level of Cu2+-induced ROS, and restored MMP and SOD activity in APPsw cells. Meanwhile, dauricine could suppress the activation of caspase-3 and to upregulate the expression of Bcl-2. Dauricine also regulated the proteins levels of Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) that is necessary for the activation of Nrf2 in APPsw cell. As oxidative stress induced by Aß or paraquat (PQ), dauricine showed protective effects in the survival experiment of GMC101 worms. SIGNIFICANCE: Those data revealed that dauricine has the pharmacological activity of anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Tetra-Hidroisoquinolinas/uso terapêutico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Geneticamente Modificados , Antioxidantes/farmacologia , Benzilisoquinolinas/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Linhagem Celular , Cobre/farmacologia , Modelos Animais de Doenças , Humanos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
3.
Chem Pharm Bull (Tokyo) ; 67(11): 1211-1224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685749

RESUMO

A novel series of 2,6,7-substituted 3-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to find a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist. Among the derivatives, (E)-7-[2-(cyclopent-3-eny)-5-methyloxazol-4-ylmethoxy]-2-[3-(2-furyl)acryloyl]-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (20g) exhibited potent partial agonist activity (EC50 = 13 nM, maximal response 30%) and very weak protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 1100 nM), indicating a selective PPARγ partial agonist. A computational docking calculation revealed that 20g bound to PPARγ in a similar manner to that of known partial agonists. In male and female KK-Ay mice with insulin resistance and hyperglycemia, 20g at 30 mg/kg for 7 d significantly reduced plasma glucose levels, but not triglyceride levels. The effects of 20g were similar to those of pioglitazone at 10 mg/kg. In conclusion, the 2,6,7-substituted 1,2,3,4-tetrahydroisoquinoline with an acidic group at the 6-position provides a novel scaffold for selective PPARγ partial agonists and 20g exerted anti-diabetic effects via the partial activation of PPARγ.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/química
4.
Mar Drugs ; 17(9)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527453

RESUMO

Renieramycin M (RM) is a KCN-stabilized tetrahydroisoquinoline purified from the blue sponge Xestospongia sp., with nanomolar IC50s against several cancer cell lines. Our goal is to evaluate its combination effects with doxorubicin (DOX) in estrogen receptor positive MCF-7 breast cancer cells. MCF-7 cells were treated simultaneously or sequentially with various combination ratios of RM and DOX for 72 h. Cell viability was determined using the MTT assay. Synergism or antagonism was determined using curve-shift analysis, combination index method and isobologram analysis. Synergism was observed with pharmacologically achievable concentrations of DOX when administered simultaneously, but not sequentially. The IC95 values of RM and DOX after combination were reduced by up to four-fold and eight-fold, respectively. To gain insights on the mechanism of synergy, real-time profiling, cell cycle analysis, apoptosis assays, and transcriptome analysis were conducted. The combination treatment displayed a similar profile with DNA-damaging agents and induced a greater and faster cell killing. The combination treatment also showed an increase in apoptosis. DOX induced S and G2/M arrest while RM did not induce significant changes in the cell cycle. DNA replication and repair genes were downregulated commonly by RM and DOX. p53 signaling and cell cycle checkpoints were regulated by DOX while ErbB/PI3K-Akt, integrin and focal adhesion signaling were regulated by RM upon combination. Genes involved in cytochrome C release and interferon gamma signaling were regulated specifically in the combination treatment. This study serves as a basis for in vivo studies and provides a rationale for using RM in combination with other anticancer drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Xestospongia/química , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Transdução de Sinais/efeitos dos fármacos , Tetra-Hidroisoquinolinas/isolamento & purificação , Tetra-Hidroisoquinolinas/uso terapêutico , Transcriptoma/efeitos dos fármacos
5.
Planta Med ; 85(9-10): 738-744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185502

RESUMO

Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of ß 2-adrenergic receptor signaling in combination with the presently preferred ß 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for ß-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent ß-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both ß 1-adrenergic receptor and ß 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a ß 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for ß 1/ß 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in ß 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios de Triagem em Larga Escala/métodos , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Tetra-Hidroisoquinolinas/química
6.
Mar Drugs ; 17(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117253

RESUMO

Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/fisiopatologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Poríferos/química , Proteólise/efeitos dos fármacos , Tetra-Hidroisoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas/toxicidade , Ubiquitinação/efeitos dos fármacos
7.
Biomed Pharmacother ; 115: 108881, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028997

RESUMO

Higenamine (HG) is a well-known selective activator of beta2-adrenergic receptor (ß2-AR) with a positive inotropic effect. The present study showed that HG combined with [6]-gingerol (HG/[6]-GR) protects H9c2 cells from doxorubicin (DOX)-induced mitochondrial energy metabolism disorder and respiratory dysfunction. H9c2 cells were pretreated with HG/[6]-GR for 2 h before DOX treatment in all procedures. Cell viability was quantified by a cell counting kit­8 assay. Cardiomyocyte morphology, proliferation, and mitochondrial function were detected by a high content screening (HCS) assay. Cell mitochondrial stress was measured by a Seahorse XFp analyzer. To further investigate the protective mechanism of HG/[6]-GR, mRNA and protein expression levels of PPARα/PGC-1α/Sirt3 pathway-related molecules were detected. The present data demonstrated that protective effects of HG/[6]-GR combination were presented in mitochondria, which increased cell viability, ameliorated DOX-induced mitochondrial dysfunction, increased mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Most importantly, the protective effects were abrogated by GW6471 (a PPARα inhibitor) and ameliorated by Wy14643 (a PPARα agonist). Moreover, the combined use of HG and [6]-GR exerted more profound protective effects than either drug as a single agent. In conclusion, the results suggested that HG/[6]-GR ameliorates DOX-induced mitochondrial energy metabolism disorder and respiratory function impairment in H9c2 cells, and it indicated that the protective mechanism may be related to upregulation of the PPARα/PGC-1α/Sirt3 pathway, which promotes mitochondrial energy metabolism and protects against heart failure.


Assuntos
Alcaloides/farmacologia , Catecóis/farmacologia , Doxorrubicina/toxicidade , Álcoois Graxos/farmacologia , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Translocador 1 do Nucleotídeo Adenina/genética , Translocador 1 do Nucleotídeo Adenina/metabolismo , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/farmacologia , Alcaloides/administração & dosagem , Animais , Antibióticos Antineoplásicos/toxicidade , Catecóis/administração & dosagem , Linhagem Celular , Sobrevivência Celular , Metabolismo Energético/efeitos dos fármacos , Álcoois Graxos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Sirtuínas/genética , Sirtuínas/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismo
8.
Arch Biochem Biophys ; 666: 99-106, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946805

RESUMO

Acute lung injury (ALI) is a challenging clinical problem worldwide characterized by severe pulmonary inflammation. Dauricine, extracted from the root of traditional Chinese medicine Menispermum dauricum DC, is employed as anti-inflammatory herbs. In this study, we explored the inhibitory effects of dauricine on lipopolysaccharide (LPS)-induced inflammation in macrophages and LPS- or cecal ligation and puncture (CLP)-induced ALI in C57BL/6 mice. Our in vitro study identified that pretreatment of dauricine dose-dependently inhibited pro-inflammatory cytokines including nitric oxide (NO), interleukin-1ß (IL1ß), IL6, tumor necrosis factor-α (TNFα), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) in LPS-stimulated macrophages. Moreover, dauricine could suppress LPS-mediated nuclear translocation and transcriptional activity of nuclear factor-kappaB (NF-κB) by suppressing the phosphorylation of NF-κB inhibitors (IκB). In vivo studies, administration of dauricine, especially high-dose dauricine, potently improved the survival rate, reduced the production of pro-inflammatory cytokines in serum, and ameliorated ALI induced by LPS or CLP via blockage of NF-κB activation. Collectively, the present study discovers a new biological effect of dauricine in prevention of inflammation, indicating that dauricine can be served as a potential therapeutic agent to treat inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzilisoquinolinas/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Fitoterapia , Células RAW 264.7
9.
Pharmacol Biochem Behav ; 181: 17-27, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30965047

RESUMO

Anxiety is a common symptom of schizophrenia. Ketamine, which acts as a noncompetitive antagonist of glutamatergic NMDA receptors by binding to the phencyclidine site, may induce schizophrenia-like symptoms and promote anxiogenic-like behaviour. The symptoms of anxiety in rodents can be measured by the elevated plus maze (EPM) test. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), as a neuroprotective and antiaddictive substance, produces pharmacological effects by influencing monoaminergic and glutamatergic activity, as previously demonstrated by us. The aim of the present study was to investigate the anxiolytic-like potential of 1MeTIQ after the administration of ketamine. These results were compared to the effects of olanzapine, an antipsychotic drug commonly used in the treatment of schizophrenia. We conducted the EPM test, during which the percentage of time spent in and the number of entries into the open arms were measured. In addition, locomotor activity was measured. Furthermore, we conducted biochemical analyses to verify changes in the levels of neurotransmitters and their metabolites in selected rat brain structures. Behavioural analyses showed that 1MeTIQ, similar to olanzapine, completely inhibited ketamine-induced anxiogenic effects in the EPM test. On the other hand, neurochemical data indicated that 1MeTIQ, as a reversible inhibitor of MAO, significantly blocked the dopamine MAO-dependent oxidation pathway, whereas olanzapine significantly increased the activity of this pathway. The results above suggest that the anxiolytic-like properties of 1MeTIQ are connected to its influence on the catabolism of dopamine, the elevation of serotonin concentrations and the reduction in the levels of noradrenaline.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Olanzapina/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Análise de Variância , Animais , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Norepinefrina/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
10.
Front Biosci (Landmark Ed) ; 24: 859-869, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844718

RESUMO

Cerebral ischemia reperfusion (I/R) injury is associated with a high incidence of neurological morbidity and mortality worldwide. Higenamine has anti-inflammatory, anti-oxidative and anti-apoptotic capacities and has been successfully used in myocardial and intestinal ischemia reperfusion. We hypothesized that higenamine might serve the same effects in cerebral I/R. In a rat model of cerebral I/R, higenamine improved functional state of nerves, significantly inhibited the I/R-induced increase in the serum level of tumor necrosis factor α (TNF-alpha) and interleukins (ILs) such as IL-1, IL-6 and IL-18, and CD14+ cells, while decreasing the axonal nerve degeneration. Together, the data demonstrate that higenamine has therapeutic effect in cerebral I/R injury.


Assuntos
Alcaloides/farmacologia , Isquemia Encefálica/sangue , Traumatismo por Reperfusão/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Axônios/patologia , Encéfalo/patologia , Caspase 3/metabolismo , Circulação Cerebrovascular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Inflamação , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Regeneração Nervosa , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
11.
Mar Drugs ; 17(2)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754694

RESUMO

Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Xestospongia/química , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Tetra-Hidroisoquinolinas/química
12.
Artigo em Inglês | MEDLINE | ID: mdl-30707990

RESUMO

Accumulating evidence indicates that dopamine (DA) D3 receptor (DAD3R) antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the selective DAD3R antagonist SB-277011-A on the reinstatement of cocaine-induced conditioned place preference (CPP) produced by a priming dose of cocaine, by social defeat stress and by two kinds of physiological stressors (restraint and tail pinch) in male adult mice. We also explored reinstatement-related plasma corticosterone levels (as marker of stress response) and the effects of blocking DAD3R. Administration of SB-277011-A (24 or 48 mg/kg i.p.) did not modify conditioned reinstatement of cocaine seeking triggered by cocaine prime. By contrast, we found that the vulnerability to reinstatement of the CPP of defeated animals that have undergone CPP extinction was abolished by the DAD3R antagonist (24 mg/kg) given 30 min before the test session. Reactivation of the CPP response produced by physiological stress stimuli was also attenuated by SB-277011-A (48 mg/kg i.p.). On the other hand, the blockade of DAD3R significantly prevented the increased corticosterone release during reinstatement of cocaine-induced CPP that was seen in social defeated animals, in mice suffering physiological stress and after cocaine prime. Present results demonstrate a modulation by DAD3R of the reactivation of the incentive value of cocaine-associated cues induced by social and physiological stress stimuli, which was associated to a glucocorticoid-dependent mechanism. Our results also point to a possible potential therapeutic use of selective DAD3R antagonists for the prevention of stress-induced cocaine-seeking and relapse.


Assuntos
Cocaína/antagonistas & inibidores , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Nitrilos/farmacologia , Estresse Psicológico/psicologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Cocaína/farmacologia , Corticosterona/sangue , Masculino , Camundongos , Estresse Fisiológico/efeitos dos fármacos , Estresse Psicológico/sangue
13.
Eur J Med Chem ; 167: 133-145, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771601

RESUMO

A novel series of tetrahydroisoquinoline-benzimidazole hybrids have been designed and synthesized as multifunctional agents against Alzheimer's disease (AD). These compounds were evaluated for their inhibition of neuroinflammation and human ß-secretase (hBACE1), and neuroprotective activity. Among them, compound BD3 possessed significant anti-neuroinflammatory activity (IC50 = 5.07 µM against nitric oxide production) through inhibiting the expression and secretion of proinflammatory cytokines in BV2 cells. Compound BD3 also exhibited moderate hBACE1 inhibitory activity (65.7% inhibition at 20 µM) and potent neuroprotective effect by increasing GSH level and reducing ROS production (91.8% cell viability at 5 µM). Parallel artificial membrane permeation assay demonstrated that BD3 could cross the blood-brain barrier (BBB). Thus, this study demonstrates that the compounds with tetrahydroisoquinoline-benzimidazole scaffold are potential anti-AD agents, and they are worth for the further development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzimidazóis/uso terapêutico , Desenho de Drogas , Tetra-Hidroisoquinolinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular , Permeabilidade da Membrana Celular , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia
14.
Phytother Res ; 33(3): 708-717, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30648306

RESUMO

The α1 -adrenoceptor (α1 -AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α1 -AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α1A -, α1B -, and α1D -AR in vitro, rat mesenteric artery ex vivo, Wistar-Kyoto rats and spontaneously hypertensive rats in vivo. The radioligand binding assay showed that HG competitively inhibited the binding of [3 H]-prazosin to α1 -AR in a concentration-dependent manner. The affinities (pKi) of HG for the cloned α1A -, α1B -, and α1D -AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α1 -AR subtypes. In in vitro studies, HG was able to blunt inositol monophosphate production. It also displayed an inhibitory effect on the influx and entry of calcium ions and phosphorylation of extracellular signal-regulated kinase 1 and 2 induced by phenylephrine (PE). In ex vivo studies, PE caused a dose-dependent inotropic response curve, and the pA2 value for HG was 6.86 ± 0.29. In addition, the in vivo results showed that HG could decrease the blood pressure in normotension, spontaneous hypertension, and PE-induced hypertension models. These results indicate that HG can directly bind to α1 -AR and it appears to be a novel antagonist for α1 -AR, which may contribute to its hypotensive effect.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Alcaloides/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Células HEK293 , Humanos , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
Mol Divers ; 23(3): 709-722, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30603938

RESUMO

A series of 8- and 11-substituted hybrids of oxoisoaporphine-tetrahydroisoquinoline have been designed and synthesized. The new derivatives strongly suppressed NO and iNOS production and modulated the production of cytokines by decreasing TNF-α and IL-1ß formation in lipopolysaccharide-activated BV-2 microglia and RAW 264.7 macrophages. Meanwhile, incubation of these derivatives with SH-SY5Y cells that were transfected with human APP containing the Swedish mutations significantly decreased the secretion of Aß42. Moreover, these hybrids could strongly inhibit the activity of acetylcholinesterase and butyrylcholinesterase. Further investigations in vivo indicated that the 8-substituted hybrid 3b significantly delayed paralysis caused by Aß1-42 toxicity in GMC101. In sum, these new hybrids could target multiple pathogenetic factors in Alzheimer's disease and merit further investigation.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Aporfinas/química , Fragmentos de Peptídeos/química , Agregados Proteicos/efeitos dos fármacos , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Terapia de Alvo Molecular , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fragmentos de Peptídeos/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/biossíntese
16.
Eur J Med Chem ; 164: 317-333, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605830

RESUMO

Protein arginine methyltransferases 5 (PRMT5) represents an attractive drug target in epigenetic field for the treatment of leukemia and lymphoma. Here, a series of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amide derivatives targeting PRMT5 were designed with structure-based approach and synthesized. Among them, compound 46 showed potent and selective PRMT5 inhibition activity with an IC50 of 8.5 nM, which was approximately equivalent with the phase I clinical trial PRMT5 inhibitor GSK-3326595 (IC50 = 5.5 nM). Compound 46 also displayed pronounced anti-proliferative activity in MV4-11 cells (GI50 = 18 nM) and antitumor activity in MV4-11 mouse xenografts model. This molecule can serve as an excellent tool compound for probing the biological function of PRMT5.


Assuntos
Descoberta de Drogas , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Xenoenxertos , Humanos , Camundongos , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química
17.
Toxicol In Vitro ; 54: 295-303, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30342220

RESUMO

Our previous study found that 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines (CATHIQs) have excellent anti-cancer activity and obvious apoptosis induction phenomenon. As our continuing research, this study further explored their underlying molecular mechanism of apoptosis induction in cancer cells. Flow cytometry analysis showed that the NB4 cells treated by 1-cyano-2-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline or the MKN-45 cells treated by 1-cyano-2-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline for 48 h were at early stage of apoptosis, and the cell cycle arrest was only slightly affected. Apoptosis rates of the cells significantly increase with the treatment concentration of the compounds. The compounds could significantly decrease the activities of SOD, raise the MDA level and promote the LDH leakage, suggesting that the excessive formation of ROS should be involved in the cell apoptosis. Western blot analysis showed that the compounds improved both Bax/Bcl-2 ratio and cleavages of procaspase-3, promoted efflux of cytochrome c to cytosol and phosphorylation of p38 and JNK, and attenuated phosphorylations of Akt and ERK. Together, inhibitions of PI3K/Akt and ERK and activation of p38 mediated the compounds-induced apoptosis through modulating the mitochondrial pathway and/or ROS production.


Assuntos
Antineoplásicos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Humanos , L-Lactato Desidrogenase/metabolismo , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfotransferases/metabolismo , Superóxido Dismutase/metabolismo
18.
Bioorg Chem ; 83: 450-460, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448723

RESUMO

Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a, 2b, carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC50 values ranged from 2.72 to 12.53 µM, which were more potent than that of dauricine (higher than 15.53 µM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzilisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/química , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
19.
Eur J Med Chem ; 161: 433-444, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384046

RESUMO

A series of coniugates bearing a 1,2,3,4-tetrahydroisoquinoline motif linked to substituted 7-hydroxy-2H-chromen-2-ones was synthesized and assayed through calcein-AM test in Madin-Darby Canine Kidney (MDCK) cells overexpressing P-glycoprotein (P-gp) and closely related multidrug resistance associated protein 1 (MRP1) to probe the interference with efflux mechanisms mediated by P-gp and MRP1, respectively. A number of substituents at C3 and C4 of coumarin nucleus along with differently sized and shaped spacers was enrolled to investigate the effects of focused structural modifications over affinity and selectivity. Linker length and flexibility played a key role in enhancing P-gp affinity as proved by the most potent P-gp modulator (3h, IC50 = 70 nM). A phenyl ring within the spacer (3k, 3l, 3o) and bulkier groups (Br in 3r, Ph in 3u) at coumarin C3 led to derivatives showing nanomolar activity (160 nM < IC50 < 280 nM) along with outstanding selectivity over MRP1 (SI > 350). Molecular docking calculations carried out on a human MDR1 homology model structure contributed to gain insights into the ligands' binding modes. Some compounds (3d, 3h, 3l, 3r, 3t, 3u) reversed MDR thereby restoring doxorubicin cytotoxicity when co-administered with the drug into MDCK-MDR1 cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Cumarínicos/farmacologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Cães , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
20.
J Med Chem ; 62(2): 974-986, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30584838

RESUMO

P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4'-(6,7-dimethoxy-3,4-dihydro-1 H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70), modifying the phenolic group of the lead compound. Among them, compound 5b emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the transporter.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Antineoplásicos/farmacologia , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Tetra-Hidroisoquinolinas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cães , Doxorrubicina/farmacologia , Edição de Genes , Humanos , Ligantes , Células Madin Darby de Rim Canino , Simulação de Dinâmica Molecular , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Permeabilidade/efeitos dos fármacos , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
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