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[PMID]:29482394
[Au] Autor:Marcinkowska M; Kotanska M; Zagórska A; Sniecikowska J; Kubacka M; Siwek A; Bucki A; Pawlowski M; Bednarski M; Sapa J; Starek M; Dabrowska M; Kolaczkowski M
[Ad] Endereço:a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland.
[Ti] Título:Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents.
[So] Source:J Enzyme Inhib Med Chem;33(1):536-545, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC of 26.9 µM and 20.5 µM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.
[Mh] Termos MeSH primário: Isoquinolinas/farmacologia
Piperazinas/farmacologia
Inibidores da Agregação de Plaquetas/farmacologia
Receptores Adrenérgicos alfa 2/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Modelos Moleculares
Estrutura Molecular
Piperazinas/síntese química
Piperazinas/química
Agregação Plaquetária/efeitos dos fármacos
Inibidores da Agregação de Plaquetas/síntese química
Inibidores da Agregação de Plaquetas/química
Testes de Função Plaquetária
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADRA2B protein, human); 0 (Isoquinolines); 0 (Piperazines); 0 (Platelet Aggregation Inhibitors); 0 (Receptors, Adrenergic, alpha-2); 1RTM4PAL0V (piperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437155


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[PMID]:28449948
[Au] Autor:Lutz SZ; Ullrich A; Häring HU; Ullrich S; Gerst F
[Ad] Endereço:German Center for Diabetes Research (DZD e.V.), Germany; Institute for Diabetes Research and Metabolic Diseases IDM of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Germany; University Hospital Tübingen, Internal Medicine IV, Endocrinology, Diabetology, Angiology, Nephrol
[Ti] Título:Sunitinib specifically augments glucose-induced insulin secretion.
[So] Source:Cell Signal;36:91-97, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting ß-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2µM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on ß-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans.
[Mh] Termos MeSH primário: Glucose/farmacologia
Indóis/farmacologia
Insulina/secreção
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Compostos de Anilina
Animais
Linhagem Celular
Colforsina/farmacologia
AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Isoquinolinas/farmacologia
Fenilpropionatos
Fosforilação/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Ratos
Transdução de Sinais/efeitos dos fármacos
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (H-89 dihydrochloride hydrate); 0 (Indoles); 0 (Insulin); 0 (Isoquinolines); 0 (Phenylpropionates); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 0 (Sulfonamides); 0 (TUG-469); 1F7A44V6OU (Colforsin); 67763-96-6 (Insulin-Like Growth Factor I); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); IY9XDZ35W2 (Glucose); V99T50803M (sunitinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:29348454
[Au] Autor:Krishnan N; Bonham CA; Rus IA; Shrestha OK; Gauss CM; Haque A; Tocilj A; Joshua-Tor L; Tonks NK
[Ad] Endereço:Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.
[Ti] Título:Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.
[So] Source:Nat Commun;9(1):283, 2018 01 18.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.
[Mh] Termos MeSH primário: Fármacos Antiobesidade/química
Inibidores Enzimáticos/química
Hipoglicemiantes/química
Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores
Anticorpos de Cadeia Única/química
Bibliotecas de Moléculas Pequenas/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Fármacos Antiobesidade/metabolismo
Benzofenantridinas/química
Benzofenantridinas/metabolismo
Sítios de Ligação
Clonagem Molecular
Cristalografia por Raios X
Inibidores Enzimáticos/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Seres Humanos
Hipoglicemiantes/metabolismo
Insulina/química
Insulina/metabolismo
Isoquinolinas/química
Isoquinolinas/metabolismo
Leptina/química
Leptina/metabolismo
Levamisol/química
Levamisol/metabolismo
Simulação de Acoplamento Molecular
Oxirredução
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Proteína Tirosina Fosfatase não Receptora Tipo 1/química
Proteína Tirosina Fosfatase não Receptora Tipo 1/genética
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Anticorpos de Cadeia Única/genética
Anticorpos de Cadeia Única/metabolismo
Bibliotecas de Moléculas Pequenas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Obesity Agents); 0 (Benzophenanthridines); 0 (Enzyme Inhibitors); 0 (Hypoglycemic Agents); 0 (Insulin); 0 (Isoquinolines); 0 (Leptin); 0 (Recombinant Proteins); 0 (Single-Chain Antibodies); 0 (Small Molecule Libraries); 2880D3468G (Levamisole); AV9VK043SS (sanguinarine); E3B045W6X0 (chelerythrine); EC 3.1.3.48 (PTPN1 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02252-2


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[PMID]:29254377
[Au] Autor:Del Vecchio L; Locatelli F
[Ad] Endereço:a Department of Nephrology and Dialysis , A. Manzoni Hospital , Lecco , Italy.
[Ti] Título:Roxadustat in the treatment of anaemia in chronic kidney disease.
[So] Source:Expert Opin Investig Drugs;27(1):125-133, 2018 Jan.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia-inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies.
[Mh] Termos MeSH primário: Anemia/tratamento farmacológico
Glicina/análogos & derivados
Isoquinolinas/uso terapêutico
Insuficiência Renal Crônica/complicações
[Mh] Termos MeSH secundário: Anemia/etiologia
Animais
Doenças Cardiovasculares/etiologia
Doenças Cardiovasculares/prevenção & controle
Eritropoetina/metabolismo
Glicina/efeitos adversos
Glicina/farmacologia
Glicina/uso terapêutico
Hematínicos/efeitos adversos
Hematínicos/uso terapêutico
Seres Humanos
Isoquinolinas/efeitos adversos
Isoquinolinas/farmacologia
Inibidores de Prolil-Hidrolase/efeitos adversos
Inibidores de Prolil-Hidrolase/farmacologia
Inibidores de Prolil-Hidrolase/uso terapêutico
Qualidade de Vida
Diálise Renal
Insuficiência Renal Crônica/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FG-4592); 0 (Hematinics); 0 (Isoquinolines); 0 (Prolyl-Hydroxylase Inhibitors); 11096-26-7 (Erythropoietin); TE7660XO1C (Glycine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2018.1417386


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[PMID]:28467359
[Au] Autor:Yoshida K; Hai H; Tamori A; Teranishi Y; Kozuka R; Motoyama H; Kawamura E; Hagihara A; Uchida-Kobayashi S; Morikawa H; Enomoto M; Murakami Y; Kawada N
[Ad] Endereço:Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. m2028081@med.osaka-cu.ac.jp.
[Ti] Título:Long-Term Follow-Up of Resistance-Associated Substitutions in Hepatitis C Virus in Patients in Which Direct Acting Antiviral-Based Therapy Failed.
[So] Source:Int J Mol Sci;18(5), 2017 May 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
Hepacivirus/genética
Hepatite C Crônica/tratamento farmacológico
Serina Proteases/genética
Proteínas não Estruturais Virais/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Antivirais/farmacologia
Antivirais/uso terapêutico
Quimioterapia Combinada
Feminino
Seguimentos
Hepacivirus/efeitos dos fármacos
Hepatite C Crônica/virologia
Seres Humanos
Imidazóis/farmacologia
Imidazóis/uso terapêutico
Interferon-alfa/uso terapêutico
Isoquinolinas/farmacologia
Isoquinolinas/uso terapêutico
Masculino
Meia-Idade
Polietilenoglicóis/uso terapêutico
Inibidores de Proteases/farmacologia
Inibidores de Proteases/uso terapêutico
Proteínas Recombinantes/uso terapêutico
Ribavirina/farmacologia
Ribavirina/uso terapêutico
Simeprevir/farmacologia
Simeprevir/uso terapêutico
Sulfonamidas/farmacologia
Sulfonamidas/uso terapêutico
Fatores de Tempo
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (BMS-790052); 0 (Imidazoles); 0 (Interferon-alpha); 0 (Isoquinolines); 0 (NS-5 protein, hepatitis C virus); 0 (Protease Inhibitors); 0 (Recombinant Proteins); 0 (Sulfonamides); 0 (Viral Nonstructural Proteins); 30IQX730WE (Polyethylene Glycols); 49717AWG6K (Ribavirin); 9WS5RD66HZ (Simeprevir); EC 3.4.- (NS3-4A serine protease, Hepatitis C virus); EC 3.4.- (Serine Proteases); G8RGG88B68 (peginterferon alfa-2b); S9X0KRJ00S (asunaprevir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:29317208
[Au] Autor:Xiao XH; Qi XY; Wang YD; Ran L; Yang J; Zhang HL; Xu CX; Wen GB; Liu JH
[Ad] Endereço:Department of Metabolism and Endocrinology, University of South China, Hengyang, 421001, Hunan Province, China.
[Ti] Título:Zinc alpha2 glycoprotein promotes browning in adipocytes.
[So] Source:Biochem Biophys Res Commun;496(2):287-293, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.
[Mh] Termos MeSH primário: Adipócitos Marrons/metabolismo
Proteínas de Transporte/genética
Regulação da Expressão Gênica
Glicoproteínas/genética
Metabolismo dos Lipídeos/genética
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos Marrons/citologia
Adipócitos Marrons/efeitos dos fármacos
Animais
Proteínas Reguladoras de Apoptose/genética
Proteínas Reguladoras de Apoptose/metabolismo
Carbono-Carbono Ligases/genética
Carbono-Carbono Ligases/metabolismo
Carnitina O-Palmitoiltransferase/genética
Carnitina O-Palmitoiltransferase/metabolismo
Proteínas de Transporte/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Glicoproteínas/metabolismo
Imidazóis/farmacologia
Isoquinolinas/farmacologia
Lipase/genética
Lipase/metabolismo
Camundongos
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Fator 1 Nuclear Respiratório/genética
Fator 1 Nuclear Respiratório/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
Piridinas/farmacologia
Transdução de Sinais
Sulfonamidas/farmacologia
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Proteína Desacopladora 1/genética
Proteína Desacopladora 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AZGP1 protein, mouse); 0 (Apoptosis Regulatory Proteins); 0 (Carrier Proteins); 0 (Cidea protein, mouse); 0 (DNA-Binding Proteins); 0 (Glycoproteins); 0 (Imidazoles); 0 (Isoquinolines); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Nrf1 protein, mouse); 0 (Nuclear Respiratory Factor 1); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (Prdm16 protein, mouse); 0 (Pyridines); 0 (Sulfonamides); 0 (Transcription Factors); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1); EC 2.3.1.21 (CPT1B protein, mouse); EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (PNPLA2 protein, mouse); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase); M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide); OU13V1EYWQ (SB 203580)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:29207336
[Au] Autor:Mohamed MF; Hassaneen HM; Abdelhamid IA
[Ad] Endereço:Department of Chemistry (Biochemistry Branch), Faculty of Science, Cairo University, Giza, Egypt. Electronic address: magdafikry85@yahoo.com.
[Ti] Título:Cytotoxicity, molecular modeling, cell cycle arrest, and apoptotic induction induced by novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones.
[So] Source:Eur J Med Chem;143:532-541, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one derivatives were synthesized and their structures were confirmed by different spectral tools. Cytotoxicity test revealed that some compounds exhibited strong to moderate effect, while others showed weak action against different cancer cell lines (MCF7, A549, HCT116, and Hepg2). Breast carcinoma revealed higher sensitivity toward all derivatives especially compounds 5 and 8 which offered the lowest IC values (50.05, and 27.15 µg/ml) respectively, relative to the positive control 5-fluorouracil (5-FU) (IC = 178 µg/ml). In addition, the two compounds exhibited less toxic effect toward normal melanocytes (HFB4). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis using the two promising novels 5 and 8. Docking simulation studies against the two proteins EGFR and DHFR demonstrate that compound 8 showed higher binding affinity toward the two proteins more than compound 5, suggesting that trimethoxy groups may be responsible for this higher activity through the formation of five hydrogen bonding with the active domain (4r3r) and other four interactions with the active domain (1dls). Real time PCR assay illustrates that the two compounds up regulated BAX, p53, caspase-3 genes and down regulated BCL2, MMP1, CDK4 ones. In addition, it was noted that compound 8 was more effective in gene regulation and apoptotic induction than compound 5. Also, flow cytometer analysis demonstrates that both compounds 5 and 8 induced cell growth arrest at G1 phase and thus, inhibit G1/S transition and cell cycle progression. In addition, both compounds stimulate apoptotic death of breast cells significantly to reach 8.72%, and 17.28% respectively, compared to their control (0.55%). Apoptotic induction of breast cells was enhanced effectively through activation of caspase-3 by compound 8 using Elisa assay.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Chalconas/farmacologia
Isoquinolinas/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Chalconas/síntese química
Chalconas/química
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Triazóis/síntese química
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Chalcones); 0 (Isoquinolines); 0 (Triazoles); 0 (tetrahydro-(1,2,4)triazolo(3,4-a)isoquinoline)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


  8 / 15588 MEDLINE  
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[PMID]:29216198
[Au] Autor:Canini L; Imamura M; Kawakami Y; Uprichard SL; Cotler SJ; Dahari H; Chayama K
[Ad] Endereço:The program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, United States of America.
[Ti] Título:HCV kinetic and modeling analyses project shorter durations to cure under combined therapy with daclatasvir and asunaprevir in chronic HCV-infected patients.
[So] Source:PLoS One;12(12):e0187409, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. METHODS: HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points. RESULTS: Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure. CONCLUSION: Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened.
[Mh] Termos MeSH primário: Antivirais/uso terapêutico
Hepacivirus/fisiologia
Hepatite C Crônica/tratamento farmacológico
Imidazóis/uso terapêutico
Isoquinolinas/uso terapêutico
Sulfonamidas/uso terapêutico
[Mh] Termos MeSH secundário: Antivirais/administração & dosagem
Seres Humanos
Imidazóis/administração & dosagem
Isoquinolinas/administração & dosagem
Cinética
Sulfonamidas/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (BMS-790052); 0 (Imidazoles); 0 (Isoquinolines); 0 (Sulfonamides); S9X0KRJ00S (asunaprevir)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187409


  9 / 15588 MEDLINE  
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[PMID]:29174815
[Au] Autor:Khadka DB; Park S; Jin Y; Han J; Kwon Y; Cho WJ
[Ad] Endereço:College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
[Ti] Título:Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors.
[So] Source:Eur J Med Chem;143:200-215, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 µM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo I/metabolismo
Desenho de Drogas
Isoquinolinas/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Biocatálise
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Estrutura Molecular
Polimerização/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoquinolines); 0 (Topoisomerase I Inhibitors); 0 (Tubulin); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  10 / 15588 MEDLINE  
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[PMID]:28449418
[Au] Autor:Haase VH
[Ad] Endereço:Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
[Ti] Título:HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
[So] Source:Hemodial Int;21 Suppl 1:S110-S124, 2017 Jun.
[Is] ISSN:1542-4758
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
[Mh] Termos MeSH primário: Eritropoese/efeitos dos fármacos
Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia
Ferro/metabolismo
Inibidores de Prolil-Hidrolase/uso terapêutico
[Mh] Termos MeSH secundário: Anemia/tratamento farmacológico
Barbitúricos/efeitos adversos
Barbitúricos/uso terapêutico
Ensaios Clínicos como Assunto
Eritropoetina/biossíntese
Glicina/efeitos adversos
Glicina/análogos & derivados
Glicina/uso terapêutico
Seres Humanos
Isoquinolinas/efeitos adversos
Isoquinolinas/uso terapêutico
Ácidos Picolínicos/efeitos adversos
Ácidos Picolínicos/uso terapêutico
Diálise Renal/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Barbiturates); 0 (EPO protein, human); 0 (FG-4592); 0 (GSK1278863); 0 (Isoquinolines); 0 (Picolinic Acids); 0 (Prolyl-Hydroxylase Inhibitors); 0 (vadadustat); 11096-26-7 (Erythropoietin); E1UOL152H7 (Iron); EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases); TE7660XO1C (Glycine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1111/hdi.12567



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