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[PMID]:29247859
[Au] Autor:Zhao S; Li K; Jin Y; Lin J
[Ad] Endereço:Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
[Ti] Título:Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors.
[So] Source:Eur J Med Chem;144:41-51, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 µM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC is from 10.7 to 39.9 µM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Timidina Fosforilase/antagonistas & inibidores
Uracila/análogos & derivados
Uracila/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/síntese química
Inibidores da Angiogênese/química
Inibidores da Angiogênese/farmacologia
Inibidores Enzimáticos/síntese química
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Concentração Inibidora 50
Modelos Moleculares
Oximas/síntese química
Oximas/química
Oximas/farmacologia
Relação Estrutura-Atividade
Timidina Fosforilase/metabolismo
Uracila/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Enzyme Inhibitors); 0 (Oximes); 56HH86ZVCT (Uracil); EC 2.4.2.4 (Thymidine Phosphorylase)
[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:171217
[St] Status:MEDLINE


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[PMID]:28460440
[Au] Autor:Massari NA; Nicoud MB; Sambuco L; Cricco GP; Martinel Lamas DJ; Herrero Ducloux MV; Blanco H; Rivera ES; Medina VA
[Ad] Endereço:Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
[Ti] Título:Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation.
[So] Source:Oncotarget;8(16):26471-26491, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Histamina/farmacologia
Melanoma/metabolismo
Melanoma/patologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/uso terapêutico
Biomarcadores
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Senescência Celular/efeitos dos fármacos
Terapia Combinada
Modelos Animais de Doenças
Histamina/uso terapêutico
Seres Humanos
Imuno-Histoquímica
Indóis/farmacologia
Melanoma/terapia
Camundongos
Camundongos Nus
Metástase Neoplásica
Estadiamento de Neoplasias
Oximas/farmacologia
Radiação Ionizante
Receptores Histamínicos H4/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers); 0 (Indoles); 0 (JNJ28610244); 0 (Oximes); 0 (Receptors, Histamine H4); 820484N8I3 (Histamine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15594


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[PMID]:27775691
[Au] Autor:Hendrix MJ; Kandela I; Mazar AP; Seftor EA; Seftor RE; Margaryan NV; Strizzi L; Murphy GF; Long GV; Scolyer RA
[Ad] Endereço:Department of Biology, Shepherd University, Shepherdstown, WV, USA.
[Ti] Título:Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells.
[So] Source:Lab Invest;97(2):176-186, 2017 02.
[Is] ISSN:1530-0307
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Melanoma/tratamento farmacológico
Proteína Nodal/antagonistas & inibidores
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Neoplasias Cutâneas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/administração & dosagem
Western Blotting
Linhagem Celular Tumoral
Feminino
Seres Humanos
Imidazóis/administração & dosagem
Imuno-Histoquímica
Neoplasias Pulmonares/prevenção & controle
Neoplasias Pulmonares/secundário
Melanoma/genética
Melanoma/metabolismo
Camundongos Nus
Terapia de Alvo Molecular/métodos
Mutação
Proteína Nodal/imunologia
Proteína Nodal/metabolismo
Oximas/administração & dosagem
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas B-raf/metabolismo
Piridonas/administração & dosagem
Pirimidinonas/administração & dosagem
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/metabolismo
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Imidazoles); 0 (Nodal Protein); 0 (Oximes); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); QGP4HA4G1B (dabrafenib)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1038/labinvest.2016.107


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[PMID]:29291440
[Au] Autor:Vágvölgyi M; Martins A; Kulmány Á; Zupkó I; Gáti T; Simon A; Tóth G; Hunyadi A
[Ad] Endereço:Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary.
[Ti] Título:Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam.
[So] Source:Eur J Med Chem;144:730-739, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Multidrug resistance is a widespread problem among various diseases and cancer is no exception. We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells. We have also shown that these molecules have a marked selectivity towards the MDR cells. Recent studies on the oximation of various steroid derivatives indicated remarkable increase in their antitumor activity, but there is no related bioactivity data on ecdysteroid oximes. In our present study, 13 novel ecdysteroid derivatives (oximes, oxime ethers and a lactam) and one known compound were synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and fully characterized by comprehensive NMR techniques revealing their complete H and C signal assignments. The compounds exerted moderate to strong in vitro antiproliferative activity on HeLa, SiHa, MCF-7 and MDA-MB-231 cell lines. Oxime and particularly oxime ether formation strongly increased their inhibitory activity on the efflux of rhodamine 123 by P-glycoprotein (P-gp), while the new ecdysteroid lactam did not interfere with the efflux function. All compounds exerted potent chemo-sensitizing activity towards doxorubicin on a mouse lymphoma cell line and on its MDR counterpart, and, on the latter, the lactam was found the most active. Because of its MDR-selective chemo-sensitizing activity with no functional effect on P-gp, this lactam is of high potential interest as a new lead for further antitumor studies.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ecdisteroides/farmacologia
Éteres/farmacologia
Lactamas/farmacologia
Neoplasias/tratamento farmacológico
Nitrogênio/farmacologia
Oximas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Ecdisteroides/síntese química
Ecdisteroides/química
Éteres/síntese química
Éteres/química
Seres Humanos
Lactamas/síntese química
Lactamas/química
Estrutura Molecular
Neoplasias/patologia
Nitrogênio/química
Oximas/síntese química
Oximas/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Ecdysteroids); 0 (Ethers); 0 (Lactams); 0 (Oximes); N762921K75 (Nitrogen)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180102
[St] Status:MEDLINE


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[PMID]:29384960
[Au] Autor:Martín Algarra S; Soriano V; Fernández-Morales L; Berciano-Guerrero MÁ; Mujika K; Manzano JL; Puértolas Hernández T; Soria A; Rodríguez-Abreu D; Espinosa Arranz E; Medina Martínez J; Márquez-Rodas I; Rubió-Casadevall J; Ortega ME; Jurado García JM; Lecumberri Biurrun MJ; Palacio I; Rodríguez de la Borbolla Artacho M; Altozano JP; Castellón Rubio VE; García A; Luna P; Ballesteros A; Fernández O; López Martín JA; Berrocal A; Arance A
[Ad] Endereço:Medical Oncology, Clínica Universidad de Navarra, Pamplona.
[Ti] Título:Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.
[So] Source:Medicine (Baltimore);96(52):e9523, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Imidazóis/uso terapêutico
Melanoma/tratamento farmacológico
Melanoma/patologia
Oximas/uso terapêutico
Piridonas/uso terapêutico
Pirimidinonas/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Ensaios de Uso Compassivo
Feminino
Seres Humanos
Imidazóis/administração & dosagem
Imidazóis/efeitos adversos
Masculino
Meia-Idade
Metástase Neoplásica
Oximas/administração & dosagem
Oximas/efeitos adversos
Piridonas/administração & dosagem
Piridonas/efeitos adversos
Pirimidinonas/administração & dosagem
Pirimidinonas/efeitos adversos
Estudos Retrospectivos
Espanha
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Imidazoles); 0 (Oximes); 0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); QGP4HA4G1B (dabrafenib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009523


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[PMID]:29191554
[Au] Autor:Futamura-Takahashi J; Tanaka T; Sugawara H; Iwashita S; Imajo S; Oyama Y; Muto T
[Ad] Endereço:Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Electronic address: futamura.junko.b6@asubio.co.jp.
[Ti] Título:Structure-based design, synthesis, and binding mode analysis of novel and potent chymase inhibitors.
[So] Source:Bioorg Med Chem Lett;28(2):188-192, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.
[Mh] Termos MeSH primário: Quimases/antagonistas & inibidores
Desenho de Drogas
Oximas/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Quimases/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Oximas/síntese química
Oximas/química
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oximes); 0 (Serine Proteinase Inhibitors); 0 (amidoxime); EC 3.4.21.39 (Chymases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:29274785
[Au] Autor:Tanaka T; Ohashi S; Saito H; Wada T; Aoyama T; Ichimaru Y; Miyairi S; Kobayashi S
[Ad] Endereço:Department of Biochemistry, School of Pharmacy, Nihon University, Narashinodai, Funabashi, Chiba 274-8555, Japan.
[Ti] Título:Indirubin 3'-oxime inhibits anticancer agent-induced YB-1 nuclear translocation in HepG2 human hepatocellular carcinoma cells.
[So] Source:Biochem Biophys Res Commun;496(1):7-11, 2018 01 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hepatocellular carcinoma (HCC) is a disease with poor prognosis. Nuclear accumulation of YB-1 is closely related to the malignancy of HCC. Treatment with anticancer agents often induces translocation of YB-1 from cytoplasm to nucleus and activates the expression of multidrug resistance gene 1 (MDR1). Therefore, any effective inhibitor of this phenomenon would be useful for cancer treatment. Here we examined various indirubin derivatives and found that indirubin 3'-oxime inhibits actinomycin D-induced nuclear transport of YB-1 and suppresses the activation of MDR1 gene expression in the human hepatocellular carcinoma cell line HepG2. Furthermore, use of both indirubin 3'-oxime and actinomycin D in combination increased the anticancer effect on HepG2 cells. Indirubin 3'-oxime is a novel and efficient inhibitor of anticancer agent-induced YB-1 nuclear translocation.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Carcinoma Hepatocelular/tratamento farmacológico
Carcinoma Hepatocelular/metabolismo
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Indóis/administração & dosagem
Oximas/administração & dosagem
Proteína 1 de Ligação a Y-Box/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Inibidores da Angiogênese/administração & dosagem
Carcinoma Hepatocelular/patologia
Núcleo Celular/patologia
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Células Hep G2
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents); 0 (Indoles); 0 (Oximes); 0 (Y-Box-Binding Protein 1); 0 (YBX1 protein, human); 0 (indirubin-3'-monoxime)
[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:171225
[St] Status:MEDLINE


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[PMID]:29216560
[Au] Autor:Yuan MC; Yeh TK; Chen CT; Song JS; Huang YC; Hsieh TC; Huang CY; Huang YL; Wang MH; Wu SH; Yao CH; Chao YS; Lee JC
[Ad] Endereço:Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli 35053, Taiwan.
[Ti] Título:Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.
[So] Source:Eur J Med Chem;143:611-620, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC > 50 µM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 µM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Hipoglicemiantes/farmacologia
Monossacarídeos/farmacologia
Oximas/farmacologia
Transportador 2 de Glucose-Sódio/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Intravenosa
Administração Oral
Animais
Compostos Benzidrílicos/administração & dosagem
Compostos Benzidrílicos/farmacologia
Glicemia/efeitos dos fármacos
Relação Dose-Resposta a Droga
Glucose/análise
Glucosídeos/administração & dosagem
Glucosídeos/farmacologia
Seres Humanos
Hipoglicemiantes/administração & dosagem
Hipoglicemiantes/química
Estrutura Molecular
Monossacarídeos/química
Oximas/administração & dosagem
Oximas/química
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol); 0 (Benzhydryl Compounds); 0 (Blood Glucose); 0 (C-glucosylarene); 0 (Glucosides); 0 (Hypoglycemic Agents); 0 (Monosaccharides); 0 (Oximes); 0 (SLC5A2 protein, human); 0 (Sodium-Glucose Transporter 2); IY9XDZ35W2 (Glucose)
[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:171208
[St] Status:MEDLINE


  9 / 6849 MEDLINE  
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[PMID]:28450070
[Au] Autor:Acharya PC; Bansal R
[Ad] Endereço:University Institute of Pharmaceutical Sciences, Panjab University, Sector 14, Chandigarh 160 014, India.
[Ti] Título:Synthesis of androstene oxime-nitrogen mustard bioconjugates as potent antineoplastic agents.
[So] Source:Steroids;123:73-83, 2017 Jul.
[Is] ISSN:1878-5867
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the present study, synthesis and antineoplastic activity of phenylacetic acid and benzoic acid nitrogen mustard conjugates of various steroidal oximes are reported for the first time. The conjugation was achieved through a more stable oxime-ester linkage and the resulting newly synthesized conjugates were evaluated in vitro on various human cancer cell lines for cytotoxicity. The extent of their alkylating activity was investigated by the in vitro colorimetric 4-(p-nitrobenzyl)pyridine (NBP) assay. The 17E-steroidal oxime-benzoic acid mustard ester 3ß-acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino)]benzoyloxyimino-androst-5-ene (8) emerged as the most potent conjugate having significant cytotoxicity on most of the NCI 60-cell lines. Outstanding growth inhibition was observed on the IGROV1 ovarian cancer cell line with GI =0.937µM. In general, the D-ring derived androstene oxime-nitrogen mustard conjugates were found to possess better antineoplastic activity over a variety of cancer cells in comparison to those derived from other rings of the steroid skeleton.
[Mh] Termos MeSH primário: Androstenos/síntese química
Androstenos/farmacologia
Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Mecloretamina/química
Oximas/química
[Mh] Termos MeSH secundário: Androstenos/química
Androstenos/toxicidade
Animais
Antineoplásicos/química
Antineoplásicos/toxicidade
Linhagem Celular Tumoral
Técnicas de Química Sintética
Seres Humanos
Macrófagos/efeitos dos fármacos
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenes); 0 (Antineoplastic Agents); 0 (Oximes); 50D9XSG0VR (Mechlorethamine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  10 / 6849 MEDLINE  
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[PMID]:29174813
[Au] Autor:Huang G; Zhao HR; Meng QQ; Zhang QJ; Dong JY; Zhu BQ; Li SS
[Ad] Endereço:School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: guanghuangmedchem@hotmail.com.
[Ti] Título:Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents.
[So] Source:Eur J Med Chem;143:166-181, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC ranging from 0.27 ± 0.02 to 9.23 ± 0.12 µM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Naftoquinonas/farmacologia
Oximas/farmacologia
Enxofre/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Naftoquinonas/síntese química
Naftoquinonas/química
Óxido Nítrico/análise
Óxido Nítrico/metabolismo
Oximas/síntese química
Oximas/química
Relação Estrutura-Atividade
Enxofre/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Naphthoquinones); 0 (Oximes); 31C4KY9ESH (Nitric Oxide); 3IK6592UBW (shikonin); 70FD1KFU70 (Sulfur)
[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



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