Base de dados : MEDLINE
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[PMID]:29267661
[Au] Autor:Almeida LJDS; Penha KJS; Souza AF; Lula ECO; Magalhães FC; Lima DM; Firoozmand LM
[Ad] Endereço:Universidade Federal do Maranhão - UFMA, Department of Dentistry I, São Luís, MA, Brazil.
[Ti] Título:Is there correlation between polymerization shrinkage, gap formation, and void in bulk fill composites? A µCT study.
[So] Source:Braz Oral Res;31:e100, 2017 Dec 18.
[Is] ISSN:1807-3107
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:This in vitro study aimed to evaluate the volume of polymerization shrinkage (VS), gap (VG), and void (VV) using computerized microtomography (µCT) in bulk fill resin composites and conventional class I restorations, and to establish a correlation between these factors. Class I cavities (4 x 5 x 4 mm), C-factor = 4.2, were performed on caries-free human third molars and randomly divided into five groups (n = 6): FSI (Filtek Supreme XTE incremental insertion); FSS [(Filtek Supreme XTE single insertion(SI)]; TBF [(Tetric Bulk Fill: SI and manual filling (MF)]; SFM (Sonic Fill: SI/MF); and SFS (SonicFill: SI and sonic filling). The teeth were scanned and analyzed by µCT at T0, after filling the cavity with resin, and at T1, after polymerization for VG and VV, and for VS (T1-T0). There was statistically significant difference in VS in µCT for the FSI and FSS groups and between SFS and FSS as well as some difference in VV for FSI and bulk fill resin composites and no difference in VG between the conventional technique and bulk fill composites. Bulk fill resin composites presented similar VS and gap formation to those of incrementally inserted conventional resin composites. There is a moderate and weak positive correlation between polymerization shrinkage and gap formation and void, respectively. The final gap formation was more dependent on the initial gap than on polymerization shrinkage or void volume.
[Mh] Termos MeSH primário: Resinas Compostas/química
Restauração Dentária Permanente/métodos
Polimerização
[Mh] Termos MeSH secundário: Análise de Variância
Luzes de Cura Dentária
Cimentos Dentários/química
Seres Humanos
Teste de Materiais
Valores de Referência
Reprodutibilidade dos Testes
Estatísticas não Paramétricas
Fatores de Tempo
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Composite Resins); 0 (Dental Cements)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


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[PMID]:28455168
[Au] Autor:Cummings CS; Fein K; Murata H; Ball RL; Russell AJ; Whitehead KA
[Ad] Endereço:Center for Polymer-based Protein Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States.
[Ti] Título:ATRP-grown protein-polymer conjugates containing phenylpiperazine selectively enhance transepithelial protein transport.
[So] Source:J Control Release;255:270-278, 2017 Jun 10.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Despite its patient-friendliness, the oral route is not yet a viable strategy for the delivery of biomacromolecular therapeutics. This is, in part, due to the large size of proteins, which greatly limits their absorption across the intestinal epithelium. Although chemical permeation enhancers can improve macromolecular transport, their positive impact is often accompanied by toxicity. One element potentially contributing to this toxicity is the lack of co-localization of the enhancer with the protein drug, which can result in non-specific permeation of the intestine as well as enhancer overdosing in some areas due to non-uniform distribution. To circumvent these issues, this study describes a new way of increasing protein permeability via a polymer conjugation process that co-localizes permeation enhancer with the protein. Based on previous reports demonstrating the utility of 1-phenylpiperazine as an intestinal permeation enhancer, we synthesized protein-polymer conjugates with a phenylpiperazine-containing polymer using polymer-based protein engineering. A novel phenylpiperazine acrylamide monomer was synthesized and chain extended using atom transfer radical polymerization from the model protein bovine serum albumin (BSA). At non-cytotoxic doses, the protein-polymer conjugates induced a dose dependent reduction in the trans-epithelial electrical resistance of Caco-2 monolayers and an impressive ~30-fold increase in BSA permeability. Furthermore, this permeability increase was selective, as the permeability of the small molecule calcein co-incubated with the protein-polymer conjugate increased only 5-fold. Together, these data represent an important first step in the development of protein polymer conjugates that facilitate selective protein transport across membranes that are typically impermeable to macromolecules.
[Mh] Termos MeSH primário: Piperazinas/administração & dosagem
Soroalbumina Bovina/administração & dosagem
[Mh] Termos MeSH secundário: Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Absorção Intestinal
Permeabilidade
Piperazinas/química
Polimerização
Transporte Proteico
Soroalbumina Bovina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Piperazines); 27432CM55Q (Serum Albumin, Bovine); J9225CBI7D (phenylpiperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29412223
[Au] Autor:Genari B; Leitune VCB; Jornada DS; Aldrigui BR; Pohlmann AR; Guterres SS; Samuel SMW; Collares FM
[Ad] Endereço:Universidade Federal do Rio Grande do Sul - UFRGS, School of Dentistry, Dental Materials Laboratory, Porto Alegre, RS, Brazil.
[Ti] Título:Effect on adhesion of a nanocapsules-loaded adhesive system.
[So] Source:Braz Oral Res;32:e008, 2018 Feb 01.
[Is] ISSN:1807-3107
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:This study aimed to evaluate the in situ degree of conversion, contact angle, and immediate and long-term bond strengths of a commercial primer and an experimental adhesive containing indomethacin- and triclosan-loaded nanocapsules (NCs). The indomethacin- and triclosan-loaded NCs, which promote anti-inflammatory and antibacterial effects through controlled release, were incorporated into the primer at a concentration of 2% and in the adhesive at concentrations of 1, 2, 5, and 10%. The in situ degree of conversion (DC, n=3) was evaluated by micro-Raman spectroscopy. The contact angle of the primer and adhesive on the dentin surface (n = 3) was determined by an optical tensiometer. For the microtensile bond strength µTBS test (12 teeth per group), stick-shaped specimens were tested under tensile stress immediately after preparation and after storage in water for 1 year. The data were analyzed using two-way ANOVA, three-way ANOVA and Tukey's post hoc tests with α=0.05. The use of the NC-loaded adhesive resulted in a higher in situ degree of conversion. The DC values varied from 75.07 ± 8.83% to 96.18 ± 0.87%. The use of NCs in only the adhesive up to a concentration of 5% had no influence on the bond strength. The contact angle of the primer remained the same with and without NCs. The use of both the primer and adhesive with NCs (for all concentrations) resulted in a higher contact angle of the adhesive. The longitudinal µTBS was inversely proportional to the concentration of NCs in the adhesive system, exhibiting decreasing values for the groups with primer containing NCs and adhesives with increasing concentrations of NCs. Adhesives containing up to 5% of nanocapsules and primer with no NCs maintained the in situ degree of conversion, contact angle, and immediate and long-term bond strengths. Therefore, the NC-loaded adhesive can be an alternative method for combining the bond performance and therapeutic effects. The use of an adhesive with up to 5% nanocapsules containing indomethacin and triclosan and a primer with no nanocapsules maintained the long-term bond performance.
[Mh] Termos MeSH primário: Colagem Dentária/métodos
Indometacina/química
Nanocápsulas/química
Cimentos de Resina/química
Triclosan/química
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Bovinos
Falha de Restauração Dentária
Dentina/efeitos dos fármacos
Teste de Materiais
Transição de Fase/efeitos dos fármacos
Polimerização/efeitos dos fármacos
Valores de Referência
Reprodutibilidade dos Testes
Análise Espectral Raman
Propriedades de Superfície/efeitos dos fármacos
Resistência à Tração
Fatores de Tempo
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nanocapsules); 0 (Resin Cements); 4NM5039Y5X (Triclosan); 90881-69-9 (Scotchbond); XXE1CET956 (Indomethacin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE


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[PMID]:29306206
[Au] Autor:Zhou P; Liang Y; Zhang H; Jiang H; Feng K; Xu P; Wang J; Wang X; Ding K; Luo C; Liu M; Wang Y
[Ad] Endereço:School of Pharmacy, Fudan University, Shanghai 201203, China; State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
[Ti] Título:Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral ß-lactam bridged combretastatin A-4 analogues as potent antitumor agents.
[So] Source:Eur J Med Chem;144:817-842, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A diverse of chiral ß-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC values of 0.001-0.021 µM, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Estilbenos/farmacologia
Moduladores de Tubulina/farmacologia
Tubulina (Proteína)/química
beta-Lactamas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Células HeLa
Seres Humanos
Camundongos
Camundongos Endogâmicos
Camundongos Nus
Modelos Moleculares
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/patologia
Polimerização/efeitos dos fármacos
Estilbenos/química
Relação Estrutura-Atividade
Tubulina (Proteína)/metabolismo
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/química
beta-Lactamas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Stilbenes); 0 (Tubulin); 0 (Tubulin Modulators); 0 (beta-Lactams); I5590ES2QZ (fosbretabulin)
[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:180107
[St] Status:MEDLINE


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[PMID]:29291446
[Au] Autor:Stefanski T; Mikstacka R; Kurczab R; Dutkiewicz Z; Kucinska M; Murias M; Zielinska-Przyjemska M; Cichocki M; Teubert A; Kaczmarek M; Hogendorf A; Sobiak S
[Ad] Endereço:Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland. Electronic address: tstefanski@ump.edu.pl.
[Ti] Título:Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents.
[So] Source:Eur J Med Chem;144:797-816, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC values of 0.86, 1.05, and 0.85 µM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Microtúbulos/efeitos dos fármacos
Estilbenos/farmacologia
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Técnicas de Química Combinatória
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Polimerização/efeitos dos fármacos
Estilbenos/síntese química
Estilbenos/química
Relação Estrutura-Atividade
Tubulina (Proteína)/metabolismo
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Stilbenes); 0 (Tubulin); 0 (Tubulin Modulators); I5590ES2QZ (fosbretabulin)
[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]:29210370
[Au] Autor:Vinciguerra D; Tran J; Nicolas J
[Ad] Endereço:Institut Galien Paris-Sud, UMR CNRS 8612, Univ Paris-Sud, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry cedex, France. julien.nicolas@u-psud.fr.
[Ti] Título:Telechelic polymers from reversible-deactivation radical polymerization for biomedical applications.
[So] Source:Chem Commun (Camb);54(3):228-240, 2018 Jan 02.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The main strategies for the design of telechelic polymers synthesized by reversible-activation radical polymerization for biomedical applications are covered spanning from drug delivery and targeting to theranostics and sensing.
[Mh] Termos MeSH primário: Polímeros/química
[Mh] Termos MeSH secundário: Animais
Portadores de Fármacos/síntese química
Portadores de Fármacos/química
Portadores de Fármacos/farmacologia
Corantes Fluorescentes/síntese química
Corantes Fluorescentes/química
Corantes Fluorescentes/farmacologia
Seres Humanos
Camundongos
Polimerização
Polímeros/síntese química
Polímeros/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Drug Carriers); 0 (Fluorescent Dyes); 0 (Polymers)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1039/c7cc08544c


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[PMID]:28748978
[Au] Autor:Song L; Ding AX; Zhang KX; Gong B; Lu ZL; He L
[Ad] Endereço:Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China. luzl@bnu.edu.cn.
[Ti] Título:Degradable polyesters via ring-opening polymerization of functional valerolactones for efficient gene delivery.
[So] Source:Org Biomol Chem;15(31):6567-6574, 2017 Aug 09.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Degradable polymers as gene and drug carriers are emerging as one of the most promising types of materials in the biomedical and pharmaceutical areas. Herein, we report the synthesis of a series of block co-polyesters (B1-B6) and random co-polyesters (C1-C4) via ring-opening polymerization of tertiary amine-bearing valerolactone and alkylated valerolactone monomers. These polymers can completely inhibit the electrophoretic migrations of plasmid DNAs (pDNAs) at a w/w ratio of 2-6. The polyplexes of these polymers with pDNAs were steadily formed in a narrow range of sizes (75 to 220 nm) and could be effectively internalized into the cytoplasm. The results of transfection experiments showed that the block copolymers generally exhibited better performance than their random counterparts and the aliphatic chain lengths on the backbone of the polymers obviously affected the transfection efficiency (TE). Block copolymer B5 with n-octyl chains generated the best TE in Hek293T cells, which was 2.2 fold that of polyethylenimine (PEI) 25k under the optimal conditions. Moreover, these polymers were found to be more biocompatible compared to PEI 25k, and showed degradable properties. Our results suggest that these polymers are potentially reliable/efficient non-viral gene vectors.
[Mh] Termos MeSH primário: DNA/administração & dosagem
Técnicas de Transferência de Genes
Lactonas/química
Plasmídeos/administração & dosagem
Poliésteres/química
[Mh] Termos MeSH secundário: DNA/genética
Vetores Genéticos/administração & dosagem
Vetores Genéticos/genética
Células HEK293
Seres Humanos
Lactonas/síntese química
Plasmídeos/genética
Poliésteres/síntese química
Polimerização
Transfecção/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lactones); 0 (Polyesters); 9007-49-2 (DNA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob00822h


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[PMID]:28471002
[Au] Autor:Cecchini MM; Reale S; Manini P; d'Ischia M; De Angelis F
[Ad] Endereço:Department of Physical and Chemical Sciences, University of L'Aquila, Via Vetoio, Coppito, L'Aquila, Italy.
[Ti] Título:Modeling Fungal Melanin Buildup: Biomimetic Polymerization of 1,8-Dihydroxynaphthalene Mapped by Mass Spectrometry.
[So] Source:Chemistry;23(33):8092-8098, 2017 Jun 12.
[Is] ISSN:1521-3765
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Due to the emerging biomedical relevance and technological potential of fungal melanins, and prompted by the virtual lack of information about their structural arrangement, an optimized synthetic protocol has been devised for a potential structural model of Ascomyces allomelanin through enzyme-catalyzed oxidative polymerization of 1,8-dihydroxynaphthalene (1,8-DHN). Electrospray ionization mass spectrometry (ESI-MS) measurements of freshly synthesized DHN-polymer recorded in the negative ion mode allowed detection of oligomers up to m/z 4000, separated by 158 Da, corresponding to the in-chain DHN-unit. The dominant peaks were assigned to singly-charged distribution, up to 23 repeating units, whereas a doubly charged polymer distribution was also detectable. Chemical derivatization, ultra-performance liquid chromatography (UPLC)-ESI MS, and MS/MS data confirmed that oxidative polymerization of 1,8-DHN proceeds through C-C coupling of the naphthalene rings. The new insights reported here into synthetic 1,8-DHN oligomers/polymers as a mimic of fungal melanins may guide novel interesting advances and applications in the field of biomimetic functional materials.
[Mh] Termos MeSH primário: Materiais Biomiméticos/química
Proteínas Fúngicas/metabolismo
Fungos/metabolismo
Melaninas/metabolismo
Naftóis/química
[Mh] Termos MeSH secundário: Biocatálise
Materiais Biomiméticos/metabolismo
Cromatografia Líquida de Alta Pressão
Proteínas Fúngicas/química
Peroxidase do Rábano Silvestre/metabolismo
Melaninas/química
Oxirredução
Polimerização
Espectrometria de Massas por Ionização por Electrospray
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Melanins); 0 (Naphthols); 569-42-6 (1,8-dihydroxynaphthalene); EC 1.11.1.- (Horseradish Peroxidase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/chem.201701951


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[PMID]:29197729
[Au] Autor:Bortolozzi R; Mattiuzzo E; Dal Pra M; Sturlese M; Moro S; Hamel E; Carta D; Viola G; Ferlin MG
[Ad] Endereço:Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, Italy.
[Ti] Título:Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs.
[So] Source:Eur J Med Chem;143:244-258, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31, the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI values) was observed with 21 and 24, both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of ß-tubulin.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Quinolonas/farmacologia
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células HeLa
Seres Humanos
Leucócitos Mononucleares/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Estrutura Molecular
Polimerização/efeitos dos fármacos
Quinolonas/síntese química
Quinolonas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Quinolones); 0 (Tubulin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


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[PMID]:29220790
[Au] Autor:Romagnoli R; Kimatrai Salvador M; Schiaffino Ortega S; Baraldi PG; Oliva P; Baraldi S; Lopez-Cara LC; Brancale A; Ferla S; Hamel E; Balzarini J; Liekens S; Mattiuzzo E; Basso G; Viola G
[Ad] Endereço:Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
[Ti] Título:2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.
[So] Source:Eur J Med Chem;143:683-698, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC values ranging from 0.13 to 0.84 µM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC value of 140 nM, inhibited tubulin polymerization with an IC value of 1.2 µM, similar to that of CA-4 (IC : 1.1 µM), and induced apoptosis in HeLa cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Microtúbulos/efeitos dos fármacos
Tiofenos/farmacologia
Moduladores de Tubulina/farmacologia
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Modelos Moleculares
Estrutura Molecular
Polimerização/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
Tiofenos/síntese química
Tiofenos/química
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Reactive Oxygen Species); 0 (Thiophenes); 0 (Tubulin); 0 (Tubulin Modulators)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE



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