Base de dados : MEDLINE
Pesquisa : D03.661.368 [Categoria DeCS]
Referências encontradas : 112 [refinar]
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  1 / 112 MEDLINE  
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[PMID]:29239411
[Au] Autor:Ogasawara H; Grzybowski M; Hosokawa R; Sato Y; Taki M; Yamaguchi S
[Ad] Endereço:Department of Chemistry, Graduate School of Science and Integrated Research Consortium on Chemical Sciences (IRCCS), Nagoya University, Furo, Chikusa, Nagoya 464-8602, Japan.
[Ti] Título:A far-red fluorescent probe based on a phospha-fluorescein scaffold for cytosolic calcium imaging.
[So] Source:Chem Commun (Camb);54(3):299-302, 2018 Jan 02.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The far-red emissive fluorescent probe CaPF-1 based on a phospha-fluorescein scaffold enables the detection of cytosolic calcium ions in living cells. The probe can be excited in the red region (λ = 636 nm) and exhibits a sufficiently high fluorescence turn-on response in the far-red region (λ = 663 nm) upon complexation with calcium ions. The hydrophilic and anionic characteristics of this phospha-fluorescein fluorophore allowed the cytosolic localization of CaPF-1. Moreover, it was possible to visualize histamine-induced calcium oscillation in HeLa cells using CaPF-1.
[Mh] Termos MeSH primário: Cálcio/análise
Óxidos P-Cíclicos/farmacologia
Fluoresceínas/farmacologia
Corantes Fluorescentes/farmacologia
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Óxidos P-Cíclicos/síntese química
Óxidos P-Cíclicos/química
Fluoresceínas/síntese química
Fluoresceínas/química
Fluorescência
Corantes Fluorescentes/síntese química
Corantes Fluorescentes/química
Células HeLa
Histamina/metabolismo
Seres Humanos
Concentração de Íons de Hidrogênio
Microscopia Confocal
Imagem Molecular
Imagem Óptica
Receptores Histamínicos H1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic P-Oxides); 0 (Fluoresceins); 0 (Fluorescent Dyes); 0 (Receptors, Histamine H1); 820484N8I3 (Histamine); SY7Q814VUP (Calcium)
[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:171215
[St] Status:MEDLINE
[do] DOI:10.1039/c7cc07344e


  2 / 112 MEDLINE  
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[PMID]:28532652
[Au] Autor:Tian C; Yuan Z; Xu D; Ding P; Wang T; Zhang L; Jiang Z
[Ad] Endereço:Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
[Ti] Título:Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+ cancer.
[So] Source:Exp Cell Res;357(2):211-221, 2017 Aug 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Upregulation of glycolysis was often observed in human HER2-overexpressing cancers. In this study, we demonstrated that KU004, a dual novel EGFR/HER2 inhibitor, disrupted cancer cell proliferation via modulation of glycolysis. KU004, inhibited the Warburg effect by suppressing hexokinase II (HK2) expression at the transcriptional and post-translational levels. Further study demonstrated that the downregulation of HKII by KU004 was mainly mediated by the PI3K/Akt signaling pathway. Furthermore, the role of HKII downregulation in KU004-mediated antitumor effect was also confirmed in our in vivo xenograft model. Collectively, these data suggest that multifaceted targeting the aberrant glucose metabolism along with the upstream HER2 may be an effective approach for clinical treatment against HER2+ cancer.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias da Mama/metabolismo
Óxidos P-Cíclicos/farmacologia
Quinazolinas/farmacologia
Receptor ErbB-2/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Glicólise/efeitos dos fármacos
Seres Humanos
Fosfatidilinositol 3-Quinases/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cyclic P-Oxides); 0 (KU004 compound); 0 (Quinazolines); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE


  3 / 112 MEDLINE  
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[PMID]:26928308
[Au] Autor:Hirsch C; Striegl B; Mathes S; Adlhart C; Edelmann M; Bono E; Gaan S; Salmeia KA; Hoelting L; Krebs A; Nyffeler J; Pape R; Bürkle A; Leist M; Wick P; Schildknecht S
[Ad] Endereço:Particles-Biology Interactions Laboratory, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland. Cordula.Hirsch@empa.ch.
[Ti] Título:Multiparameter toxicity assessment of novel DOPO-derived organophosphorus flame retardants.
[So] Source:Arch Toxicol;91(1):407-425, 2017 Jan.
[Is] ISSN:1432-0738
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Halogen-free organophosphorus flame retardants are considered as replacements for the phased-out class of polybrominated diphenyl ethers (PBDEs). However, toxicological information on new flame retardants is still limited. Based on their excellent flame retardation potential, we have selected three novel 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) derivatives and assessed their toxicological profile using a battery of in vitro test systems in order to provide toxicological information before their large-scale production and use. PBDE-99, applied as a reference compound, exhibited distinct neuro-selective cytotoxicity at concentrations ≥10 µM. 6-(2-((6-oxido-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)ethoxy)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (ETA-DOPO) and 6,6'-(ethane-1,2-diylbis(oxy))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EG-DOPO) displayed adverse effects at concentrations >10 µM in test systems reflecting the properties of human central and peripheral nervous system neurons, as well as in a set of non-neuronal cell types. DOPO and its derivative 6,6'-(ethane-1,2-diylbis(azanediyl))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EDA-DOPO) were neither neurotoxic, nor did they exhibit an influence on neural crest cell migration, or on the integrity of human skin equivalents. The two compounds furthermore displayed no inflammatory activation potential, nor did they affect algae growth or daphnia viability at concentrations ≤400 µM. Based on the superior flame retardation properties, biophysical features suited for use in polyurethane foams, and low cytotoxicity of EDA-DOPO, our results suggest that it is a candidate for the replacement of currently applied flame retardants.
[Mh] Termos MeSH primário: Retardadores de Chama/toxicidade
Queratinócitos/efeitos dos fármacos
Monócitos/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Compostos Organofosforados/toxicidade
Mucosa Respiratória/efeitos dos fármacos
Pele/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células A549
Animais
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Óxidos P-Cíclicos/toxicidade
Células-Tronco Embrionárias Humanas/citologia
Seres Humanos
Queratinócitos/citologia
Queratinócitos/imunologia
Queratinócitos/metabolismo
Monócitos/citologia
Monócitos/imunologia
Monócitos/metabolismo
Neurônios/citologia
Neurônios/imunologia
Neurônios/metabolismo
Células-Tronco Pluripotentes/citologia
Mucosa Respiratória/citologia
Mucosa Respiratória/imunologia
Mucosa Respiratória/metabolismo
Pele/citologia
Pele/imunologia
Pele/metabolismo
Absorção Cutânea
Testes de Irritação da Pele
Sus scrofa
Tecidos Suporte/química
Testes de Toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic P-Oxides); 0 (EDA-DOPO compound); 0 (EG-DOPO compound); 0 (ETA-DOPO compound); 0 (Flame Retardants); 0 (Organophosphorus Compounds)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160302
[St] Status:MEDLINE
[do] DOI:10.1007/s00204-016-1680-4


  4 / 112 MEDLINE  
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[PMID]:26110470
[Au] Autor:Taki M; Ogasawara H; Osaki H; Fukazawa A; Sato Y; Ogasawara K; Higashiyama T; Yamaguchi S
[Ad] Endereço:Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo, Chikusa, Nagoya 464-8602, Japan. taki@itbm.nagoya-u.ac.jp yamaguchi@chem.naogya-u.ac.jp.
[Ti] Título:A red-emitting ratiometric fluorescent probe based on a benzophosphole P-oxide scaffold for the detection of intracellular sodium ions.
[So] Source:Chem Commun (Camb);51(59):11880-3, 2015 Jul 28.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We disclose the development of a ratiometric fluorescent probe based on a benzophosphole P-oxide and its application for the detection of intracellular Na(+) ions. Excitation by visible light induced red emission from this probe in water, which was subjected to a hypsochromic shift upon complexation with Na(+). Based on this change, a ratiometric analysis enabled us to visualise changes in the Na(+) concentration in living mammalian cells.
[Mh] Termos MeSH primário: Óxidos P-Cíclicos/química
Corantes Fluorescentes/química
Óxidos/química
Sódio/análise
[Mh] Termos MeSH secundário: Óxidos P-Cíclicos/síntese química
Corantes Fluorescentes/síntese química
Células HeLa
Seres Humanos
Íons/análise
Estrutura Molecular
Óxidos/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclic P-Oxides); 0 (Fluorescent Dyes); 0 (Ions); 0 (Oxides); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150709
[Lr] Data última revisão:
150709
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150626
[St] Status:MEDLINE
[do] DOI:10.1039/c5cc03547c


  5 / 112 MEDLINE  
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[PMID]:25182647
[Au] Autor:Lam AM; Edwards TE; Mosley RT; Murakami E; Bansal S; Lugo C; Bao H; Otto MJ; Sofia MJ; Furman PA
[Ad] Endereço:Pharmasset, Inc., Princeton, New Jersey, USA alam@noviratherapeutics.com tedwards@be4.com.
[Ti] Título:Molecular and structural basis for the roles of hepatitis C virus polymerase NS5B amino acids 15, 223, and 321 in viral replication and drug resistance.
[So] Source:Antimicrob Agents Chemother;58(11):6861-9, 2014 Nov.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Resistance to the 2'-F-2'-C-methylguanosine monophosphate nucleotide hepatitis C virus (HCV) inhibitors PSI-352938 and PSI-353661 was associated with a combination of amino acid changes (changes of S to G at position 15 [S15G], C223H, and V321I) within the genotype 2a nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase. To understand the role of these residues in viral replication, we examined the effects of single and multiple point mutations on replication fitness and inhibition by a series of nucleotide analog inhibitors. An acidic residue at position 15 reduced replicon fitness, consistent with its proximity to the RNA template. A change of the residue at position 223 to an acidic or large residue reduced replicon fitness, consistent with its proposed proximity to the incoming nucleoside triphosphate (NTP). A change of the residue at position 321 to a charged residue was not tolerated, consistent with its position within a hydrophobic cavity. This triple resistance mutation was specific to both genotype 2a virus and 2'-F-2'-C-methylguanosine inhibitors. A crystal structure of the NS5B S15G/C223H/V321I mutant of the JFH-1 isolate exhibited rearrangement to a conformation potentially consistent with short primer-template RNA binding, which could suggest a mechanism of resistance accomplished through a change in the NS5B conformation, which was better tolerated by genotype 2a virus than by viruses of other genotypes.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
Hepacivirus/genética
Proteínas não Estruturais Virais/genética
Proteínas não Estruturais Virais/ultraestrutura
Replicação Viral/genética
[Mh] Termos MeSH secundário: Antivirais/farmacologia
Cristalografia por Raios X
Óxidos P-Cíclicos/farmacologia
Guanosina Monofosfato/análogos & derivados
Guanosina Monofosfato/farmacologia
Hepacivirus/efeitos dos fármacos
Hepacivirus/crescimento & desenvolvimento
Seres Humanos
Nucleosídeos/farmacologia
Estrutura Terciária de Proteína
RNA Viral/genética
Proteínas de Ligação a RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-((5-(2-amino-6-methoxypurin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy)phenoxyphosphorylamino)propionic acid isopropyl ester); 0 (Antiviral Agents); 0 (Cyclic P-Oxides); 0 (NS-5 protein, hepatitis C virus); 0 (Nucleosides); 0 (PSI 352938); 0 (RNA, Viral); 0 (RNA-Binding Proteins); 0 (Viral Nonstructural Proteins); 85-32-5 (Guanosine Monophosphate)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140904
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.03847-14


  6 / 112 MEDLINE  
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[PMID]:24510520
[Au] Autor:Bagi P; Fekete A; Kállay M; Hessz D; Kubinyi M; Holczbauer T; Czugler M; Fogassy E; Keglevich G
[Ad] Endereço:Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary.
[Ti] Título:Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide with TADDOL derivatives and calcium salts of O,O'-Dibenzoyl-(2R,3R)- or O,O'-di-p-toluoyl-(2R,3R)-tartaric acid.
[So] Source:Chirality;26(3):174-82, 2014 Mar.
[Is] ISSN:1520-636X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The resolution methods applying (-)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane ("TADDOL"), (-)-(2R,3R)-α,α,α',α'-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol ("spiro-TADDOL"), as well as the acidic and neutral Ca(2+) salts of (-)-O,O'-dibenzoyl- and (-)-O,O'-di-p-toluoyl-(2R,3R)-tartaric acid were extended for the preparation of 1-n-butyl-3-methyl-3-phospholene 1-oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single-crystal X-ray analysis. The absolute P-configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra.
[Mh] Termos MeSH primário: Cálcio/química
Óxidos P-Cíclicos/química
Óxidos P-Cíclicos/isolamento & purificação
Dioxolanos/química
Metanol/análogos & derivados
Compostos Organofosforados/química
Compostos Organofosforados/isolamento & purificação
Tartaratos/química
[Mh] Termos MeSH secundário: Óxidos P-Cíclicos/análise
Metanol/química
Modelos Moleculares
Conformação Molecular
Compostos Organofosforados/análise
Sais/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclic P-Oxides); 0 (Dioxolanes); 0 (Organophosphorus Compounds); 0 (Salts); 0 (Tartrates); 0 (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol); SY7Q814VUP (Calcium); W4888I119H (tartaric acid); Y4S76JWI15 (Methanol)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:140227
[Lr] Data última revisão:
140227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140211
[St] Status:MEDLINE
[do] DOI:10.1002/chir.22293


  7 / 112 MEDLINE  
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[PMID]:24464551
[Au] Autor:Guedj J; Pang PS; Denning J; Rodriguez-Torres M; Lawitz E; Symonds W; Perelson AS
[Ad] Endereço:INSERM UMR 738, University Paris Diderot, F-75018 Paris, France.
[Ti] Título:Analysis of hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938.
[So] Source:Antivir Ther;19(2):211-20, 2014.
[Is] ISSN:2040-2058
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sofosbuvir (GS-7977) and GS-0938 are nucleotide analogue HCV polymerase inhibitors, with sofosbuvir being a pyrimidine and GS-0938 being a purine. Mathematical modelling has provided important insights for characterizing HCV RNA decline and for estimating the in vivo effectiveness of single direct-acting antiviral agents (DAAs); however it has not been used to characterize viral kinetics with combination DAA therapy. METHODS: We evaluated the antiviral activity of sofosbuvir and GS-0938 given alone and in combination for 14 days in 32 HCV genotype 1 treatment-naive patients (P2938-0212; NUCLEAR study). RESULTS: Viral load declined rapidly in a biphasic manner in all subjects and could be well fitted by assuming that both drugs had a similar and additive level of effectiveness in reducing viral production equal to 99.96%, on average. The model predicted that this level of effectiveness was not reached until 0.6 and 2 days for GS-0938 and sofosbuvir, respectively, and likely represents the time needed to accumulate intracellular triphosphates. Subsequently, both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d(-1). No effect of IL28B-polymorphism was found on viral kinetic parameters. CONCLUSIONS: Both sofosbuvir and GS-0938 are highly effective at blocking viral production from HCV-infected cells. Both drugs led to a rapid and consistent second phase viral decline and exhibited no breakthroughs or other signs of resistance. From a kinetics perspective, because both drugs were of the same class there was little benefit in combining them, suggesting that future DAA combinations should consider utilizing drugs with different modes of action.
[Mh] Termos MeSH primário: Antivirais/uso terapêutico
Óxidos P-Cíclicos/uso terapêutico
Hepacivirus/efeitos dos fármacos
Hepatite C/tratamento farmacológico
Nucleosídeos/uso terapêutico
Uridina Monofosfato/análogos & derivados
[Mh] Termos MeSH secundário: Adulto
Método Duplo-Cego
Feminino
Genótipo
Hepacivirus/genética
Hepatite C/virologia
Seres Humanos
Masculino
Meia-Idade
RNA Viral
Sofosbuvir
Uridina Monofosfato/uso terapêutico
Carga Viral
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Cyclic P-Oxides); 0 (Nucleosides); 0 (PSI 352938); 0 (RNA, Viral); E2OU15WN0N (Uridine Monophosphate); WJ6CA3ZU8B (Sofosbuvir)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140128
[St] Status:MEDLINE
[do] DOI:10.3851/IMP2733


  8 / 112 MEDLINE  
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[PMID]:23369026
[Au] Autor:Han ZS; Goyal N; Herbage MA; Sieber JD; Qu B; Xu Y; Li Z; Reeves JT; Desrosiers JN; Ma S; Grinberg N; Lee H; Mangunuru HP; Zhang Y; Krishnamurthy D; Lu BZ; Song JJ; Wang G; Senanayake CH
[Ad] Endereço:Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, USA. steve.han@boehringer-ingelheim.com
[Ti] Título:Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents.
[So] Source:J Am Chem Soc;135(7):2474-7, 2013 Feb 20.
[Is] ISSN:1520-5126
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.
[Mh] Termos MeSH primário: Óxidos P-Cíclicos/síntese química
Fosfinas/síntese química
[Mh] Termos MeSH secundário: Óxidos P-Cíclicos/química
Ligantes
Estrutura Molecular
Fosfinas/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic P-Oxides); 0 (Ligands); 0 (Phosphines); FW6947296I (phosphine)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130202
[St] Status:MEDLINE
[do] DOI:10.1021/ja312352p


  9 / 112 MEDLINE  
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[PMID]:22526308
[Au] Autor:Niu C; Tolstykh T; Bao H; Park Y; Babusis D; Lam AM; Bansal S; Du J; Chang W; Reddy PG; Zhang HR; Woolley J; Wang LQ; Chao PB; Ray AS; Otto MJ; Sofia MJ; Furman PA; Murakami E
[Ad] Endereço:Pharmasset, Inc, Princeton, New Jersey, USA.
[Ti] Título:Metabolic activation of the anti-hepatitis C virus nucleotide prodrug PSI-352938.
[So] Source:Antimicrob Agents Chemother;56(7):3767-75, 2012 Jul.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PSI-352938 is a novel cyclic phosphate prodrug of ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-methylguanosine-5'-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During in vitro incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3',5'-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the O(6)-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5'-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically.
[Mh] Termos MeSH primário: Antivirais/metabolismo
Óxidos P-Cíclicos/metabolismo
Hepacivirus/efeitos dos fármacos
Nucleosídeos/metabolismo
[Mh] Termos MeSH secundário: Células Cultivadas
Citocromo P-450 CYP3A/metabolismo
Guanilato Quinases/metabolismo
Hepatócitos/metabolismo
Seres Humanos
Núcleosídeo-Difosfato Quinase/metabolismo
Diester Fosfórico Hidrolases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Cyclic P-Oxides); 0 (Nucleosides); 0 (PSI 352938); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.7.4.6 (Nucleoside-Diphosphate Kinase); EC 2.7.4.8 (Guanylate Kinases); EC 3.1.4.- (Phosphoric Diester Hydrolases)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120425
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00530-12


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[PMID]:22268526
[Au] Autor:Clarion L; Jacquard C; Sainte-Catherine O; Loiseau S; Filippini D; Hirlemann MH; Volle JN; Virieux D; Lecouvey M; Pirat JL; Bakalara N
[Ad] Endereço:INSERM U-1051, Institut des Neurosciences de Montpellier, 80 rue Augustin Fliche 34091 Montpellier, France.
[Ti] Título:Oxaphosphinanes: new therapeutic perspectives for glioblastoma.
[So] Source:J Med Chem;55(5):2196-211, 2012 Mar 08.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This paper reports the design and the synthesis of a new family of compounds, the phostines, belonging to the [1,2]oxaphosphinane family. Twenty-six compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its easy synthesis and low EC(50) value (500 nM against the C6 rat glioma cell line), compound 3.1a was selected for further biological study. Moreover, the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a has a higher antiproliferative activity than Temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Óxidos P-Cíclicos/síntese química
Organofosfonatos/síntese química
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Astrócitos/citologia
Astrócitos/efeitos dos fármacos
Neoplasias Encefálicas/tratamento farmacológico
Contagem de Células
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Óxidos P-Cíclicos/química
Óxidos P-Cíclicos/farmacologia
Ensaios de Seleção de Medicamentos Antitumorais
Glioblastoma/tratamento farmacológico
Seres Humanos
Organofosfonatos/química
Organofosfonatos/farmacologia
Ácidos Fosforosos
Ratos
Estereoisomerismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-hydroxy-4,5-bis(benzyloxy)-6-benzyloxymethyl-2-phenyl-2-oxo-2lambda(5)-(1,2)oxaphosphinane); 0 (Antineoplastic Agents); 0 (Cyclic P-Oxides); 0 (Organophosphonates); 0 (Phosphorous Acids)
[Em] Mês de entrada:1207
[Cu] Atualização por classe:121115
[Lr] Data última revisão:
121115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120125
[St] Status:MEDLINE
[do] DOI:10.1021/jm201428a



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