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[PMID]:28637373
[Au] Autor:Phillips RM; Hendriks HR; Sweeney JB; Reddy G; Peters GJ
[Ad] Endereço:a Department of Pharmacy , University of Huddersfield , Huddersfield , UK.
[Ti] Título:Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer.
[So] Source:Expert Opin Drug Metab Toxicol;13(7):783-791, 2017 Jul.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Apaziquone (also known as EO9 and Qapzola ) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Aziridinas/administração & dosagem
Indolquinonas/administração & dosagem
Neoplasias da Bexiga Urinária/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Intravesical
Animais
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Aziridinas/farmacocinética
Aziridinas/farmacologia
Seres Humanos
Indolquinonas/farmacocinética
Indolquinonas/farmacologia
Invasividade Neoplásica
Recidiva Local de Neoplasia
Neoplasias da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Aziridines); 0 (Indolequinones); H464ZO600O (apaziquone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1341490


  2 / 2448 MEDLINE  
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[PMID]:28621541
[Au] Autor:McGregor LM; Jenkins ML; Kerwin C; Burke JE; Shokat KM
[Ad] Endereço:Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco , San Francisco, California 94158, United States.
[Ti] Título:Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes.
[So] Source:Biochemistry;56(25):3178-3183, 2017 Jun 27.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation.
[Mh] Termos MeSH primário: Aziridinas/farmacologia
Ácidos Carboxílicos/metabolismo
Oncogenes
Proteínas Proto-Oncogênicas p21(ras)/química
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
Compostos de Sulfidrila/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aziridines); 0 (Carboxylic Acids); 0 (KRAS protein, human); 0 (Sulfhydryl Compounds); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00271


  3 / 2448 MEDLINE  
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[PMID]:28538738
[Au] Autor:Chung BKW; White CJ; Yudin AK
[Ad] Endereço:NuChem Therapeutics, Montréal, Québec, Canada.
[Ti] Título:Solid-phase synthesis, cyclization, and site-specific functionalization of aziridine-containing tetrapeptides.
[So] Source:Nat Protoc;12(6):1277-1287, 2017 Jun.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cyclic tetrapeptides comprise a potent and selective class of molecules with a wide range of biological activities, including the phytotoxic activity of tentoxin and the histone deacetylase (HDAC) inhibitory effects of chlamydocin. The incorporation of a functional aziridine group within cyclic peptides enables their conformational control and allows for late-stage and site-selective functionalization of these molecules, thereby creating the potential for covalent protein labeling. This protocol describes the solid-phase synthesis, cyclization, and site-specific structural modification of aziridine-containing tetrapeptides. The linear precursors are assembled by solid-phase peptide synthesis using Fmoc-protected amino acid building blocks, followed by head-to-tail peptide cyclization. Cyclization is performed using a slow reverse-addition method that prevents the formation of undesired higher-order cyclo-oligomeric side products. Site-specific structural modification of the resulting macrocycles is described using sodium azide or thiophenol as representative examples. It requires ∼4 d to prepare peptide macrocycles from their respective Fmoc-protected amino acid starting materials, an improvement upon the 3 weeks required for conventional solution-phase methods. This protocol also addresses important considerations regarding the handling of these compounds, whose electrophilic aziridine functionalities can otherwise be prone to undesired side reactions. With recent developments in aziridine-containing macrocyclic peptide synthesis and the potential for covalent protein labeling, these scaffolds represent a valuable addition to many screening libraries, and we expect that access to these macrocycles will facilitate efforts in drug discovery and molecular probe development.
[Mh] Termos MeSH primário: Aziridinas/química
Aziridinas/síntese química
Peptídeos Cíclicos/química
Peptídeos Cíclicos/síntese química
Técnicas de Síntese em Fase Sólida/métodos
[Mh] Termos MeSH secundário: Ciclização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aziridines); 0 (Peptides, Cyclic); 54P5FEX9FH (aziridine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.035


  4 / 2448 MEDLINE  
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[PMID]:28398740
[Au] Autor:Tyler AR; Mosaei H; Morton S; Waddell PG; Wills C; McFarlane W; Gray J; Goodfellow M; Errington J; Allenby N; Zenkin N; Hall MJ
[Ti] Título:Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1, and MBJ-0035.
[So] Source:J Nat Prod;80(5):1558-1562, 2017 May 26.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The madurastatins are pentapeptide siderophores originally described as containing an unusual salicylate-capped N-terminal aziridine ring. Isolation of madurastatin C1 (1) (also designated MBJ-0034), from Actinomadura sp. DEM31376 (itself isolated from a deep sea sediment), prompted structural reevaluation of the madurastatin siderophores, in line with the recent work of Thorson and Shaaban. NMR spectroscopy in combination with partial synthesis allowed confirmation of the structure of madurastatin C1 (1) as containing an N-terminal 2-(2-hydroxyphenyl)oxazoline in place of the originally postulated aziridine, while absolute stereochemistry was determined via Harada's advanced Marfey's method. Therefore, this work further supports Thorson and Shaaban's proposed structural revision of the madurastatin class of siderophores (madurastatins A1 (2), B1 (3), C1 (1), and MBJ-0036 (4)) as N-terminal 2-(2-hydroxyphenyl)oxazolines.
[Mh] Termos MeSH primário: Aziridinas/química
Oligopeptídeos/química
Peptídeos/química
Piperidonas/química
Sideróforos/química
[Mh] Termos MeSH secundário: Espectroscopia de Ressonância Magnética
Estrutura Molecular
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aziridines); 0 (MBJ-0034); 0 (MBJ-0035); 0 (Oligopeptides); 0 (Peptides); 0 (Piperidones); 0 (Siderophores); 0 (madurastatin A1); 0 (madurastatin B1); 0 (madurastatin C1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.7b00082


  5 / 2448 MEDLINE  
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[PMID]:28183972
[Au] Autor:Lin S; Yang X; Jia S; Weeks AM; Hornsby M; Lee PS; Nichiporuk RV; Iavarone AT; Wells JA; Toste FD; Chang CJ
[Ad] Endereço:Department of Chemistry, University of California, Berkeley, CA, USA.
[Ti] Título:Redox-based reagents for chemoselective methionine bioconjugation.
[So] Source:Science;355(6325):597-602, 2017 02 10.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.
[Mh] Termos MeSH primário: Aziridinas/química
Cisteína/química
Imunoconjugados/química
Metionina/química
[Mh] Termos MeSH secundário: Actinas/química
Edição de Genes
Técnicas de Inativação de Genes
Metionina/análise
Mutação
Oxirredução
Fosfopiruvato Hidratase/genética
Domínios Proteicos
Proteínas/química
Proteômica/métodos
Saccharomyces cerevisiae/efeitos dos fármacos
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/crescimento & desenvolvimento
Proteínas de Saccharomyces cerevisiae/genética
Hipoclorito de Sódio/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Actins); 0 (Aziridines); 0 (Immunoconjugates); 0 (Proteins); 0 (Saccharomyces cerevisiae Proteins); AE28F7PNPL (Methionine); DY38VHM5OD (Sodium Hypochlorite); EC 4.2.1.11 (ENO1 protein, S cerevisiae); EC 4.2.1.11 (Phosphopyruvate Hydratase); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1126/science.aal3316


  6 / 2448 MEDLINE  
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[PMID]:28114804
[Au] Autor:Zhu SJ; Xu SC; Zhao ZD
[Ad] Endereço:a Institute of Chemical Industry of Forest Products , CAF , Nanjing , China.
[Ti] Título:An efficient synthesis method targeted to a novel aziridine derivative of p-menthane from turpentine and its herbicidal activity.
[So] Source:Nat Prod Res;31(13):1536-1543, 2017 Jul.
[Is] ISSN:1478-6427
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel aziridine compound N-acetyl-1,2-azacyclo-p-menthane d was synthesised using turpentine as raw material and characterised by FT-IR, H NMR, C NMR, ESI -MS and HRMS. The pre-emergence herbicidal activities of d and its synthetic intermediates cis- and trans-N,N'-diacetyl-p-menthane-1,8-diamine (b2 and b1) were determined. The result showed that d exhibited much higher herbicidal activities against annual ryegrass, Digitaria sanguinalis and Ixeris denticulate than b2 and b1. The IC of d against the root and shoot growth of these three plants were lower than 1 mmol L . In contrast, the IC of b1 and b2 against the root and shoot growth of these plants were more than 10 mmol L .
[Mh] Termos MeSH primário: Aziridinas/síntese química
Aziridinas/farmacologia
Herbicidas/síntese química
Terebintina/química
[Mh] Termos MeSH secundário: Herbicidas/química
Herbicidas/farmacologia
Mentol/análogos & derivados
Mentol/química
Plantas/efeitos dos fármacos
Espectroscopia de Infravermelho com Transformada de Fourier
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aziridines); 0 (Herbicides); 1490-04-6 (Menthol); 54P5FEX9FH (aziridine); 8006-64-2 (Turpentine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1080/14786419.2017.1280494


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[PMID]:27984182
[Au] Autor:Smith BJ; Côté PD; Tremblay F
[Ad] Endereço:Department of Biology, Dalhousie University, 1355 Oxford St., PO Box 15000, Halifax, NS B3H 4R2, Canada. Electronic address: BN948751@dal.ca.
[Ti] Título:Contribution of Na 1.8 sodium channels to retinal function.
[So] Source:Neuroscience;340:279-290, 2017 Jan 06.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We examined the contribution of the sodium channel isoform Na 1.8 to retinal function using the specific blocker A803467. We found that A803467 has little influence on the electroretinogram (ERG) a- and b-waves, but significantly reduces the oscillatory potentials (OPs) to 40-60% of their original amplitude, with significant changes in implicit time in the rod-driven range. To date, only two cell types were found in mouse to express Na 1.8; the starburst amacrine cells (SBACs), and a subtype of retinal ganglion cells (RGCs). When we recorded light responses from ganglion cells using a multielectrode array we found significant and opposing changes in two physiological groups of RGCs. ON-sustained cells showed significant decreases while transient ON-OFF cells showed significant increases. The effects on ON-OFF transient cells but not ON-sustained cells disappeared in the presence of an inhibitory cocktail. We have previously shown that RGCs have only a minor contribution to the OPs (Smith et al., 2014), therefore suggesting that SBACs might be a significant contributor to this ERG component. Targeting SBACs with the cholinergic neurotoxin ethylcholine mustard aziridinium (AF64A) caused a reduction in the amplitude of the OPs similar to A803467. Our results, both using the ERG and MEA recordings from RGCs, suggest that Na 1.8 plays a role in modulating specific aspects of the retinal physiology and that SBACs are a fundamental cellular contributor to the OPs in mice, a clear demonstration of the dichotomy between ERG b-wave and OPs.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo
Retina/metabolismo
Visão Ocular/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Potenciais de Ação/fisiologia
Compostos de Anilina/farmacologia
Animais
Aziridinas/farmacologia
Colina/análogos & derivados
Colina/farmacologia
Antagonistas Colinérgicos/farmacologia
Eletrorretinografia
Furanos/farmacologia
Glicinérgicos/farmacologia
Camundongos Endogâmicos C57BL
Microeletrodos
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Periodicidade
Estimulação Luminosa
Retina/efeitos dos fármacos
Bloqueadores dos Canais de Sódio/farmacologia
Estricnina/farmacologia
Técnicas de Cultura de Tecidos
Visão Ocular/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (A 803467); 0 (Aniline Compounds); 0 (Aziridines); 0 (Cholinergic Antagonists); 0 (Furans); 0 (Glycine Agents); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (Scn10a protein, mouse); 0 (Sodium Channel Blockers); A668M9E227 (ethylcholine aziridinium); H9Y79VD43J (Strychnine); N91BDP6H0X (Choline)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE


  8 / 2448 MEDLINE  
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[PMID]:27871887
[Au] Autor:Cha Y; Lee SH; Jang SK; Guo H; Ban YH; Park D; Jang GY; Yeon S; Lee JY; Choi EK; Joo SS; Jeong HS; Kim YB
[Ad] Endereço:College of Veterinary Medicine, Veterinary Medical Center, Chungbuk National University, Cheongju, Republic of Korea.
[Ti] Título:A silk peptide fraction restores cognitive function in AF64A-induced Alzheimer disease model rats by increasing expression of choline acetyltransferase gene.
[So] Source:Toxicol Appl Pharmacol;314:48-54, 2017 Jan 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This study investigated the effects of a silk peptide fraction obtained by incubating silk proteins with Protease N and Neutrase (SP-NN) on cognitive dysfunction of Alzheimer disease model rats. In order to elucidate underlying mechanisms, the effect of SP-NN on the expression of choline acetyltransferase (ChAT) mRNA was assessed in F3.ChAT neural stem cells and Neuro2a neuroblastoma cells; active amino acid sequence was identified using HPLC-MS. The expression of ChAT mRNA in F3.ChAT cells increased by 3.79-fold of the control level by treatment with SP-NN fraction. The active peptide in SP-NN was identified as tyrosine-glycine with 238.1 of molecular weight. Male rats were orally administered with SP-NN (50 or 300mg/kg) and challenged with a cholinotoxin AF64A. As a result of brain injury and decreased brain acetylcholine level, AF64A induced astrocytic activation, resulting in impairment of learning and memory function. Treatment with SP-NN exerted recovering activities on acetylcholine depletion and brain injury, as well as cognitive deficit induced by AF64A. The results indicate that, in addition to a neuroprotective activity, the SP-NN preparation restores cognitive function of Alzheimer disease model rats by increasing the release of acetylcholine.
[Mh] Termos MeSH primário: Doença de Alzheimer/psicologia
Aziridinas/toxicidade
Colina O-Acetiltransferase/genética
Colina/análogos & derivados
Cognição/efeitos dos fármacos
Modelos Animais de Doenças
Proteínas de Insetos/química
Fragmentos de Peptídeos/farmacologia
Seda/química
[Mh] Termos MeSH secundário: Doença de Alzheimer/induzido quimicamente
Animais
Aprendizagem da Esquiva/efeitos dos fármacos
Linhagem Celular Tumoral
Colina/toxicidade
Regulação Enzimológica da Expressão Gênica
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aziridines); 0 (Insect Proteins); 0 (Peptide Fragments); 0 (Silk); A668M9E227 (ethylcholine aziridinium); EC 2.3.1.6 (Choline O-Acetyltransferase); N91BDP6H0X (Choline)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE


  9 / 2448 MEDLINE  
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[PMID]:27840931
[Au] Autor:Teng G; Ju Y; Yang Y; Hua H; Chi J; Mu X
[Ad] Endereço:Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, Shandong 250021, P.R. China.
[Ti] Título:Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro.
[So] Source:Mol Med Rep;14(6):5164-5170, 2016 Dec.
[Is] ISSN:1791-3004
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ­rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ­rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ­rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ­ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Aziridinas/farmacologia
Raios gama
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos da radiação
Genes Transgênicos Suicidas
Nitrorredutases/genética
Pró-Fármacos
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Apoptose/genética
Apoptose/efeitos da radiação
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Proliferação Celular/efeitos da radiação
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Sobrevivência Celular/efeitos da radiação
Expressão Gênica
Vetores Genéticos/genética
Células HeLa
Seres Humanos
Nitrorredutases/metabolismo
Tolerância a Radiação/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Aziridines); 0 (Prodrugs); 7865D5D01M (tretazicar); EC 1.7.- (Nitroreductases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170407
[Lr] Data última revisão:
170407
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161115
[St] Status:MEDLINE
[do] DOI:10.3892/mmr.2016.5917


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[PMID]:27826850
[Au] Autor:Tomkuviene M; Kriukiene E; Klimasauskas S
[Ad] Endereço:Institute of Biotechnology, Vilnius University, Vilnius, LT-10222, Lithuania.
[Ti] Título:DNA Labeling Using DNA Methyltransferases.
[So] Source:Adv Exp Med Biol;945:511-535, 2016.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA methyltransferases (MTases) uniquely combine the ability to recognize and covalently modify specific target sequences in DNA using the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet). Although DNA methylation plays important roles in biological signaling, the transferred methyl group is a poor reporter and is highly inert to further biocompatible derivatization. To unlock the biotechnological power of these enzymes, two major types of cofactor AdoMet analogs were developed that permit targeted MTase-directed attachment of larger moieties containing functional or reporter groups onto DNA. One such approach (named sequence-specific methyltransferase-induced labeling, SMILing) uses reactive aziridine or N-mustard mimics of the cofactor AdoMet, which render targeted coupling of a whole cofactor molecule to the target DNA. The second approach (methyltransferase-directed transfer of activated groups, mTAG) uses AdoMet analogs with a sulfonium-bound extended side chain replacing the methyl group, which permits MTase-directed covalent transfer of the activated side chain alone. As the enlarged cofactors are not always compatible with the active sites of native MTases, steric engineering of the active site has been employed to optimize their alkyltransferase activity. In addition to the described cofactor analogs, recently discovered atypical reactions of DNA cytosine-5 MTases involving non-cofactor-like compounds can also be exploited for targeted derivatization and labeling of DNA. Altogether, these approaches offer new powerful tools for sequence-specific covalent DNA labeling, which not only pave the way to developing a variety of useful techniques in DNA research, diagnostics, and nanotechnologies but have already proven practical utility for optical DNA mapping and epigenome studies.
[Mh] Termos MeSH primário: Metilação de DNA/genética
Metilases de Modificação do DNA/isolamento & purificação
DNA/isolamento & purificação
Coloração e Rotulagem/métodos
[Mh] Termos MeSH secundário: Aziridinas/química
DNA/química
DNA/genética
Metilases de Modificação do DNA/química
Metilases de Modificação do DNA/genética
Epigenômica
Seres Humanos
S-Adenosilmetionina/química
S-Adenosilmetionina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Aziridines); 54P5FEX9FH (aziridine); 7LP2MPO46S (S-Adenosylmethionine); 9007-49-2 (DNA); EC 2.1.1.- (DNA Modification Methylases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161110
[St] Status:MEDLINE



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