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[PMID]: 29318318 [Au] Autor: Vajs J; Pevec A; Gazvoda M; Urankar D; Goreshnik E; Polanc S; Kosmrlj J [Ti] Título: Synthesis and X-ray Structural Analysis of the Ruthenium(III) Complex Na[trans-RuCl4(DMSO) (PyrDiaz)], the Diazene Derivative of Antitumor NAMI-Pyr. [So] Source: Acta Chim Slov;64(4):763-770, 2017 Dec. [Is] ISSN: 1318-0207 [Cp] País de publicação: Slovenia [La] Idioma: eng [Ab] Resumo: Novel tetrachloridoruthenium(III) complex Na[trans-RuCl4(DMSO)(PyrDiaz)] (3) with pyridine-tethered diazenedicarboxamide PyrDiaz ligand (PyrDiaz = N1-(4-isopropylphenyl)-N2-(pyridin-2-ylmethyl)diazene-1,2-dicarboxamide) was synthesized by direct coupling of PyrDiaz with sodium trans-bis(dimethyl sulfoxide)tetrachloridoruthenate(III) (Na-[trans-Ru(DMSO)2Cl4]). Compound 3 is the analogue of the antimetastatic Ru(III) complex NAMI-A and NAMI-Pyr. Single crystal X. [Mh] Termos MeSH primário: Antineoplásicos/síntese química Dimetil Sulfóxido/análogos & derivados Compostos Organometálicos/química Rutênio/química [Mh] Termos MeSH secundário: Antineoplásicos/química Cristalografia por Raios X Dimetil Sulfóxido/química Imidas/síntese química Imidas/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Imides); 0 (Organometallic Compounds); 7UI0TKC3U5 (Ruthenium); LM321PYV3Y (diazene); YOW8V9698H (Dimethyl Sulfoxide) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180111 [St] Status: MEDLINE

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[PMID]: 29324345 [Au] Autor: Xu M; Wang Y; Yang F; Wu C; Wang Z; Ye B; Jiang X; Zhao Q; Li J; Liu Y; Zhang J; Tian G; He Y; Shen J; Jiang H [Ad] Endereço: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. [Ti] Título: Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect. [So] Source: Eur J Med Chem;145:74-85, 2018 Feb 10. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D , serotonin 5-HT and 5-HT receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D /5-HT /5-HT receptors, but also endowed with low to moderate activities on 5-HT , H , α , M receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine-induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development. [Mh] Termos MeSH primário: Antipsicóticos/farmacologia Catalepsia/tratamento farmacológico Imidas/farmacologia [Mh] Termos MeSH secundário: Animais Antipsicóticos/síntese química Antipsicóticos/química Catalepsia/induzido quimicamente Relação Dose-Resposta a Droga Seres Humanos Imidas/síntese química Imidas/química Locomoção/efeitos dos fármacos Masculino Camundongos Camundongos Endogâmicos ICR Estrutura Molecular Fenciclidina Ratos Ratos Sprague-Dawley Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antipsychotic Agents); 0 (Imides); J1DOI7UV76 (Phencyclidine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180112 [St] Status: MEDLINE

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[PMID]: 28931154 [Au] Autor: Xu M; Xu F; Wu X [Ad] Endereço: Co-Innovation Center for Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing, Jiangsu 210037, China. [Ti] Título: Differentially Expressed Proteins From the Peritrophic Membrane Related to the Lethal, Synergistic Mechanisms Observed in Hyphantria cunea Larvae Treated With a Mixture of Bt and Chlorbenzuron. [So] Source: J Insect Sci;17(2), 2017 Jan 01. [Is] ISSN: 1536-2442 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Hyphantria cunea (Drury) (Lepidoptera: Arctiidae) is an important forest insect pest around the world. It attacks a variety of broad-leaf trees. It has caused serious economic and ecological damage to its new habitats. A mixture of Bt and chlorbenzuron has a higher toxicity and faster killed than those of either agent alone to the 4th instar larvae of H. cunea both by the lab and field test results, and the toxic effect of the mixture treatment was significantly enhanced. Using proteomics technology, including SDS-PAGE and MALDI-TOF-TOF MS, we analyzed differentially expressed proteins of the peritrophic membrane (PM) of the 4th instar larvae of H. cunea, which were treated with the mixture. We identified 91 significantly differentially expressed proteins of the PM of the 4th instar larvae of H. cunea and those proteins were found to be involved in different metabolic pathways and processes. The energy-related and structural proteins made up the largest proportion of all of the identified proteins, and the mixture treatment of proteins was the small proportion of the identified structural proteins and energy-related proteins among the Bt, chlorbenzuron, and mixture treatments. Based on the proteomic data, we found that some proteins and their corresponding functions and pathways were related to the lethal mechanisms observed in 4th instar larvae of H. cunea when treated by the mixture. [Mh] Termos MeSH primário: Bacillus thuringiensis/química Imidas Controle de Insetos Inseticidas Mariposas Controle Biológico de Vetores Compostos de Fenilureia [Mh] Termos MeSH secundário: Animais Expressão Gênica Proteínas de Insetos/genética Proteínas de Insetos/metabolismo Larva/genética Larva/crescimento & desenvolvimento Larva/metabolismo Mariposas/genética Mariposas/crescimento & desenvolvimento Mariposas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Imides); 0 (Insect Proteins); 0 (Insecticides); 0 (Phenylurea Compounds); 0 (chlorbenzuron) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171025 [Lr] Data última revisão: 171025 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170921 [St] Status: MEDLINE [do] DOI: 10.1093/jisesa/iew126

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[PMID]: 28789908 [Au] Autor: Angeli A; Abdel-Aziz AA; Nocentini A; El-Azab AS; Gratteri P; Supuran CT [Ad] Endereço: Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. [Ti] Título: Synthesis and carbonic anhydrase inhibition of polycyclic imides incorporating N-benzenesulfonamide moieties. [So] Source: Bioorg Med Chem;25(20):5373-5379, 2017 Oct 15. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A series of polycyclic imides was prepared by reaction of the benzenesulfonamide with an appropriate polycyclic acid anhydride in refluxing glacial acetic acid. The synthesized mono- and bis-sulfonamides were evaluated as a carbonic anhydrase inhibitors (CA, EC 4.2.1.1), more precisely against the human (h) isoforms hCA I, II, IX and XII, some of which are involved in various pathologies, such as glaucoma, epilepsy and cancer. Several low nanomolar and isoform-selective hCA II, IX and XII inhibitors were detected, and the structure-activity relationship for CA inhibition with this class of compounds is discussed in details. Computational studies allowed us to explain the efficacy and isoform-selective behaviour for some of these enzyme inhiibtors. [Mh] Termos MeSH primário: Inibidores da Anidrase Carbônica/farmacologia Anidrases Carbônicas/metabolismo Imidas/farmacologia Sulfonamidas/farmacologia [Mh] Termos MeSH secundário: Inibidores da Anidrase Carbônica/síntese química Inibidores da Anidrase Carbônica/química Relação Dose-Resposta a Droga Seres Humanos Imidas/química Estrutura Molecular Relação Estrutura-Atividade Sulfonamidas/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carbonic Anhydrase Inhibitors); 0 (Imides); 0 (Sulfonamides); 98-10-2 (benzenesulfonamide); EC 4.2.1.1 (Carbonic Anhydrases) [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: 170810 [St] Status: MEDLINE

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[PMID]: 28472820 [Au] Autor: Coussy F; Lallemand F; Vacher S; Schnitzler A; Chemlali W; Caly M; Nicolas A; Richon S; Meseure D; El Botty R; De-Plater L; Fuhrmann L; Dubois T; Roman-Roman S; Dangles-Marie V; Marangoni E; Bièche I [Ad] Endereço: Unit of pharmacogenomics, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France. [Ti] Título: Clinical value of R-spondins in triple-negative and metaplastic breast cancers. [So] Source: Br J Cancer;116(12):1595-1603, 2017 Jun 06. [Is] ISSN: 1532-1827 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: RSPO ligands, activators of the Wnt/ß-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). METHODS: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/ß-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/ß-catenin pathway, was examined on the growth of an RSPO2-positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC. RESULTS: We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO, and amplification or hypomethylation of RSPO genes. Patients with RSPO2-overexpressing tumours have a poorer metastasis-free survival (P=3.6 × 10 ). RSPO2 and RSPO4 stimulate Wnt/ß-catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2-overexpressing PDX. CONCLUSIONS: RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC. [Mh] Termos MeSH primário: Carcinoma Ductal de Mama/genética Carcinoma Ductal de Mama/secundário Expressão Gênica RNA Mensageiro/análise Neoplasias de Mama Triplo Negativas/genética Neoplasias de Mama Triplo Negativas/patologia [Mh] Termos MeSH secundário: Animais Antineoplásicos/uso terapêutico Carcinoma Ductal de Mama/química Carcinoma Ductal de Mama/tratamento farmacológico Proliferação Celular Meios de Cultivo Condicionados/farmacologia Feminino Expressão Gênica/efeitos dos fármacos Células HEK293 Seres Humanos Imidas/uso terapêutico Peptídeos e Proteínas de Sinalização Intercelular/análise Peptídeos e Proteínas de Sinalização Intercelular/genética Peptídeos e Proteínas de Sinalização Intercelular/metabolismo Metaplasia/genética Metaplasia/patologia Camundongos Nus Transplante de Neoplasias Quinolinas/uso terapêutico RNA Interferente Pequeno/genética Receptores Acoplados a Proteínas-G/genética Proteína de Ligação a TATA-Box/genética Trombospondinas/genética Trombospondinas/metabolismo Neoplasias de Mama Triplo Negativas/química Neoplasias de Mama Triplo Negativas/tratamento farmacológico Via de Sinalização Wnt Proteína Wnt3A/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Culture Media, Conditioned); 0 (IWR-1 compound); 0 (Imides); 0 (Intercellular Signaling Peptides and Proteins); 0 (LGR4 protein, human); 0 (LGR5 protein, human); 0 (LGR6 protein, human); 0 (Quinolines); 0 (R-spondin2 protein, human); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (RSPO1 protein, human); 0 (RSPO3 protein, human); 0 (RSPO4 protein, human); 0 (Receptors, G-Protein-Coupled); 0 (TATA-Box Binding Protein); 0 (TBP protein, human); 0 (Thrombospondins); 0 (WNT3A protein, human); 0 (Wnt3A Protein) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170822 [Lr] Data última revisão: 170822 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1038/bjc.2017.131

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[PMID]: 28318946 [Au] Autor: Tirapegui C; Acevedo-Fuentes W; Dahech P; Torrent C; Barrias P; Rojas-Poblete M; Mascayano C [Ad] Endereço: Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile; Facultad de Química y Biología, Universidad de Santiago de Chile, Casilla 40, correo 33, Santiago, Chile. Electronic address: cristian.tirapeguic@usach.cl. [Ti] Título: Easy and rapid preparation of benzoylhydrazides and their diazene derivatives as inhibitors of 15-lipoxygenase. [So] Source: Bioorg Med Chem Lett;27(8):1649-1653, 2017 04 15. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Two series of diaza derivatives were prepared by solvent-free condensation of benzoic acid and 4-substituted phenylhydrazines in order to obtain phenylhydrazides (HYD series) and, by oxidation of these compounds, the corresponding benzoyldiazenes (DIA series). Both sets were evaluated as inhibitors of soybean 15-lipoxygenase activity and antioxidant capability in the FRAP and CUPRAC assays. The most potent inhibitors of both series exhibited IC values in the low micromolar range. Kinetic studies showed that at least the more active compounds were competitive inhibitors. Docking results indicated that the most potent inhibitor interacts strongly with Ile-839 and iron in the active site. [Mh] Termos MeSH primário: Antioxidantes/química Araquidonato 15-Lipoxigenase/metabolismo Benzoatos/química Hidrazinas/química Imidas/química Inibidores de Lipoxigenase/química [Mh] Termos MeSH secundário: Antioxidantes/síntese química Antioxidantes/farmacologia Benzoatos/síntese química Benzoatos/farmacologia Técnicas de Química Sintética/economia Técnicas de Química Sintética/métodos Seres Humanos Hidrazinas/síntese química Hidrazinas/farmacologia Imidas/síntese química Imidas/farmacologia Inibidores de Lipoxigenase/síntese química Inibidores de Lipoxigenase/farmacologia Simulação de Acoplamento Molecular Oxirredução Feijão de Soja/efeitos dos fármacos Feijão de Soja/enzimologia Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antioxidants); 0 (Benzoates); 0 (Hydrazines); 0 (Imides); 0 (Lipoxygenase Inhibitors); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase); LM321PYV3Y (diazene) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171125 [Lr] Data última revisão: 171125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170321 [St] Status: MEDLINE

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[PMID]: 28221711 [Au] Autor: Morioka T; Nakano K; Tominaga Y [Ad] Endereço: Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan. [Ti] Título: Ion-Conductive Properties of a Polymer Electrolyte Based on Ethylene Carbonate/Ethylene Oxide Random Copolymer. [So] Source: Macromol Rapid Commun;38(8), 2017 Apr. [Is] ISSN: 1521-3927 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: A random copolymer of ethylene oxide with CO , namely, poly(ethylene carbonate/ethylene oxide) (P(EC/EO)), has been synthesized as a novel candidate for polymer electrolytes. Electrolyte composed of P(EC/EO) and lithium bis(fluorosulfonyl)imide has an ionic conductivity of 0.48 mS cm and a Li transference number (t ) of 0.66 at 60 °C. To study ion-conductive behavior of P(EC/EO)-based electrolytes, the Fourier transform infrared (FT-IR) technique is used to analyze the interactions between Li and functional groups of the copolymer. The carbonate groups may interact preferentially with Li rather than the ether groups in P(EC/EO). This study suggests that copolymerization of carbonate and flexible ether units can realize both high conductivity and t for polymer electrolytes. High-performance P(EC/EO) electrolyte is expected to be a candidate material for use in all-solid-state batteries. [Mh] Termos MeSH primário: Eletrólitos/química Polietilenoglicóis/química Polietilenos/química Polímeros/química [Mh] Termos MeSH secundário: Carbonatos/química Condutividade Elétrica Imidas/química Íons/química Lítio/química Estrutura Molecular Peso Molecular Compostos Orgânicos/química Espectroscopia de Infravermelho com Transformada de Fourier Temperatura Ambiente [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carbonates); 0 (Electrolytes); 0 (Imides); 0 (Ions); 0 (Organic Chemicals); 0 (Polyethylenes); 0 (Polymers); 25718-55-2 (polyethylene carbonate); 30IQX730WE (Polyethylene Glycols); 9FN79X2M3F (Lithium) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170601 [Lr] Data última revisão: 170601 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170222 [St] Status: MEDLINE [do] DOI: 10.1002/marc.201600652

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[PMID]: 28187297 [Au] Autor: Hu R; Zhang X; Xu Q; Lu DQ; Yang YH; Xu QQ; Ruan Q; Mo LT; Zhang XB [Ad] Endereço: College of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650092, Yunnan, PR China. Electronic address: hudierong_168@163.com. [Ti] Título: A universal aptameric biosensor: Multiplexed detection of small analytes via aggregated perylene-based broad-spectrum quencher. [So] Source: Biosens Bioelectron;92:40-46, 2017 Jun 15. [Is] ISSN: 1873-4235 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A universal aptameric system based on the taking advantage of double-stranded DNA/perylene diimide (dsDNA/PDI) as the signal probe was developed for multiplexed detection of small molecules. Aptamers are single-stranded DNA or RNA oligonucleotides which are selected in vitro by a process known as systematic evolution of ligands by exponential enrichment. In this work, we synthesized a new kind of PDI and reported this aggregated PDI could quench the double-stranded DNA (dsDNA)-labeled fluorophores with a high quenching efficiency. The quenching efficiencies on the fluorescence of FAM, TAMRA and Cy5 could reach to 98.3%±0.9%, 97.2%±0.6% and 98.1%±1.1%, respectively. This broad-spectrum quencher was then adopted to construct a multicolor biosensor via a label-free approach. A structure-switching-triggered enzymatic recycling amplification was employed for signal amplification. High quenching efficiency combined with autocatalytic target recycling amplification afforded the biosensor with high sensitivity towards small analytes. For other targets, changing the corresponding aptamer can achieve the goal. The quencher did not interfere with the catalytic activity of nuclease. The biosensor could be manipulated with similar sensitivity no matter in pre-addition or post-addition manner. Moreover, simultaneous and multiplexed analysis of several small molecules in homogeneous solution was achieved, demonstrating its potential application in the rapid screening of multiple biotargets. [Mh] Termos MeSH primário: Adenosina/análise Aptâmeros de Nucleotídeos/química Técnicas Biossensoriais/métodos Cocaína/análise Inibidores da Captação de Dopamina/análise Corantes Fluorescentes/química Imidas/química Perileno/análogos & derivados [Mh] Termos MeSH secundário: Adenosina/sangue Carbocianinas/química Cocaína/sangue Inibidores da Captação de Dopamina/sangue Seres Humanos Limite de Detecção Perileno/química Espectrometria de Fluorescência/métodos [Pt] Tipo de publicação: EVALUATION STUDIES; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Aptamers, Nucleotide); 0 (Carbocyanines); 0 (Dopamine Uptake Inhibitors); 0 (Fluorescent Dyes); 0 (Imides); 0 (cyanine dye 5); 0 (perylenediimide); 5QD5427UN7 (Perylene); I5Y540LHVR (Cocaine); K72T3FS567 (Adenosine) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170328 [Lr] Data última revisão: 170328 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170211 [St] Status: MEDLINE

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[PMID]: 28179481 [Au] Autor: Tanaka N; Mashima T; Mizutani A; Sato A; Aoyama A; Gong B; Yoshida H; Muramatsu Y; Nakata K; Matsuura M; Katayama R; Nagayama S; Fujita N; Sugimoto Y; Seimiya H [Ad] Endereço: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. [Ti] Título: Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer. [So] Source: Mol Cancer Ther;16(4):752-762, 2017 Apr. [Is] ISSN: 1538-8514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In most colorectal cancers, Wnt/ß-catenin signaling is activated by loss-of-function mutations in the ( ) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of ß-catenin, and upregulate ß-catenin signaling. Tankyrase inhibitors downregulate ß-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated ß-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven ß-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased ß-catenin, Tcf/LEF transcriptional activity and its target gene expression. Under these conditions, tankyrase inhibitors were able to downregulate ß-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent ß-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. . [Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo/genética Biomarcadores Tumorais/genética Neoplasias Colorretais/genética Inibidores Enzimáticos/farmacologia Tanquirases/antagonistas & inibidores Via de Sinalização Wnt/efeitos dos fármacos [Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/metabolismo Sítios de Ligação Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Neoplasias Colorretais/tratamento farmacológico Neoplasias Colorretais/enzimologia Células HCT116 Células HT29 Compostos Heterocíclicos com 3 Anéis/farmacologia Seres Humanos Imidas/farmacologia Ligação Proteica Quinolinas/farmacologia Sulfonas/farmacologia Triazóis/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein); 0 (Biomarkers, Tumor); 0 (Enzyme Inhibitors); 0 (G007-LK); 0 (Heterocyclic Compounds, 3-Ring); 0 (IWR-1 compound); 0 (Imides); 0 (Quinolines); 0 (Sulfones); 0 (Triazoles); 0 (XAV939); EC 2.4.2.30 (Tankyrases) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170801 [Lr] Data última revisão: 170801 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170210 [St] Status: MEDLINE [do] DOI: 10.1158/1535-7163.MCT-16-0578

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[PMID]: 28161252 [Au] Autor: Abdel-Aziz AA; Angeli A; El-Azab AS; Abu El-Enin MA; Supuran CT [Ad] Endereço: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, [Ti] Título: Synthesis and biological evaluation of cyclic imides incorporating benzenesulfonamide moieties as carbonic anhydrase I, II, IV and IX inhibitors. [So] Source: Bioorg Med Chem;25(5):1666-1671, 2017 Mar 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A group of cyclic imides was synthesized by reaction of amino-substituted benzenesulfonamides with a series of acid anhydrides such as succinic, maleic, tetrahydrophthalic, pyrazine-2,3-dicarboxylic acid anhydride, and substituted phthalic anhydrides. The synthesized sulfonamides were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV and IX, involved in a variety of diseases among which glaucoma, retinitis pigmentosa, etc. Some of these sulfonamides showed effective inhibitory action (in the nanomolar range) against the cytosolic isoform hCA II and the transmembrane, tumor-associated one hCA IX, making them interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. hCA I and IV were on the other hand less inhibited by these sulfonamides, with inhibition constants in the micromolar range. [Mh] Termos MeSH primário: Inibidores da Anidrase Carbônica/síntese química Inibidores da Anidrase Carbônica/farmacologia Imidas/síntese química Imidas/farmacologia Sulfonamidas/química [Mh] Termos MeSH secundário: Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 Inibidores da Anidrase Carbônica/química Seres Humanos Imidas/química Espectroscopia de Prótons por Ressonância Magnética Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carbonic Anhydrase Inhibitors); 0 (Imides); 0 (Sulfonamides); 98-10-2 (benzenesulfonamide) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170808 [Lr] Data última revisão: 170808 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170206 [St] Status: MEDLINE

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