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[PMID]: 28454775 [Au] Autor: Eggert F; Kulikov K; Domnick C; Leifels P; Kath-Schorr S [Ad] Endereço: LIMES Institute, Chemical Biology & Medicinal Chemistry Unit, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany. [Ti] Título: Iluminated by foreign letters - Strategies for site-specific cyclopropene modification of large functional RNAs via in vitro transcription. [So] Source: Methods;120:17-27, 2017 May 01. [Is] ISSN: 1095-9130 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The synthesis of sequence-specifically modified long RNA molecules, which cannot entirely be prepared via solid phase synthesis methods is experimentally challenging. We are using a new approach based on an expanded genetic alphabet preparing site-specifically modified RNA molecules via standard in vitro transcription. In this report, the site-specific labeling of functional RNAs, in particular ribozymes and a long non-coding RNA with cyclopropene moieties, is presented. We provide detailed instructions for RNA labeling via in vitro transcription and include required analytical methods to verify production and identity of the transcript. We further present post-transcriptional inverse electron demand Diels-Alder cycloaddition reactions on the cyclopropene-modified sequences and discuss applications of the genetic alphabet expansion transcription for in vitro preparation of labeled functional RNAs with complex foldings. In detail, the glmS and CPEB3 ribozymes were site-specifically decorated with methyl cyclopropene moieties using the unnatural TPT3 triphosphate and were proven to be still functional. In addition, the structurally complex A region of the Xist lncRNA (401nt) was site-specifically modified with methyl cyclopropene and detected by fluorescence after cycloaddition reaction with a tetrazine-BODIPY conjugate. [Mh] Termos MeSH primário: Reação de Cicloadição/métodos Ciclopropanos/química RNA Catalítico/química RNA Longo não Codificante/química Coloração e Rotulagem/métodos [Mh] Termos MeSH secundário: Elétrons Corantes Fluorescentes/química Técnicas In Vitro/métodos Nucleotídeos/química Processamento Pós-Transcricional do RNA Transcrição Genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclopropanes); 0 (Fluorescent Dyes); 0 (Nucleotides); 0 (RNA, Catalytic); 0 (RNA, Long Noncoding); J6UJO23JGU (1-methylcyclopropene) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 29311461 [Au] Autor: Nambu H [Ad] Endereço: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama. [Ti] Título: [Novel Methods for the Synthesis of Heterocycles Using Highly Reactive Spirocyclopropanes]. [So] Source: Yakugaku Zasshi;138(1):19-25, 2018. [Is] ISSN: 1347-5231 [Cp] País de publicação: Japan [La] Idioma: jpn [Ab] Resumo: This review describes our recent efforts to develop efficient methods for the synthesis of heterocyclic compounds, such as indoles and benzofurans, employing ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes, which were prepared by the reaction of 1,3-cyclohexanediones with sulfonium salts. Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines proceeded at room temperature to provide 2-substituted tetrahydroindol-4(5H)-ones in good to excellent yield. The obtained product was readily converted into a 2-substituted 4-hydroxyindole derivative. Furthermore, acid-catalyzed ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes proceeded smoothly at room temperature to provide 2-substituted tetrahydrobenzofuran-4(2H)-ones in excellent yield. The obtained product was converted into a 2-substituted 4-hydroxybenzofuran derivative. The synthetic utility of this catalytic protocol was demonstrated by the total synthesis of cuspidan B. [Mh] Termos MeSH primário: Química Orgânica/métodos Compostos Heterocíclicos/síntese química [Mh] Termos MeSH secundário: Aminas/química Benzofuranos/síntese química Catálise Ciclização Cicloexanos/síntese química Cicloexanonas/química Ciclopropanos/síntese química Indóis/síntese química Fenômenos de Química Orgânica Alimentos de Soja Estilbenos/síntese química Compostos de Sulfônio/química [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Amines); 0 (Benzofurans); 0 (Cyclohexanes); 0 (Cyclohexanones); 0 (Cyclopropanes); 0 (Heterocyclic Compounds); 0 (Indoles); 0 (Stilbenes); 0 (Sulfonium Compounds); 0 (cuspidan B); 6UK3D2BXJT (1,3-cyclohexanedione) [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: 180110 [St] Status: MEDLINE [do] DOI: 10.1248/yakushi.17-00188

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[PMID]: 29443750 [Au] Autor: Liu DY; Wang ZG; Gao Y; Zhang HM; Zhang YX; Wang XJ; Peng D [Ad] Endereço: Department of Respiratory Medicine, The People's Hospital of Yan'an, Yan'an. [Ti] Título: Effect and safety of roflumilast for chronic obstructive pulmonary disease in Chinese patients. [So] Source: Medicine (Baltimore);97(7):e9864, 2018 Feb. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: This trial aimed to evaluate the efficacy and safety of roflumilast for treating Chinese patients with chronic obstructive pulmonary disease (COPD). METHODS: A total of 120 patients with COPD were recruited and were randomly divided into 2 groups (an intervention group and a placebo group) at a 1:1 ratio. Patients received either roflumilast or placebo 500 µg once daily for a total of 12 months. The primary outcome was lung function, measured by the change from baseline of forced expiratory volume in 1 second (FEV1), FVC = forced vital capacity (FVC), and FEF25-75%. The secondary outcome measurements included the quality of life, measured with the St. George's Respiratory Questionnaire (SGRQ). All outcomes were measured at the end of 12-month treatment and 3-month follow-up after the treatment. In addition, adverse events (AEs) were also recorded during the treatment period. RESULTS: FEV1, FVC, FEF25-75%, and SGRQ were significantly better in the intervention group than those in the placebo group at the end of 12-month treatment and 3-month follow up after treatment. Moreover, AEs were much higher with roflumilast than placebo in this study. CONCLUSIONS: The findings suggest that roflumilast has promising effect to improve lung function in Chinese population with COPD. [Mh] Termos MeSH primário: Aminopiridinas Benzamidas Doença Pulmonar Obstrutiva Crônica Qualidade de Vida [Mh] Termos MeSH secundário: Idoso Aminopiridinas/administração & dosagem Aminopiridinas/efeitos adversos Grupo com Ancestrais do Continente Asiático Benzamidas/administração & dosagem Benzamidas/efeitos adversos Ciclopropanos/administração & dosagem Ciclopropanos/efeitos adversos Método Duplo-Cego Monitoramento de Medicamentos Feminino Seres Humanos Masculino Meia-Idade Avaliação de Processos e Resultados (Cuidados de Saúde) Inibidores da Fosfodiesterase 4/administração & dosagem Inibidores da Fosfodiesterase 4/efeitos adversos Doença Pulmonar Obstrutiva Crônica/diagnóstico Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico Doença Pulmonar Obstrutiva Crônica/etnologia Doença Pulmonar Obstrutiva Crônica/psicologia Testes de Função Respiratória/métodos Inquéritos e Questionários [Pt] Tipo de publicação: JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Aminopyridines); 0 (Benzamides); 0 (Cyclopropanes); 0 (Phosphodiesterase 4 Inhibitors); 0P6C6ZOP5U (Roflumilast) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 180215 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000009864

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[PMID]: 28470621 [Au] Autor: Wallace S; Balskus EP [Ad] Endereço: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA. [Ti] Título: Interfacing Biocompatible Reactions with Engineered Escherichia coli. [So] Source: Methods Mol Biol;1586:409-421, 2017. [Is] ISSN: 1940-6029 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Biocompatible chemistry represents a new way of merging chemical and biological synthesis by interfacing nonenzymatic reactions with metabolic pathways. This approach can enable the production of nonnatural molecules directly from renewable starting materials via microbial fermentation. When developing a new biocompatible reaction certain criteria must be satisfied, i.e., the reaction must be (1) functional in aqueous growth media at ambient temperature and pH, (2) nontoxic to the producing microorganism, and (3) have negligible effects on the targeted metabolic pathway. This chapter provides a detailed outline of two biocompatible reaction procedures (hydrogenation and cyclopropanation), and describes some of the chemical and microbiological experiments and considerations required during biocompatible reaction development. [Mh] Termos MeSH primário: Escherichia coli/genética Escherichia coli/metabolismo Engenharia Metabólica/métodos [Mh] Termos MeSH secundário: Catálise Ciclopropanos/metabolismo Escherichia coli/crescimento & desenvolvimento Fermentação Glucose Hidrogenação Redes e Vias Metabólicas Biologia Sintética/métodos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclopropanes); 99TB643425 (cyclopropane); IY9XDZ35W2 (Glucose) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180220 [Lr] Data última revisão: 180220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1007/978-1-4939-6887-9_27

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[PMID]: 29306026 [Au] Autor: So EC; Wu SN; Lo YC; Su K [Ad] Endereço: Department of Anesthesia, An Nan Hospital, China Medical University, 70965, Tainan City, Taiwan; Department of Anesthesia, China Medical University, 40447 Taichung City, Taiwan. Electronic address: d11320@mail.tmanh.org.tw. [Ti] Título: Differential regulation of tefluthrin and telmisartan on the gating charges of I activation and inactivation as well as on resurgent and persistent I in a pituitary cell line (GH ). [So] Source: Toxicol Lett;285:104-112, 2018 Mar 15. [Is] ISSN: 1879-3169 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Voltage-gated Na currents (I ), known to contain many components (e.g., transient, resurgent and persistent I ) with unique gating properties, are involved in the generation and propagation of action potentials in excitable cells. In this study, how tefluthrin (Tef), a synthetic pyrethoid, and telmisartan (TEL), blocker of angiotensin II receptors can perturb those components of I was investigated. The presence of either Tef or TEL increased the values of the gating charges of I involved in the activation (z ) and inactivation (z ). Tef also increased the amplitude of resurgent I (I ) or persistent I (I ) in a pituitary cell line (GH ), while TEL produced minimal effects on them. Subsequent addition of either ranolazine (a blocker of late I ) or d-limonene (a monoterpene), could reverse the changes by TEL or Tef on z or z . In SCN5A-expressing HEK293T cells, addition of Tef or TEL also increased the peak amplitude and the inactivation time constant of I which was accompanied by the increased z value of I . Taken together, the results indicated that Tef- or TEL-mediated changes in the gating kinetics of I are linked to their actions on functional activity of neurons, neuroendocrine or endocrine cells. [Mh] Termos MeSH primário: Benzimidazóis/farmacologia Benzoatos/farmacologia Ciclopropanos/farmacologia Hidrocarbonetos Fluorados/farmacologia Ativação do Canal Iônico/efeitos dos fármacos Somatotrofos/efeitos dos fármacos Canais de Sódio Disparados por Voltagem/metabolismo [Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos Animais Linhagem Celular Tumoral Cicloexenos/farmacologia Células HEK293 Seres Humanos Canal de Sódio Disparado por Voltagem NAV1.5/genética Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo Ranolazina/farmacologia Ratos Somatotrofos/metabolismo Terpenos/farmacologia Transfecção Canais de Sódio Disparados por Voltagem/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzimidazoles); 0 (Benzoates); 0 (Cyclohexenes); 0 (Cyclopropanes); 0 (Hydrocarbons, Fluorinated); 0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (SCN5A protein, human); 0 (Terpenes); 0 (Voltage-Gated Sodium Channels); 2HE8P42H2J (2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1RS)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate); 9MC3I34447 (limonene); A6IEZ5M406 (Ranolazine); U5SYW473RQ (telmisartan) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180219 [Lr] Data última revisão: 180219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180107 [St] Status: MEDLINE

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[PMID]: 28455137 [Au] Autor: Ben Mouhoub R; El May A; Cheraief I; Landoulsi A [Ad] Endereço: Biochemistry and Molecular Biology, Code UR13ES34 Research Unit, Faculty of Sciences of Bizerte, Zarzouna 7021, Carthage University, Tunisia. Electronic address: ramlabenmouhoub@gmail.com. [Ti] Título: Influence of static magnetic field exposure on fatty acid composition in Salmonella Hadar. [So] Source: Microb Pathog;108:13-20, 2017 Jul. [Is] ISSN: 1096-1208 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: We have been interested, in this work, to investigate the effect of the exposure to static magnetic field at 200 mT (SMF) on the fatty acid (FA) composition of Salmonella enterica subsp Enterica serovar Hadar isolate 287: effects on the proportion of saturated and unsaturated fatty acids (SFAs, UFAs), cyclopropane fatty acids (CFAs) and hydroxy fatty acids after exposure to the static magnetic field at 200 mT (SMF). Analysis with Gas Chromatography-Mass Spectrometry (GC-MS) of total lipid showed that the proportion of the most fatty acids was clearly affected. The comparison of UFAs/SFAs ratio in exposed bacteria and controls showed a diminution after 3 and 6 h of exposure. This ration reached a balance after 9 h of treatment with SMF. So we can conclude that S. Hadar tries to adapt to magnetic stress by changing the proportions of SFAs and UFAs over time to maintain an equilibrium after 9 h of exposure, thus to maintain the inner membranes fluidity. Also, a decrease in the proportion of hydroxy FAs was observed after 6 h but an increase of this proportion after 9 h of exposure. Concerning CFAs, its proportion raised after 6 h of exposure to the SMF but it decreased after 9 h of exposure. These results are strongly correlated with those of cfa (cyclopropane fatty acid synthase) gene expression which showed a decrease of its expression after 9 h of exposure. [Mh] Termos MeSH primário: Ácidos Graxos/análise Campos Magnéticos Salmonella enterica/metabolismo Salmonella enterica/efeitos da radiação [Mh] Termos MeSH secundário: Ciclopropanos/análise Ciclopropanos/química Ácidos Graxos/química Ácidos Graxos/genética Ácidos Graxos Insaturados/análise Ácidos Graxos Insaturados/química Ácidos Graxos Insaturados/genética Cromatografia Gasosa-Espectrometria de Massas Regulação Bacteriana da Expressão Gênica/efeitos da radiação Fluidez de Membrana/efeitos da radiação Lipídeos de Membrana Metiltransferases/genética Metiltransferases/efeitos da radiação RNA Bacteriano/análise RNA Ribossômico 16S/genética Salmonella enterica/genética Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclopropanes); 0 (Fatty Acids); 0 (Fatty Acids, Unsaturated); 0 (Membrane Lipids); 0 (RNA, Bacterial); 0 (RNA, Ribosomal, 16S); 0 (cyclopropane fatty acids); EC 2.1.1.- (Methyltransferases); EC 2.1.1.- (cyclopropane synthetase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180108 [Lr] Data última revisão: 180108 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 28805802 [Au] Autor: Zha L; Jiang Y; Henke MT; Wilson MR; Wang JX; Kelleher NL; Balskus EP [Ad] Endereço: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. [Ti] Título: Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring. [So] Source: Nat Chem Biol;13(10):1063-1065, 2017 Oct. [Is] ISSN: 1552-4469 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity. [Mh] Termos MeSH primário: Ciclopropanos/química Ciclopropanos/metabolismo Peptídeo Sintases/metabolismo Peptídeos/metabolismo Policetídeos/metabolismo S-Adenosilmetionina/metabolismo [Mh] Termos MeSH secundário: Escherichia coli/metabolismo Peptídeo Sintases/química Peptídeos/química Policetídeos/química S-Adenosilmetionina/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclopropanes); 0 (Peptides); 0 (Polyketides); 0 (colibactin); 7LP2MPO46S (S-Adenosylmethionine); 99TB643425 (cyclopropane); EC 6.3.2.- (Peptide Synthases) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171028 [Lr] Data última revisão: 171028 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170815 [St] Status: MEDLINE [do] DOI: 10.1038/nchembio.2448

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[PMID]: 28707880 [Au] Autor: Masuya T; Murai M; Ito T; Aburaya S; Aoki W; Miyoshi H [Ad] Endereço: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University , Sakyo-ku, Kyoto 606-8502, Japan. [Ti] Título: Pinpoint Chemical Modification of the Quinone-Access Channel of Mitochondrial Complex I via a Two-Step Conjugation Reaction. [So] Source: Biochemistry;56(32):4279-4287, 2017 Aug 15. [Is] ISSN: 1520-4995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We previously showed that a bulky ring-strained cycloalkyne possessing a rhodamine fluorophore directly reacts (via strain-promoted click chemistry) with the azido group incorporated (via ligand-directed tosyl chemistry) into Asp160 in the 49 kDa subunit of complex I in bovine heart submitochondrial particles [Masuya, T., et al. (2014) Biochemistry 53, 7816-7823]. This two-step conjugation may be a promising technique for specific chemical modifications of the quinone-access channel in complex I by various molecular probes, which would lead to new methodologies for studying the enzyme. However, because the reactivities of ring-strained cycloalkynes are generally high, they also react with other nucleophilic amino acids in mitochondrial proteins, resulting in significant undesired side reactions. To minimize side reactions and achieve precise pinpoint chemical modification of 49 kDa Asp160, we investigated an optimal pair of chemical tags for the two-step conjugation reaction. We found that instead of strain-promoted click chemistry, Diels-Alder cycloaddition of a pair of cyclopropene incorporated into 49 kDa Asp160 (via ligand-directed tosyl chemistry) and externally added tetrazine is more efficient for the pinpoint modification. An excess of quinone-site inhibitors did not interfere with Diels-Alder cycloaddition between the cyclopropene and tetrazine. These results along with the previous findings (cited above) strongly suggest that in contrast to the predicted quinone-access channel modeled by X-ray crystallographic and single-particle cryo-electron microscopic studies, the channel is open or undergoes large structural rearrangements to allow bulky ligands into the proximity of 49 kDa Asp160. [Mh] Termos MeSH primário: Complexo I de Transporte de Elétrons/química Mitocôndrias Cardíacas/enzimologia Modelos Moleculares Sondas Moleculares/química [Mh] Termos MeSH secundário: Animais Bovinos Química Click/métodos Ciclopropanos/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclopropanes); 0 (Molecular Probes); 7B8994OHJ0 (cyclopropene); EC 1.6.5.3 (Electron Transport Complex I) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170715 [St] Status: MEDLINE [do] DOI: 10.1021/acs.biochem.7b00612

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[PMID]: 28667074 [Au] Autor: Takagi S; Ishikawa Y; Mizutani A; Iwasaki S; Matsumoto S; Kamada Y; Nomura T; Nakamura K [Ad] Endereço: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa, Japan. kazuhide.nakamura@takeda.com Takagi_Shinji_1@yahoo.co.jp shinji.takagi@merck.com. [Ti] Título: LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B. [So] Source: Cancer Res;77(17):4652-4662, 2017 Sep 01. [Is] ISSN: 1538-7445 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells and retarded SCLC tumor growth T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. . [Mh] Termos MeSH primário: Anilidas/farmacologia Antineoplásicos/farmacologia Proliferação Celular/efeitos dos fármacos Ciclopropanos/farmacologia Histona Desmetilases/antagonistas & inibidores Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos Proteínas Proto-Oncogênicas/antagonistas & inibidores Proteínas Repressoras/antagonistas & inibidores Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico [Mh] Termos MeSH secundário: Animais Feminino Histona Desmetilases/metabolismo Seres Humanos Neoplasias Pulmonares/tratamento farmacológico Neoplasias Pulmonares/metabolismo Neoplasias Pulmonares/patologia Camundongos Endogâmicos BALB C Camundongos Nus Proteínas Proto-Oncogênicas/metabolismo Proteínas Repressoras/metabolismo Carcinoma de Pequenas Células do Pulmão/metabolismo Carcinoma de Pequenas Células do Pulmão/patologia Fatores de Transcrição da Família Snail Células Tumorais Cultivadas Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anilides); 0 (Antineoplastic Agents); 0 (Cyclopropanes); 0 (GFI1B protein, human); 0 (Proto-Oncogene Proteins); 0 (Repressor Proteins); 0 (Snail Family Transcription Factors); 0 (T-3775440); 147955-03-1 (INSM1 protein, human); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170702 [St] Status: MEDLINE [do] DOI: 10.1158/0008-5472.CAN-16-3502

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[PMID]: 28657744 [Au] Autor: Zhang G; Cheng J; McCorvy JD; Lorello PJ; Caldarone BJ; Roth BL; Kozikowski AP [Ad] Endereço: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States. [Ti] Título: Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications. [So] Source: J Med Chem;60(14):6273-6288, 2017 Jul 27. [Is] ISSN: 1520-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT )-selective agonists with a preference for G signaling. A number of these compounds exhibit 5-HT selectivity with a preference for G -mediated signaling compared with ß-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC of 23 nM in the calcium flux assay while showing no ß-arrestin recruitment activity, is the most functionally selective 5-HT agonist reported to date. The N-benzyl compound (+)-19, which showed an EC of 24 nM at the 5-HT receptor, is fully selective over the 5-HT receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT receptor with respect to antipsychotic activity. [Mh] Termos MeSH primário: Antipsicóticos/química Benzilaminas/química Ciclopropanos/química Metilaminas/química Receptor 5-HT2C de Serotonina/metabolismo Agonistas de Receptores 5-HT2 de Serotonina/química [Mh] Termos MeSH secundário: Animais Antipsicóticos/síntese química Antipsicóticos/farmacologia Benzilaminas/síntese química Benzilaminas/farmacologia Ciclopropanos/síntese química Ciclopropanos/farmacologia Células HEK293 Seres Humanos Hipercinese/induzido quimicamente Hipercinese/tratamento farmacológico Masculino Metilaminas/síntese química Metilaminas/farmacologia Camundongos Endogâmicos C57BL Receptor 5-HT2B de Serotonina/metabolismo Agonistas de Receptores 5-HT2 de Serotonina/síntese química Agonistas de Receptores 5-HT2 de Serotonina/farmacologia Estereoisomerismo Relação Estrutura-Atividade beta-Arrestinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (1-(2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-N-(2-methoxybenzyl)methanamine); 0 (Antipsychotic Agents); 0 (Benzylamines); 0 (Cyclopropanes); 0 (Methylamines); 0 (Receptor, Serotonin, 5-HT2B); 0 (Receptor, Serotonin, 5-HT2C); 0 (Serotonin 5-HT2 Receptor Agonists); 0 (beta-Arrestins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170629 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jmedchem.7b00584

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