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[PMID]:29281935
[Au] Autor:Yang Z; Jiang T; Zhong H; Kang Y
[Ad] Endereço:a School of Pharmaceutical Sciences , Jiangnan University , Jiangsu , People's Republic of China.
[Ti] Título:Bulge oligonucleotide as an inhibitory agent of bacterial topoisomerase I.
[So] Source:J Enzyme Inhib Med Chem;33(1):319-323, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Bacterial topoisomerase I (Btopo I) was defined as potential target for discovery of new antibacterial compounds. Various oligonucleotides containing bulge structure were designed and synthesised as inhibitors to Btopo I in this investigation. The results of this study demonstrated that the designed oligonucleotides display high inhibitory efficiency on the activity of Btopo I and the inhibitory effect could be modulated by the amount of bulge DNA bases. The most efficient one among them showed an IC value of 63.1 nM in its inhibition on the activity of Btopo I. In addition, our studies confirmed that the designed oligonucleotide would induce irreversible damages to Btopo I and without any effects occur to eukaryotic topoisomerase I. It is our hope that the results provided in these studies could provide a novel way to inhibit Btopo I.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
Oligonucleotídeos/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Relação Dose-Resposta a Droga
Escherichia coli/enzimologia
Oligonucleotídeos/síntese química
Oligonucleotídeos/química
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Oligonucleotides); 0 (Topoisomerase I Inhibitors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1419218


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[PMID]:29174815
[Au] Autor:Khadka DB; Park S; Jin Y; Han J; Kwon Y; Cho WJ
[Ad] Endereço:College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
[Ti] Título:Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors.
[So] Source:Eur J Med Chem;143:200-215, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 µM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo I/metabolismo
Desenho de Drogas
Isoquinolinas/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Biocatálise
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Estrutura Molecular
Polimerização/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoquinolines); 0 (Topoisomerase I Inhibitors); 0 (Tubulin); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:28797568
[Au] Autor:Koosha F; Neshasteh-Riz A; Takavar A; Eyvazzadeh N; Mazaheri Z; Eynali S; Mousavi M
[Ad] Endereço:Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
[Ti] Título:The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids.
[So] Source:Biochem Biophys Res Commun;491(4):1092-1097, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization. U87MG cells (a human glioblastoma cell line) were cultured in Poly-Hema coated flasks to reach 300 µm-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of A-966492 and Topotecan. The surviving fraction of treated cells was determined by clonogenic assay after treatment with drugs and 6 MV X-ray. The γ-H2AX expression was measured by an immunofluorescence staining method to examine the influence of A-966492, TPT and radiation on the induction of double stranded DNA breaks. Treatments using the A-966492 drug were conducted in concentration of 1 µM. Combining A-966492 and TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER ) 1.39 and 1.16 respectively. Radio- and chemo-sensitization was further enhanced when A-966492 was combined with both X-ray and TPT, with SER of 1.53. Also γ-H2AX expression was higher in the group treated with a combination of drugs and radiation. A-966492 is an effective PARP inhibitor and has significant radio-sensitivity on U87MG spheroids. By accumulating cells in the S phase and by inhibiting the DNA damage repair, TPT enhanced radio-sensitivity. A-966492 combined with TPT as a topoisomerase I inhibitor had additive radio-sensitizing effects. As a result, applying PARP and topoisomerase I inhibitors can be a suitable strategy for improving radiotherapy in clinics.
[Mh] Termos MeSH primário: Benzimidazóis/farmacologia
Glioblastoma/tratamento farmacológico
Esferoides Celulares/efeitos dos fármacos
Inibidores da Topoisomerase I/farmacologia
Topotecan/farmacologia
[Mh] Termos MeSH secundário: Benzimidazóis/administração & dosagem
Linhagem Celular Tumoral
DNA Topoisomerases Tipo I/metabolismo
Seres Humanos
Tolerância a Radiação/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/administração & dosagem
Topotecan/administração & dosagem
Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide); 0 (Benzimidazoles); 0 (Topoisomerase I Inhibitors); 7M7YKX2N15 (Topotecan); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[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:170812
[St] Status:MEDLINE


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[PMID]:28677116
[Au] Autor:Takegawa N; Nonagase Y; Yonesaka K; Sakai K; Maenishi O; Ogitani Y; Tamura T; Nishio K; Nakagawa K; Tsurutani J
[Ad] Endereço:Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan.
[Ti] Título:DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance.
[So] Source:Int J Cancer;141(8):1682-1689, 2017 Oct 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Camptotecina/análogos & derivados
Imunoconjugados/farmacologia
Neoplasias Gástricas/tratamento farmacológico
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais Humanizados/química
Camptotecina/química
Camptotecina/farmacologia
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Imunoconjugados/química
Maitansina/análogos & derivados
Maitansina/farmacologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Distribuição Aleatória
Receptor ErbB-2/biossíntese
Neoplasias Gástricas/enzimologia
Neoplasias Gástricas/imunologia
Inibidores da Topoisomerase I/química
Trastuzumab
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (DS-8201a); 0 (Immunoconjugates); 0 (Topoisomerase I Inhibitors); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170706
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30870


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[PMID]:28657311
[Au] Autor:Elsayed MSA; Su Y; Wang P; Sethi T; Agama K; Ravji A; Redon CE; Kiselev E; Horzmann KA; Freeman JL; Pommier Y; Cushman M
[Ad] Endereço:Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
[Ti] Título:Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I.
[So] Source:J Med Chem;60(13):5364-5376, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI values in the submicromolar (0.033-0.630 µM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI values of 0.063 and 0.033 µM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo I/metabolismo
Desenho de Drogas
Isoquinolinas/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Clivagem do DNA
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
Células Tumorais Cultivadas
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-azaindenoisoquinoline); 0 (Antineoplastic Agents); 0 (Isoquinolines); 0 (Topoisomerase I Inhibitors); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[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:170629
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01870


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[PMID]:28624622
[Au] Autor:Allison SJ; Sadiq M; Baronou E; Cooper PA; Dunnill C; Georgopoulos NT; Latif A; Shepherd S; Shnyder SD; Stratford IJ; Wheelhouse RT; Willans CE; Phillips RM
[Ad] Endereço:School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK.
[Ti] Título:Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands.
[So] Source:Cancer Lett;403:98-107, 2017 Sep 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Imidazóis/farmacologia
Neoplasias/tratamento farmacológico
Compostos Organometálicos/farmacologia
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/metabolismo
Antineoplásicos/química
Antineoplásicos/toxicidade
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Cisplatino/farmacologia
Dano ao DNA
DNA Topoisomerases Tipo I/metabolismo
DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Dacarbazina/análogos & derivados
Dacarbazina/farmacologia
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos
Sinergismo Farmacológico
Glicólise/efeitos dos fármacos
Seres Humanos
Imidazóis/química
Imidazóis/toxicidade
Concentração Inibidora 50
Neoplasias/metabolismo
Neoplasias/patologia
Compostos Organometálicos/química
Compostos Organometálicos/toxicidade
Estresse Oxidativo/efeitos dos fármacos
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Poli(ADP-Ribose) Polimerase-1/metabolismo
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
Tiorredoxina Redutase 1/antagonistas & inibidores
Tiorredoxina Redutase 1/metabolismo
Inibidores da Topoisomerase I/farmacologia
Inibidores da Topoisomerase II/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Imidazoles); 0 (Organometallic Compounds); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Reactive Oxygen Species); 0 (Topoisomerase I Inhibitors); 0 (Topoisomerase II Inhibitors); 7GR28W0FJI (Dacarbazine); EC 1.8.1.9 (TXNRD1 protein, human); EC 1.8.1.9 (Thioredoxin Reductase 1); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (TOP1 protein, human); EC 5.99.1.3 (DNA Topoisomerases, Type II); Q20Q21Q62J (Cisplatin); YF1K15M17Y (temozolomide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170619
[St] Status:MEDLINE


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[PMID]:28602939
[Au] Autor:Luo P; Yu Q; Liu SN; Xia WJ; Fang YY; An LK; Gu Q; Xu J
[Ad] Endereço:Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
[Ti] Título:Diterpenoids with diverse scaffolds from Vitex trifolia as potential topoisomerase I inhibitor.
[So] Source:Fitoterapia;120:108-116, 2017 Jul.
[Is] ISSN:1873-6971
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Eleven new compounds, including six labdane (1-6), three halimane (7-9), and two clerodane (10-11) diterpenoids and 16 known analogues (12-27), were isolated from the leaves of Vitex trifolia. The structures of 1-11 were established by extensive 1D- and 2D-NMR and HRMS spectroscopic data. The absolute configurations of compounds 3, 7, and 10 were assigned using X-ray diffraction. Compounds 1-27 were evaluated for DNA topoisomerases I (Top1) inhibitory activity and cytotoxicity against HCT 116 cells. Compounds 8 and 11 exhibited equipotent Top1 inhibitory activity to the positive control, camptothecin (CPT), at 100µM. Compounds 8, 9, 16, and 27 showed moderate cytotoxicity at low micromolar concentrations.
[Mh] Termos MeSH primário: Diterpenos Clerodânicos/química
Inibidores da Topoisomerase I/química
Vitex/química
[Mh] Termos MeSH secundário: DNA Topoisomerases Tipo I
Diterpenos
Diterpenos Clerodânicos/isolamento & purificação
Células HCT116
Seres Humanos
Estrutura Molecular
Folhas de Planta/química
Inibidores da Topoisomerase I/isolamento & purificação
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diterpenes); 0 (Diterpenes, Clerodane); 0 (Topoisomerase I Inhibitors); 0 (halimane); 0 (labdane); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (TOP1 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28575069
[Au] Autor:Bremer J; Skinner J; Granato M
[Ad] Endereço:Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
[Ti] Título:A small molecule screen identifies in vivo modulators of peripheral nerve regeneration in zebrafish.
[So] Source:PLoS One;12(6):e0178854, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adult vertebrates have retained the ability to regenerate peripheral nerves after injury, although regeneration is frequently incomplete, often leading to functional impairments. Small molecule screens using whole organisms have high potential to identify biologically relevant targets, yet currently available assays for in vivo peripheral nerve regeneration are either very laborious and/or require complex technology. Here we take advantage of the optical transparency of larval zebrafish to develop a simple and fast pectoral fin removal assay that measures peripheral nerve regeneration in vivo. Twenty-four hours after fin amputation we observe robust and stereotyped nerve regrowth at the fin base. Similar to laser mediated nerve transection, nerve regrowth after fin amputation requires Schwann cells and FGF signaling, confirming that the fin amputation assay identifies pathways relevant for peripheral nerve regeneration. From a library of small molecules with known targets, we identified 21 compounds that impair peripheral nerve regeneration. Several of these compounds target known regulators of nerve regeneration, further validating the fin removal assay. Twelve of the identified compounds affect targets not previously known to control peripheral nerve regeneration. Using a laser-mediated nerve transection assay we tested ten of those compounds and confirmed six of these compounds to impair peripheral nerve regeneration: an EGFR inhibitor, a glucocorticoid, prostaglandin D2, a retinoic acid agonist, an inhibitor of calcium channels and a topoisomerase I inhibitor. Thus, we established a technically simple assay to rapidly identify valuable entry points into pathways critical for vertebrate peripheral nerve regeneration.
[Mh] Termos MeSH primário: Regeneração Nervosa
Nervos Periféricos/crescimento & desenvolvimento
Bibliotecas de Moléculas Pequenas
[Mh] Termos MeSH secundário: Amputação
Animais
Inibidores da Topoisomerase I/farmacologia
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Small Molecule Libraries); 0 (Topoisomerase I Inhibitors)
[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:170603
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178854


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[PMID]:28531811
[Au] Autor:Lafayette EA; de Almeida SMV; Cavalcanti Santos RV; de Oliveira JF; Amorim CADC; da Silva RMF; Pitta MGDR; Pitta IDR; de Moura RO; de Carvalho Júnior LB; de Melo Rêgo MJB; de Lima MDCA
[Ad] Endereço:Departamento de Química e Física, Centro de Ciências Agrárias (CCA), Universidade Federal da Paraíba (UFPB), Areia, PB, Brazil.
[Ti] Título:Synthesis of novel indole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I activities.
[So] Source:Eur J Med Chem;136:511-522, 2017 Aug 18.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy H NMR, C NMR, COSY H- H and HSQC H- C. The antitumor activity was evaluated against different cancer cell lines using the antiproliferative MTT assay. DNA binding ability was analyzed by absorption spectroscopy and fluorescence technique using ethidium bromide (EB) as a fluorescent probe. Changes were observed in spectroscopic properties of the compounds after interacting with ctDNA (calf thymus DNA), with hypochromic and hyperchromic effects, besides blue or red shifts in the maxima of spectra. The indole derivative 5-(1H-Indol-3-ylmethylene)-thiazolidin-2,4-dione (4c) presented the best results in antitumor assay against the breast line tested (T47D), with IC value lower than the positive control, doxorubicin (1.93 and 4.61 µM, respectively). On the other hand, the compound 3-amino-5-(1H-indol-3-ylmethylene)-2-thioxo-thiazolidin-4-one (4a) was active against leukemia cell lines (HL60 and K562) with the high value of the DNA binding constant, Kb of 5.69 × 10 . However, this compound (4a) did not inhibit the topoisomerase-I activity evaluated by relaxation assay. These results show that the indole nucleus contribute to the incorporation of molecules into the DNA. Moreover, it was highlighted that basic side chains, such as thiazolidines and imidazolidines, and free amino group, are relevant for design of promising antitumor and DNA binding compounds.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo I/metabolismo
DNA de Neoplasias/efeitos dos fármacos
Indóis/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Sítios de Ligação/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
DNA de Neoplasias/química
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Indóis/síntese química
Indóis/química
Estrutura Molecular
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DNA, Neoplasm); 0 (Indoles); 0 (Topoisomerase I Inhibitors); 8724FJW4M5 (indole); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


  10 / 2846 MEDLINE  
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[PMID]:28513496
[Au] Autor:Rishi P; Sharma T; Sharma M; Maitray A; Dhami A; Aggarwal V; Munusamy S; Ravikumar R; Ramamurthy S
[Ad] Endereço:Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralya, Chennai, Tamil Nadu, India.
[Ti] Título:Intra-arterial chemotherapy for retinoblastoma: Two-year results from tertiary eye-care center in India.
[So] Source:Indian J Ophthalmol;65(4):311-315, 2017 Apr.
[Is] ISSN:1998-3689
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:AIM: The aim of this study is to describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for intraocular retinoblastoma (RB). MATERIALS AND METHODS: A retrospective, interventional series of 10 eyes with RB which underwent IAC using melphalan (5 mg/7.5 mg) and topotecan (1 mg), or melphalan (5 mg/7.5 mg) alone. Treatment outcomes were evaluated in terms of tumor control, vitreous seeds (VS) and subretinal seeds (SRS) control, and globe salvage rates. RESULTS: Ten eyes of 10 patients underwent 38 IAC sessions (mean = 3.8; median = 4; range = 3-5 sessions). Following IAC, complete regression of main tumor was seen in 9 eyes (90%) and partial regression in 1 (10%). All four eyes with SRS showed complete regression (100%). Of 5 eyes with VS, 3 eyes (60%) showed complete regression, 1 eye (20%) showed relapse, while 1 eye (20%) showed no response. Globe salvage was achieved in 8 of 10 eyes (80%). Complications included transient ophthalmic artery narrowing (n = 2), branched retinal vein occlusion (n = 1), forehead skin pigmentation (n = 1), and vitreous hemorrhage (n = 2). There was no case of stroke, hemiplegia, metastasis, or death. Transient hematological changes included relative pancytopenia (n = 4), relative leukopenia (n = 5), and relative thrombocytopenia (n = 4). Mean follow-up was 26 months (median = 28, range = 13-36) from the initiation of first IAC. CONCLUSIONS: IAC is an effective therapy for globe preservation in eyes with intraocular RB, in the setting of a developing country like India. Larger studies with longer follow-up are required to validate these results.
[Mh] Termos MeSH primário: Melfalan/administração & dosagem
Neoplasias da Retina/tratamento farmacológico
Retinoblastoma/tratamento farmacológico
Topotecan/administração & dosagem
[Mh] Termos MeSH secundário: Antineoplásicos Alquilantes/administração & dosagem
Pré-Escolar
Relação Dose-Resposta a Droga
Feminino
Seguimentos
Seres Humanos
Incidência
Índia/epidemiologia
Lactente
Injeções Intra-Arteriais
Masculino
Neoplasias da Retina/diagnóstico
Neoplasias da Retina/epidemiologia
Retinoblastoma/diagnóstico
Retinoblastoma/epidemiologia
Estudos Retrospectivos
Fatores de Tempo
Inibidores da Topoisomerase I/administração & dosagem
Resultado do Tratamento
Ultrassonografia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Topoisomerase I Inhibitors); 7M7YKX2N15 (Topotecan); Q41OR9510P (Melphalan)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE
[do] DOI:10.4103/ijo.IJO_843_16



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