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1.
Sci Rep ; 11(1): 23243, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853392

RESUMO

Specific guanine rich nucleic acid sequences can form non-canonical structures, like the four stranded G-quadruplex (GQ). We studied the GQ-forming sequence (named HepB) found in the genome of the hepatitis B virus. Fluorescence-, infrared- and CD-spectroscopy were used. HepB shows a hybrid form in presence of K+, but Na+, Li+, and Rb+ induce parallel structure. Higher concentrations of metal ions increase the unfolding temperature, which was explained by a short thermodynamic calculation. Temperature stability of the GQ structure was determined for all these ions. Na+ has stronger stabilizing effect on HepB than K+, which is highly unusual. The transition temperatures were 56.6, 53.8, 58.5 and 54.4 °C for Na+, K+, Li+, and Rb+ respectively. Binding constants for Na+ and K+ were 10.2 mM and 7.1 mM respectively. Study of three ligands designed in cancer research for GQ targeting (TMPyP4, BRACO19 and PhenDC3) showed unequivocally their binding to HepB. Binding was proven by the increased stability of the bound form. The stabilization was higher than 20 °C for TMPyP4 and PhenDC3, while it was considerably lower for BRACO19. These results might have medical importance in the fight against the hepatitis B virus.


Assuntos
Acridinas/metabolismo , Compostos de Anéis Fundidos/metabolismo , Quadruplex G , Vírus da Hepatite B/genética , Porfirinas/metabolismo , Acridinas/química , DNA/química , Compostos de Anéis Fundidos/química , Genoma Viral , Vírus da Hepatite B/química , Vírus da Hepatite B/metabolismo , Ligantes , Porfirinas/química , Termodinâmica
2.
Viruses ; 13(11)2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34835025

RESUMO

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses' genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV's attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.


Assuntos
Antivirais/farmacologia , Quadruplex G , Herpesvirus Suídeo 1/genética , Origem de Replicação/genética , Animais , Antivirais/química , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , DNA Viral/biossíntese , DNA Viral/química , DNA Viral/efeitos dos fármacos , Compostos de Anéis Fundidos/química , Compostos de Anéis Fundidos/farmacologia , Quadruplex G/efeitos dos fármacos , Genoma Viral/efeitos dos fármacos , Genoma Viral/genética , Herpesvirus Suídeo 1/efeitos dos fármacos , Herpesvirus Suídeo 1/fisiologia , Origem de Replicação/efeitos dos fármacos , Suínos , Replicação Viral/efeitos dos fármacos
3.
PLoS One ; 16(9): e0257808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582495

RESUMO

The Ultraviolet-visible (UV-Vis) spectra indicate that anthracenyl chalcones (ACs) have high maximum wavelengths and good transparency windows for optical applications and are suitable for optoelectronic applications owing to their HOMO-LUMO energy gaps (2.93 and 2.76 eV). Different donor substituents on the AC affect their dipole moments and nonlinear optical (NLO) responses. The positive, negative, and neutral electrostatic potential regions of the molecules were identified using molecular electrostatic potential (MEP). The stability of the molecule on account of hyperconjugative interactions and accompanying charge delocalization was analyzed using natural bond orbital (NBO) analysis. Open and closed aperture Z-scans were performed using a continuous-wave frequency-doubled diode-pumped solid-state (DPSS) laser to measure the nonlinear absorption and nonlinear refractive index coefficients, respectively. The valley-to-peak profile of AC indicated a negative nonlinear refractive index coefficient. The obtained single crystals possess reverse saturation absorption due to excited-state absorption. The structural and nonlinear optical properties of the molecules have been discussed, along with the role of anthracene substitution for enhancing the nonlinear optical properties. The calculated third-order susceptibility value was 1.10 x10-4 esu at an intensity of 4.1 kW/cm2, higher than the reported values for related chalcone derivatives. The NLO response for both ACs offers excellent potential in optical switching and limiting applications.


Assuntos
Antracenos/química , Chalconas/química , Compostos de Anéis Fundidos/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Estrutura Molecular , Teoria Quântica
4.
Nucleic Acids Res ; 49(12): 6673-6686, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139015

RESUMO

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations. The studied G4 binders (pyridostatin and PhenDC3) can induce an increase of micronuclei triggering the activation of the cytoplasmic STING (stimulator of interferon response cGAMP interactor 1) signaling pathway in human and murine cancer cells. Ligand activity can then lead to type I interferon production and innate immune gene activation. Moreover, specific gene expression patterns mediated by a G4 binder in cancer cells correlate with immunological hot features and better survival in human TCGA (The Cancer Genome Atlas) breast tumors. The findings open to the development of cytostatic G4 binders as effective immunomodulators for combination immunotherapies in unresponsive tumors.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Citostáticos/farmacologia , Quadruplex G/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Ácidos Picolínicos/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular , Feminino , Compostos de Anéis Fundidos/farmacologia , Humanos , Imunidade Inata/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Células MCF-7 , Melanoma Experimental/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Micronúcleos com Defeito Cromossômico , Nucleotidiltransferases/metabolismo , Ativação Transcricional
5.
Genes Cells ; 26(2): 65-82, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33290632

RESUMO

G-quadruplex (G4), a non-canonical higher-order structure formed by guanine-rich nucleic acid sequences, affects various genetic events in cis, including replication, transcription and translation. Whereas up-regulation of innate immune/interferon-stimulated genes (ISGs) is implicated in cancer progression, G4-forming oligonucleotides that mimic telomeric repeat-containing RNA suppress ISG induction in three-dimensional (3D) culture of cancer cells. However, it is unclear how G4 suppresses ISG expression in trans. In this study, we found that G4 binding to splicing factor 3B subunit 2 (SF3B2) down-regulated STAT1 phosphorylation and ISG expression in 3D-cultured cancer cells. Liquid chromatography-tandem mass spectrometry analysis identified SF3B2 as a G4-binding protein. Either G4-forming oligonucleotides or SF3B2 knockdown suppressed ISG induction, whereas Phen-DC3, a G4-stabilizing compound, reversed the inhibitory effect of G4-forming oligonucleotides on ISG induction. Phen-DC3 inhibited SF3B2 binding to G4 in vitro. SF3B2-mediated ISG induction appeared to occur independently of RNA splicing because SF3B2 knockdown did not affect pre-mRNA splicing under the experimental conditions, and pharmacological inhibition of splicing by pladienolide B did not repress ISG induction. These observations suggest that G4 disrupts the ability of SF3B2 to induce ISGs in cancer. We propose a new mode for gene regulation, which employs G4 as an inhibitory trans-element.


Assuntos
Quadruplex G , Regulação da Expressão Gênica , Imunidade Inata/genética , Ácidos Nucleicos/metabolismo , Fatores de Processamento de RNA/metabolismo , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , Compostos de Anéis Fundidos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Ontologia Genética , Humanos , Imunidade Inata/efeitos dos fármacos , Ligantes , Modelos Biológicos , Oligonucleotídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitinas/genética , Ubiquitinas/metabolismo
6.
Biopolymers ; 112(4): e23415, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33368198

RESUMO

G-quadruplexes (G4) play crucial roles in biology, analytical chemistry and nanotechnology. The stability of G4 structures is impacted by the number of G-quartets, the length and positions of loops, flanking motifs, as well as additional structural elements such as bulges, capping base pairs, or triads. Algorithms such as G4Hunter or Quadparser may predict if a given sequence is G4-prone by calculating a quadruplex propensity score; however, experimental validation is still required. We previously demonstrated that this validation is not always straightforward, and that a combination of techniques is often required to unambiguously establish whether a sequence forms a G-quadruplex or not. In this article, we adapted the well-known FRET-melting assay to characterize G4 in batch, where the sequence to be tested is added, as an unlabeled competitor, to a system composed of a dual-labeled probe (F21T) and a specific quadruplex ligand. PhenDC3 was preferred over TMPyP4 because of its better selectivity for G-quadruplexes. In this so-called FRET-MC (melting competition) assay, G4-forming competitors lead to a marked decrease of the ligand-induced stabilization effect (∆Tm ), while non-specific competitors (e.g., single- or double-stranded sequences) have little effect. Sixty-five known sequences with different typical secondary structures were used to validate the assay, which was subsequently employed to assess eight novel sequences that were not previously characterized.


Assuntos
Compostos de Anéis Fundidos/química , Quadruplex G , Oligonucleotídeos/química , Bioensaio/métodos , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Humanos , Técnicas In Vitro , Desnaturação de Ácido Nucleico
7.
Bioorg Chem ; 105: 104449, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189995

RESUMO

Three unusual polyketides with a 5/6/10-fused ring system, named colletotrichalactones A-Ca (1-3a), were isolated from cultures of the endophytic fungus, Colletotrichum sp. JS-0361, which was isolated from a leaf of Morus alba. Their structures, including their absolute stereochemistries, were completely established using extensive spectroscopic methods together with a chemical reaction utilizing competing enantioselective acylation coupled with LC/MS. Compounds possessing this ring skeleton were previously reported in three studies. Our rigorous chemical investigation revealed the complete configuration of this skeleton, which agreed with the results for glabramycin B with this ring skeleton established by computational chemistry and enantioselective synthesis in previous reports. 1 and 2 had unstable aldehyde groups that were easily converted to acetal groups in the presence of solvents. Meanwhile, compound 3a, with terminal acetal functionality, was deduced to be an artefact originating from compound 3 with a terminal aldehyde group. Compounds 1 and 3a displayed moderate-to-potent cytotoxic activities against MCF7 cells with IC50s of 35.06 and 25.20 µM, respectively.


Assuntos
Antineoplásicos/isolamento & purificação , Colletotrichum/química , Misturas Complexas/isolamento & purificação , Compostos de Anéis Fundidos/química , Policetídeos/química , Acilação , Antineoplásicos/farmacologia , Caprilatos/farmacologia , Misturas Complexas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/farmacologia , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Policetídeos/farmacologia , Estereoisomerismo
8.
Bioorg Chem ; 105: 104450, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189994

RESUMO

In this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, 1H NMR, 13C NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell. It was observed that synthesized compounds NHN1-16 exhibited different cytotoxic profiles. Pyrimidine derivative NHN3 and triazine derivative NHN5 can be good drug candidates for prostate cancer with IC50 values of 54.75 µM and 48.9 µM, respectively. Compounds NHN6, NHN10, NHN12, NHN14 and NHN16 were selected as prodrug candidates because of non-toxic properties against three different cell models. The NHN prodrugs and Ssap-NtrB combinations were applied to SRB assay to reveal the prodrug capabilities of these selected compounds. SRB screening results showed that the metabolites of all selected non-toxic compounds showed remarkable cytotoxicity with IC50 values in the range of 1.71-4.72 nM on prostate cancer. Among the tested compounds, especially piperazine derivatives NHN12 and NHN14 showed significant toxic effect with IC50 values of 1.75 nM and 1.79 nM against PC3 cell compared with standart prodrug CB1954 (IC50: 1.71 nM). Novel compounds NHN12 and NHN14 can be considered as promising prodrug candidates for nitroreductase-prodrug based prostate cancer therapy.


Assuntos
Antineoplásicos/química , Colletotrichum/química , Compostos de Anéis Fundidos/química , Compostos Heterocíclicos/química , Nitrocompostos/química , Nitrorredutases/antagonistas & inibidores , Pró-Fármacos/química , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/farmacologia , Aziridinas/farmacologia , Aziridinas/normas , Misturas Complexas/química , Misturas Complexas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fermentação , Compostos de Anéis Fundidos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Policetídeos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade
9.
Nucleic Acids Res ; 48(19): 10998-11015, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33045725

RESUMO

G-quadruplex (G4) structures are stable non-canonical DNA structures that are implicated in the regulation of many cellular pathways. We show here that the G4-stabilizing compound PhenDC3 causes growth defects in Schizosaccharomyces pombe cells, especially during S-phase in synchronized cultures. By visualizing individual DNA molecules, we observed shorter DNA fragments of newly replicated DNA in the PhenDC3-treated cells, suggesting that PhenDC3 impedes replication fork progression. Furthermore, a novel single DNA molecule damage assay revealed increased single-strand DNA lesions in the PhenDC3-treated cells. Moreover, chromatin immunoprecipitation showed enrichment of the leading-strand DNA polymerase at sites of predicted G4 structures, suggesting that these structures impede DNA replication. We tested a subset of these sites and showed that they form G4 structures, that they stall DNA synthesis in vitro and that they can be resolved by the breast cancer-associated Pif1 family helicases. Our results thus suggest that G4 structures occur in S. pombe and that stabilized/unresolved G4 structures are obstacles for the replication machinery. The increased levels of DNA damage might further highlight the association of the human Pif1 helicase with familial breast cancer and the onset of other human diseases connected to unresolved G4 structures.


Assuntos
Quebras de DNA de Cadeia Simples , Replicação do DNA , DNA Fúngico/química , Quadruplex G , Schizosaccharomyces/genética , DNA Helicases/fisiologia , Compostos de Anéis Fundidos/farmacologia , Fase S , Proteínas de Schizosaccharomyces pombe/fisiologia
10.
Cell Chem Biol ; 26(12): 1681-1691.e5, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31668518

RESUMO

Heme is an essential cofactor for many enzymes, but free heme is toxic and its levels are tightly regulated. G-quadruplexes bind heme avidly in vitro, raising the possibility that they may sequester heme in vivo. If so, then treatment that displaces heme from quadruplexes is predicted to induce expression of genes involved in iron and heme homeostasis. Here we show that PhenDC3, a G-quadruplex ligand structurally unrelated to heme, displaces quadruplex-bound heme in vitro and alters transcription in cultured human cells, upregulating genes that support heme degradation and iron homeostasis, and most strikingly causing a 30-fold induction of heme oxidase 1, the key enzyme in heme degradation. We propose that G-quadruplexes sequester heme to protect cells from the pathophysiological consequences of free heme.


Assuntos
Compostos de Anéis Fundidos , Quadruplex G , Heme/metabolismo , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Catalítico/metabolismo , Heme/química , Humanos , Ferro/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Transcrição Genética/efeitos dos fármacos
11.
Cell Chem Biol ; 26(12): 1716-1724.e9, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31631010

RESUMO

Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferroptosis, and other pathways. CIL56-induced cell death requires a catalytically active protein S-acyltransferase complex comprising the enzyme ZDHHC5 and an accessory subunit GOLGA7. The ZDHHC5-GOLGA7 complex is mutually stabilizing and localizes to the plasma membrane. CIL56 inhibits anterograde protein transport from the Golgi apparatus, which may be lethal in the context of ongoing ZDHHC5-GOLGA7 complex-dependent retrograde protein trafficking from the plasma membrane to internal sites. Other oxime-containing small molecules, structurally distinct from CIL56, may trigger cell death through the same pathway. These results define an unconventional form of nonapoptotic cell death regulated by protein S-acylation.


Assuntos
Aciltransferases/metabolismo , Morte Celular , Proteínas da Matriz do Complexo de Golgi/metabolismo , Acilação , Aciltransferases/química , Aciltransferases/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/metabolismo , Compostos de Anéis Fundidos/química , Compostos de Anéis Fundidos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Proteínas da Matriz do Complexo de Golgi/química , Proteínas da Matriz do Complexo de Golgi/genética , Humanos , Camundongos , Oximas/química , Oximas/farmacologia , Proteína S/metabolismo , Transporte Proteico/efeitos dos fármacos
12.
Chem Biodivers ; 16(12): e1900313, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31545879

RESUMO

Cissampelos sympodialis Eichler is well studied and investigated for its antiasthmatic properties, but there are no data in the literature describing antibacterial properties of alkaloids isolated from this botanical species. This work reports the isolation and characterization of phanostenine obtained from roots of C. sympodialis and describes for the first time its antimicrobial and antibiotic modulatory properties. Phanostenine was first isolated from Cissampelos sympodialis and its antibacterial activities were determined. Chemical structures of the alkaloid isolate were determined using spectroscopic and chemical analyses. Phanostenine was also tested for its antibacterial activity against standard strains and clinical isolates of Escherichia coli and Staphylococcus aureus. Minimal inhibitory concentration (MIC) was determined in a microdilution assay and for the evaluation of antibiotic resistance-modifying activity. MIC of the antibiotics was determined in the presence or absence of phanostenine at sub-inhibitory concentrations. The evaluation of antibacterial activity by microdilution assay showed activity for all strains with better values against S. aureus ATCC 12692 and E. coli 27 (787.69 mm). The evaluation of aminoglycoside antibiotic resistance-modifying activity showed reduction in the MIC of the aminoglycosides (amikacin, gentamicin and neomycin) when associated with phanostenine, MIC reduction of antibiotics ranging from 21 % to 80 %. The data demonstrated that phanostenine possesses a relevant ability to modify the antibiotic activity in vitro. We can suggest that phanostenine presents itself as a promising tool as an adjuvant for novel antibiotics formulations against bacterial resistance.


Assuntos
Alcaloides/química , Antibacterianos/química , Derivados de Benzeno/química , Cissampelos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Derivados de Benzeno/isolamento & purificação , Derivados de Benzeno/farmacologia , Cissampelos/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Compostos de Anéis Fundidos , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Staphylococcus aureus/efeitos dos fármacos
13.
Chem Pharm Bull (Tokyo) ; 67(6): 576-579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155563

RESUMO

Spatiotemporally controllable nitric oxide (NO) releasers are very attractive chemical tools for investigating the biological activities of NO, which is involved in the regulation of vasodilation, neurotransmission, and immune responses. We previously developed an easily synthesized, yellowish-green-light-controllable NO releaser, NO-Rosa5, and characterized its photoredox reaction mechanism. Here, we aimed to establish the biological applicability of NO-Rosa5 for in cellullo and ex vivo experiments. We successfully demonstrated yellowish-green-light-controlled NO release in HEK293T cells in vitro, as well as photomanipulation of the rat aorta response to NO in an ex vivo system. Furthermore, NO-Rosa5 showed lower toxicity than NOBL-1, a previously reported blue-light-controllable NO releaser, as determined by tetrazolium salt cell viability assay. Overall, our results indicate that NO-Rosa5 is a biocompatible, photocontrollable NO releaser with low toxicity and potentially broad applicability.


Assuntos
Compostos de Anéis Fundidos/metabolismo , Morfolinas/metabolismo , Doadores de Óxido Nítrico/química , Óxido Nítrico/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Luz , Microscopia de Fluorescência , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/farmacologia , Oxirredução , Ratos
14.
Phytomedicine ; 62: 152931, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31085375

RESUMO

BACKGROUND: Euphorbia factor L2 has potent effects on ascites, hydropsy and cancers. PURPOSE: We investigated the pharmacological effects of Euphorbia factor L2 (EFL2) on hepatocellular carcinoma (HCC). METHODS: MTT assay was conducted to determine the proliferative activity of EFL2 on Hep G2 and SMMC-7721 cells. Wound-healing assay, colony formation assay, western blotting and quantitative PCR were carried out to examine the cell migration, p-AKT and p-STAT3 signaling. Moreover, we used human tumor xenograft BALB/c nude mice to detect the effect of EFL2 on HCC in vivo. RESULTS: EFL2 inhibited the proliferation of SMMC-7721 and Hep G2 cells in concentration- and time-dependent manners. EFL2 also suppressed the cell migration and colony formation of hepatocellular carcinoma cells. Using a transforming growth factor-ß (TGF-ß)-induced epithelial-mesenchymal transition (EMT) model, we provided evidences that EFL2 could also inhibit TGF-ß induced cell growth, vimentin, N-cadherin expressions, activation of p-AKT and p-STAT3, whereas up-regulate E-cadherin expression. Furthermore, EFL2 inhibited tumor growth and STAT3 phosphorylation in vivo. CONCLUSION: In conclusion, EFL2 has the potential to be explored as a candidate treatment agent for HCC by inhibiting cell growth and migration both in vitro and in vivo.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzoatos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Euphorbia/química , Compostos de Anéis Fundidos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Compostos Macrocíclicos/farmacologia , Compostos Policíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia
15.
Chemistry ; 24(41): 10443-10451, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-29732638

RESUMO

Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. We report the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates. Essential quality control (QC) for selection of small molecules to add to a fragment library is discussed.


Assuntos
Descoberta de Drogas/métodos , Compostos de Anéis Fundidos/síntese química , Pirazóis/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Simulação por Computador
16.
Org Lett ; 19(16): 4247-4250, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28753015

RESUMO

A general method for synthesis of 1,2-bis-trifluoromethylthioarenes has been developed. Arynes generated from silyl aryl triflates or halides react with bis(trifluoromethyl)disulfide to afford 1,2-bis-trifluoromethylthioarenes. Aryl, alkyl, ester, halide, and methoxy functionalities are compatible with reaction conditions. Use of bis(perfluoroaryl)disulfides gave moderate yields of aryne disulfenylation or cyclization to fluorinated dibenzothiophenes.


Assuntos
Compostos de Anéis Fundidos/síntese química , Compostos de Espiro/síntese química , Sulfetos/síntese química , Técnicas de Química Sintética , Ciclização , Estrutura Molecular , Relação Estrutura-Atividade
17.
J Neural Transm (Vienna) ; 123(12): 1423-1433, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27287334

RESUMO

Huntington's disease is an incurable, adult-onset, autosomal dominant inherited disorder caused by an expanded trinucleotide repeat (CAG). In this study, we describe a Huntington's disease patient displaying clinical symptoms of the behavioural variant of frontotemporal dementia in the absence of tremor and ataxia. The clinical onset was at the age of 36 years and the disease progressed slowly (18 years). Genetic testing revealed expanded trinucleotide CAG repeats in the Huntingtin gene, together with a Glu318Gly polymorphism in presenilin 1. Neuropathological assessment revealed extensive amyloid ß (Aß) aggregates in all cortical regions. No inclusions displaying hyperphosphorylated tau or phosphorylated transactive response DNA-binding protein 43 (TDP43) were found. A high number of p62 (sequestosome 1) immunopositive intranuclear inclusions were seen mainly in the cortex, while subcortical areas were affected to a lesser extent. Confocal microscopy revealed that the majority of p62 intranuclear lesions co-localised with the fused-in-sarcoma protein (FUS) immunostaining. The morphology of the inclusions resembled intranuclear aggregates in Huntington's disease. The presented proband suffered from Huntington's disease showed atypical distribution of FUS positive intranuclear aggregates in the cortical areas with concomitant Alzheimer's disease pathology.


Assuntos
Encéfalo/metabolismo , Demência Frontotemporal/complicações , Doença de Huntington/complicações , Adulto , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Saúde da Família , Feminino , Compostos de Anéis Fundidos/metabolismo , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/genética , Proteínas de Ligação a RNA/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
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