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1.
J Med Chem ; 63(8): 3956-3975, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208600

RESUMO

The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.


Assuntos
Acetanilidas/química , Acetanilidas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Descoberta de Drogas/métodos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Piridonas/química , Piridonas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/metabolismo , Cães , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
2.
J Pharmacol Exp Ther ; 373(1): 122-134, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32102919

RESUMO

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.


Assuntos
Agonismo Parcial de Drogas , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Agonistas do Receptor 5-HT3 de Serotonina/química , Agonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Animais , Cães , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Síndrome do Carcinoide Maligno/fisiopatologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
3.
Science ; 367(6479): 806-810, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32001525

RESUMO

Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.


Assuntos
Farmacorresistência Viral , Inibidores de Integrase de HIV/química , Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Substituição de Aminoácidos/genética , Domínio Catalítico , Microscopia Crioeletrônica/métodos , Glutamina/genética , Glicina/genética , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Histidina/genética , Humanos , Magnésio/química , Mutação , Serina/genética , Imagem Individual de Molécula/métodos
4.
J Agric Food Chem ; 68(4): 982-988, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31909997

RESUMO

Cycloxaprid (CYC) is effective in the control of hemipteran pests, but its bioactivity against lepidopteran pests is still unclear. Here, the bioactivity of CYC against lepidopteran pests was found to be much worse than that against hemipteran insects. To reveal the mechanism, the transcriptomes of CYC-treated and untreated Ostrinia furnacalis larvae were compared. Among the top 20 differentially expressed genes, 11 encode proteins involved in cuticle formation, while only one encodes a detoxifying enzyme. Thus, the cuticle appears to be important for the insensitivity of O. furnacalis to CYC. A pretreatment of O. furnacalis larvae with methoprene enhanced the bioactivity of CYC by 1.12-fold. Moreover, mixtures of CYC with graphene oxide increased the bioactivity of CYC by 1.88-fold. Because lepidopteran and hemipteran insects often harm crops at the same time, the work can help make full use of CYC and reduce the environmental impacts of using multiple pesticides.


Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Sequência de Aminoácidos , Animais , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Estrutura Molecular , Mariposas/química , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Alinhamento de Sequência
5.
J Agric Food Chem ; 68(6): 1588-1595, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31994388

RESUMO

The discovery of new, safe, and effective pesticides is one of the main means for modern crop protection and parasitic disease control. During the search for new insecticidal secondary metabolites from endophytes in Stemona sessilifolia (a traditional Chinese medicine with a long history as an insecticide), 10 new insecticidal endostemonines A-J (1-10) were identified from an endophytic Streptomyces sp. BS-1. Their structures were determined by comprehensive spectroscopic analysis. Endostemonines A-J represent the first reported naturally occurring pyrrole-2-carboxylic ester derivatives, which consisted of different fatty acid chains at the C-2 of pyrrole ring were produced by traditional Chinese medicine endophytic microbes. All new tested compounds exhibited strong lethal activity against Aphis gossypii (LC50 value range of 3.55-32.00 mg/L after 72 h). This research highlighted the discovery of pesticide natural products from insecticidal medicinal plant endophytes for the first time, paving a new pathway for the development of pest control.


Assuntos
Endófitos/química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Inseticidas/metabolismo , Stemonaceae/microbiologia , Streptomyces/química , Streptomyces/metabolismo , Animais , Afídeos/efeitos dos fármacos , Endófitos/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/toxicidade , Inseticidas/química , Inseticidas/toxicidade , Metabolismo Secundário
6.
ACS Appl Mater Interfaces ; 12(2): 2145-2151, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31845568

RESUMO

Two-dimensional (2D) luminescent materials have received tremendous attention for their intrinsic properties and promising practical applications. Achieving 2D luminescent materials with high photoluminescence (PL) efficiency is still a great challenge. Here, ultrathin metal-free 2D luminescent nanosheets of 2,5,8-triamino-tri-s-triazine (melem) are synthesized through a facile liquid exfoliation process assisted by ultrasound. The as-obtained melem nanosheets distribute in the size range from a few nanometers to around 150 nm with a thickness of about 5 to 6 atomic layers. Melem nanosheets exhibit efficient blue emission with a PL efficiency as high as 77.09%, much higher than the heavily explored 2D luminescent g-C3N4 nanosheets. The high efficiency of melem nanosheets comes from the absence of atom vacancies and the low carrier mobility. Benefiting from the easy synthesis, good stability, low cell toxicity, and high efficiency, melem nanosheets are successfully applied as bioimaging materials on human breast cancer cells, requiring no extra treatments such as surface coating or functionalization. These metal-free 2D luminescent melem nanosheets hold great potential for various applications including bioimaging and other biorelated applications.


Assuntos
Diagnóstico por Imagem , Compostos Heterocíclicos com 3 Anéis/química , Luminescência , Metais/química , Nanoestruturas/química , Triazinas/química , Sobrevivência Celular , Elétrons , Grafite/química , Humanos , Células MCF-7 , Nanoestruturas/ultraestrutura , Compostos de Nitrogênio/química , Difração de Raios X
7.
Drugs ; 79(16): 1819-1828, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31642025

RESUMO

Upadacitinib (Rinvoq™), an orally-administered Janus kinase 1 (JAK-1) inhibitor, is being developed by AbbVie for the treatment of rheumatoid arthritis. In August 2019, based on positive results from multinational phase III trials conducted in patients with rheumatoid arthritis, upadacitinib received marketing approval in the USA for the treatment of moderately to severely active rheumatoid arthritis and an inadequate response or intolerance to methotrexate. This article summarizes the milestones in the development of upadacitinib leading to this first approval for the treatment of rheumatoid arthritis.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Aprovação de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antirreumáticos/química , Artrite Reumatoide/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Janus Quinase 1/metabolismo , Metotrexato/efeitos adversos , Metotrexato/farmacologia , Inibidores de Proteínas Quinases/química , Estados Unidos
8.
Org Biomol Chem ; 17(39): 8832-8848, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31556900

RESUMO

The reaction of indolizinones with dimethyl acetylenedicarboxylate gave direct access to 3',8a-dihydrocyclopenta[hi]indolizin-8a-ol and 1H-pyrrol-3(2H)-one in good yields. The former skeleton is a precursor to cyclazines with nitrogen on the periphery, a hitherto un-accessed 10-π system. Their formation involves initial [4 + 2] or [8 + 2] modes of cycloadditions; the retro-Diels Alder reaction of the [4 + 2] cycloadduct leads to 1H-pyrrol-3(2H)-one, whereas [8 + 2] addition followed by π-reorganization leads to the azatricyle. Analysis of substituent effects on product distribution showed that electron donating groups on the C3-aryl ring promote the formation of the azatricycle preponderantly. Treatment of one of these azatricycles (3c) with HBF4 led to the formation of the corresponding 10e-aromatic species which was detected by NMR spectroscopy. In addition, formation of the 1H-pyrrol-3(2H)-one skeleton through the normal retro-Diels Alder pathway was employed in the total synthesis of Discoipyrrole C, which is a new lead against lung cancer.


Assuntos
Alquinos/química , Compostos Heterocíclicos com 3 Anéis/química , Pirrolidinonas/química , Cristalografia por Raios X , Ciclização , Compostos Heterocíclicos com 3 Anéis/síntese química , Indolizinas/química , Modelos Moleculares , Estrutura Molecular , Pirrolidinonas/síntese química
9.
Environ Pollut ; 252(Pt B): 1593-1598, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279977

RESUMO

Exploring traditional neonicotinoid pesticides substitutes has become one of the global scientific attentions because of their hazardous environmental impacts. Cycloxaprid (CYC) is considered to be a promising candidate alternative. But the environmental behaviors and fate of CYC in different planting system remain poorly understood. The accumulation of 14C-labeled CYC stereoisomers within different parts of Chinese cabbage (Brassica chinensis L.) was investigated, with a particular focus on the foliar absorption, translocation and stereoselectivity of CYC, during a laboratory trial. In general, the stereoisomers 14C-5R,8S-CYC and 14C-5S,8R-CYC, their metabolites, as well as the breakdown and reaction products can be transferred in both acropetal and basipetal directions. Most of the two stereoisomers absorbed by plants remained in the treated leaves, whereas a small amount was distributed to the roots. The amount of 14C in the stalks varied among the experimental time points. At 192 h after treatment (HAT), the detected radioactivity of both 14C-5R,8S-CYC and 14C-5S,8R-CYC in the leaves above the treated leaf (LATL) was higher than that in the leaves below the treated leaf (LBTL). However, the stereoisomers of CYC underwent nonstereoselective absorption and translocation in this trial. This information implies that racemic CYC and its metabolites should be a main research focus. Thus, the obtained results provide implications for a more accurate prediction about the risk assessment of CYC, which will be helpful for guiding its rational use as well as securing the ecological environment safety and human health.


Assuntos
Brassica/metabolismo , Compostos Heterocíclicos com 3 Anéis/metabolismo , Inseticidas/metabolismo , Neonicotinoides/metabolismo , Folhas de Planta/metabolismo , Piridinas/metabolismo , Transporte Biológico , Compostos Heterocíclicos com 3 Anéis/química , Inseticidas/química , Modelos Teóricos , Neonicotinoides/química , Raízes de Plantas/metabolismo , Piridinas/química , Estereoisomerismo
10.
Comput Biol Chem ; 82: 25-36, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255972

RESUMO

The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Pirimidinonas/farmacologia , alfa-Glucosidases/metabolismo , Acarbose/química , Células CACO-2 , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/toxicidade , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/toxicidade , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirimidinonas/química , Pirimidinonas/toxicidade , alfa-Glucosidases/química
11.
Mar Drugs ; 17(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331101

RESUMO

Mycousfurans (1 and 2), two new usnic acid congeners, along with (-)-mycousnine (3), (-)-placodiolic acid (4), and (+)-usnic acid (5), were isolated using high-performance liquid chromatography-ultraviolet (HPLC-UV)-guided fractionation of extracts of Mycosphaerella sp. isolated from a marine sediment. The planar structures of 1 and 2 were elucidated using 1D and 2D NMR spectra. The relative configurations of the stereogenic carbons of 1 and 2 were established via analysis of their nuclear Overhauser spectroscopy (NOESY) spectra, and their absolute configurations were determined using a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1 and 2 were found to have antibacterial activity, showing moderate activity against Kocuria rhizophila and Staphylococcus aureus.


Assuntos
Antibacterianos/farmacologia , Ascomicetos/química , Benzofuranos/farmacologia , Furanos/farmacologia , Sedimentos Geológicos/microbiologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Benzofuranos/química , Benzofuranos/isolamento & purificação , Furanos/química , Furanos/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Testes de Sensibilidade Microbiana , Micrococcaceae/efeitos dos fármacos , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos
12.
Chem Commun (Camb) ; 55(54): 7776-7779, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31210218

RESUMO

An unusual class, compact in size, of fluorescent probes based on pyridazino-1,3a,6a-triazapentalene scaffolds exhibits promising fluorescent properties (quantum yield values up to 73%, large Stokes shifts, emission wavelengths located in the green-yellow range, excellent solubility) with good photostability suitable for optical imaging applications.


Assuntos
Corantes Fluorescentes/química , Compostos Heterocíclicos com 3 Anéis/química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Fotodegradação
13.
Biotechnol Appl Biochem ; 66(5): 787-793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31169325

RESUMO

Evidence suggests that Weichang'an (WCA) inhibited the metastasis of colorectal cancer (CRC) in vitro and downregulates oncogenic ß-catenin; more intriguingly, we also found an upregulation of ARHGAP25 in this process. This study aimed to investigate the mechanisms by which WCA regulated CRC metastasis in vitro. Here, HCT116 cells were transfected with siRNAs to interfere ARHGAP25 expression. WCA decoction, XAV939 (a specific Wnt/ß-catenin pathway inhibitor), and LiCl (an activator for Wnt/ß-catenin pathway) were used for treatment. Cell migratory and invasive capacities were determined using Transwell chamber. The activation of Wnt/ß-catenin pathway was assessed by determining the expression of MMP7, MMP9, ZEB1, and ß-catenin. The study suggests that WCA inhibited the migration and invasion of HCT116 cells and suppressed the activation of Wnt/ß-catenin pathway, as evidenced by retarding MMP7, MMP9, ZEB1, and ß-catenin. However, siRNA-ARHGAP25 resulted in the opposite. In siRNA-ARHGAP25-transfected HCT116 cells, WCA (0.4 mg/mL) induced the antimetastatic effects and the inactivation of Wnt/ß-catenin pathway was remarkably reversed with additional LiCl treatment. Our study concludes that inhibiting Wnt/ß-catenin pathway while promoting ARHGAP25 was the mechanism, whereby WCA retarded migration and invasion of CRC in vitro.


Assuntos
Movimento Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Proteínas Ativadoras de GTPase/metabolismo , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Proteínas Ativadoras de GTPase/genética , Células HCT116 , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Relação Estrutura-Atividade , beta Catenina/metabolismo
14.
Colloids Surf B Biointerfaces ; 178: 404-411, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30903979

RESUMO

Previous research has shown that ectoines fluidize lipid monolayers by increasing the liquid expanded region in DPPC monolayers and also decreasing the line tension responsible for the phase morphology. Here, we explored possible effects of the compatible osmolytes ectoine, hydroxyectoine and ß-hydroxybutyrate on lipid bilayer membranes, including effects of temperature and pressure. The effect of the protective osmolytes on the phase transition of DPPC bilayers was investigated by fluorescence spectroscopy, differential scanning calorimetry and pressure perturbation calorimetry. A slight change of the phase behavior was observed, which resulted in a stabilization of the gel phase, which may be caused by an alteration of the hydration properties at the lipid interface and H-bond and electrostatic interactions in the headgroup region. We then explored the cosolvents' effects on giant unilamellar vesicles (GUVs) formed by lipid mixtures exhibiting phase separation into liquid-ordered (lo) and liquid-disordered (ld) domains using BODIPY-PC and the DiI18 dye as labels. The presence of both, ectoine and hydroxyectoine showed significant effects on the lateral organization increasing the fluid domains. Moreover, we observed a considerable increase in the adhesion behavior of small vesicles onto GUV surfaces. Diffusion studies by fluorescence recovery after photobleaching experiments on POPC giant vesicles quantitatively showed a hydroxyectoine-induced increase of the diffusion coefficient values, clearly demonstrating an increase in the lateral mobility of lipid within the bilayer membrane. This study provides clear evidence for the fluidizing effect of the compatible solutes on bilayer lipid membranes. A marked effect, however, was only detected if phase separated domains exist.


Assuntos
Ácido 3-Hidroxibutírico/química , Diamino Aminoácidos/química , Bicamadas Lipídicas/química , Fosfolipídeos/química , Compostos de Boro/química , Compostos Heterocíclicos com 3 Anéis/química , Transição de Fase , Fosfatidilcolinas/química , Pressão , Temperatura , Lipossomas Unilamelares/química
15.
Carbohydr Res ; 474: 34-42, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711766

RESUMO

Legionaminic acid and 4-epi-legionaminic acid are 5,7-diacetamido nonulosonic acids and are assumed to play a crucial role in the virulence of Legionella pneumophila, the causative agent of Legionnaires' disease. Moreover, they are ideal target motifs for the development of vaccines and pathogen detection. Herein, we present a versatile de novo synthesis of legionaminic acid and 4-epi-legionaminic acid. Starting from simple d-serine, the C9-backbone is built up by two CC-bond formation reactions. First, the protected d-serine motif is elongated utilizing a highly stereoselective nitroaldol reaction to give a C6-precursor of desired d-rhamno configuration. Second, an indium-mediated allylation is employed to further elongate the carbon backbone and introduce a masked α-keto acid function.


Assuntos
Técnicas de Química Sintética , Compostos Heterocíclicos com 3 Anéis/química , Nitrocompostos/química , Serina/química , Ácidos Siálicos/síntese química , Açúcares Ácidos/química , Catálise , Humanos , Índio/química , Cinética , Legionella pneumophila/metabolismo , Estrutura Molecular , Estereoisomerismo
16.
ACS Infect Dis ; 5(4): 570-581, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30757898

RESUMO

Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential. Thus, we characterized the mechanism of action of gepotidacin against Staphylococcus aureus gyrase. Gepotidacin was a potent inhibitor of gyrase-catalyzed DNA supercoiling (IC50 ≈ 0.047 µM) and relaxation of positively supercoiled substrates (IC50 ≈ 0.6 µM). Unlike fluoroquinolones, which induce primarily double-stranded DNA breaks, gepotidacin induced high levels of gyrase-mediated single-stranded breaks. No double-stranded breaks were observed even at high gepotidacin concentration, long cleavage times, or in the presence of ATP. Moreover, gepotidacin suppressed the formation of double-stranded breaks. Gepotidacin formed gyrase-DNA cleavage complexes that were stable for >4 h. In vitro competition suggests that gyrase binding by gepotidacin and fluoroquinolones are mutually exclusive. Finally, we determined crystal structures of gepotidacin with the S. aureus gyrase core fusion truncate with nicked (2.31 Å resolution) or intact (uncleaved) DNA (2.37 Å resolution). In both cases, a single gepotidacin molecule was bound midway between the two scissile DNA bonds and in a pocket between the two GyrA subunits. A comparison of the two structures demonstrates conformational flexibility within the central linker of gepotidacin, which may contribute to the activity of the compound.


Assuntos
Acenaftenos/química , Acenaftenos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , DNA Girase/química , DNA Girase/genética , DNA Girase/metabolismo , Humanos , Cinética , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
17.
Mar Drugs ; 17(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30634617

RESUMO

The purpose of this study was to investigate the antiobesity effect and the mechanism of action of diphlorethohydroxycarmalol (DPHC) isolated from Ishige okamurae in 3T3-L1 cells. The antiobesity effects were examined by evaluating intracellular fat accumulation in Oil Red O-stained adipocytes. Based on the results, DPHC dose-dependently inhibited the lipid accumulation in 3T3-L1 adipocytes. DPHC significantly inhibited adipocyte-specific proteins such as SREBP-1c, PPARγ, C/EBP α, and adiponectin, as well as adipogenic enzymes, including perilipin, FAS, FABP4, and leptin in adipocytes. These results indicated that DPHC primarily acts by regulating adipogenic-specific proteins through inhibiting fat accumulation and fatty acid synthesis in adipocytes. DPHC treatment significantly increased both AMPK and ACC phosphorylation in adipocytes. These results indicate that DPHC inhibits the fat accumulation by activating AMPK and ACC in 3T3-L1 cells. Taken together, these results suggest that DPHC can be used as a potential therapeutic agent against obesity.


Assuntos
Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Células 3T3-L1 , Adenilato Quinase/genética , Animais , Sobrevivência Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Camundongos , Estrutura Molecular , Alga Marinha/química
18.
Nat Prod Res ; 33(20): 3011-3015, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30445873

RESUMO

With the help of chemical shifts computed with density functional theory (DFT), it is demonstrated that the reported experimental 13C NMR data of acremolin C are incompatible with the claimed structure of an N2,3-ethenoguanine with an isopropyl group at C-1'. An alternative structure, which is in agreement with both experimental and computed data, presents an isopropyl group at the C-2' position of an N2,3-ethenoguanine and leads to the conclusion that acremolin C is identical with acremolin B.


Assuntos
Alcaloides/química , Compostos Heterocíclicos com 3 Anéis/química , Estrutura Molecular , Teoria da Densidade Funcional , Espectroscopia de Ressonância Magnética , Teoria Quântica
19.
Artigo em Inglês | MEDLINE | ID: mdl-30572204

RESUMO

Dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine are antiretroviral drugs used as part of combined antiretroviral treatment for HIV-infection. For quantification of these drugs in human K2EDTA plasma samples an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was developed and validated. Stable isotope labeled internal standards were used for each analyte. Simple protein precipitation with methanol was implemented to prepare plasma samples of at least 50 µL. The method was validated for dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine over the ranges 9.7-9700, 52-10,470, 9.7-9730, 73-14,680 and 15-3010 ng/mL, respectively. Within-run and between-run accuracy and precision were within ±15% of the nominal concentration for quality controls at high, medium and low concentrations, and within ±20% at the lower limit of quantification for all analytes. Recovery was ≥76% and reproducible. Long-term stability of patient plasma samples was demonstrated for at least 12 months at -40 °C (4 months for etravirine). Currently, this robust method with a run time of 10 min is used in clinical research and for therapeutic drug monitoring of these frequently used antiretroviral drugs.


Assuntos
Antirretrovirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 3 Anéis/sangue , Quinolonas/sangue , Antirretrovirais/química , Antirretrovirais/farmacocinética , Estabilidade de Medicamentos , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Limite de Detecção , Modelos Lineares , Quinolonas/química , Quinolonas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
20.
Talanta ; 192: 233-240, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348383

RESUMO

Probe encapsulated by biologically localized embedding (PEBBLE) has emerged as a new type of sensing technique for complex systems. Generalized ratiometric PEBBLE nanosensors prepared by encapsulating an intensity-based probe and an inert reference dye inside the pores of stable matrix possess advantages of easy synthesis, immunity to interference, lower toxicity, and robustness to variations in probe loading. However, the selection of appropriate reference dyes used in generalized ratiometric PEBBLE nanosensors is a rather difficult task since they should satisfy some stringent requirements. In this contribution, the feasibility of using carbon dots (C-dots) as generic inert references in synthesizing PEBBLE nanosensors was first investigated in detail. And a dual-wavelength monitoring strategy and the quantitative fluorescence model for generalized ratiometric probes (QFMGRP) were adopted to solve the problems brought by the use of carbon dots as inert references. C-dots doped PEBBLE nanosensors (C-PEBBLE nanosensors) for the quantification of NO2- and free Ca2+ were synthesized by encapsulating C-dots and intensity based fluorescence probes (i.e., acriflavine for NO2-, and Rhod-2 for Ca2+, respectively) inside the pores of stable matrix. Experimental results showed that the combination of C-PEBBLEs, the QFMGRP model and the dual-wavelength monitoring strategy achieved accurate quantification of NO2- and the free Ca2+ in real-world samples. Their quantitative results were in good consistence with those determined by HPLC and atomic absorption spectrophotometer, respectively. The strategies proposed in this contribution have generic applicability in the synthesis of PEBBLE nanosensors and their quantitative applications.


Assuntos
Carbono/química , Corantes Fluorescentes/química , Pontos Quânticos/química , Acriflavina/química , Resinas Acrílicas/química , Cálcio/análise , Fluorescência , Compostos Heterocíclicos com 3 Anéis/química , Limite de Detecção , Nitritos/análise , Tamanho da Partícula , Polimerização , Porosidade , Espectrometria de Fluorescência/métodos
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