Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.748
Filtrar
1.
Anticancer Res ; 40(9): 5141-5149, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878802

RESUMO

BACKGROUND/AIM: This study investigated the effects of temozolomide (TMZ) and/or checkpoint kinase inhibitor AZD7762 in human glioma cells. MATERIALS AND METHODS: Glioma cells were treated with TMZ and/or AZD7762 for 24 or 48 h, then the cellular survival was studied and the expression of various proteins was investigated. RESULTS: Both TMZ and AZD7762 induced concentration- and time-dependent cytotoxic effects, and combined TMZ and AZD7762 (TMZ+AZD) caused synergistic cytotoxic effects in glioma cells (p<0.05). AZD7762 suppressed the O6-methylguanine-DNA-methyltransferase (MGMT) expression. TMZ+AZD increased the expression of phospho-p53 (p-p53), p-p38 mitogen-activated protein kinase, and phosphatase and tensin homolog; and decreased the expression of p-extracellular signal-regulated kinase 1/2 and p-signal transducer and activator of transcription 3 in glioma cells. CONCLUSION: TMZ and AZD7762 combined induced synergistic cytotoxic effects on human glioma cells and such effects may be related to the AZD7762-induced suppression of MGMT expression and the modulation of multiple signaling pathways.


Assuntos
Antineoplásicos/farmacologia , Temozolomida/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/metabolismo , Humanos , Ureia/farmacologia
2.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 911-916, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927518

RESUMO

Imatinib has created the era of precise treatment of gastrointestinal stromal tumor (GIST). However, in recent years, there has been a lack of satisfactory drugs for imatinib resistance. Recently, the emergence of a series of new agents not only brings new hope to break this situation, but also verifies that the drug development of GIST treatment still needs to lock the driving gene as the main target. New drugs, such as avapritinib and ripretinib, have shown surprising therapeutic efficacy, which may lead to a new situation in the treatment of GIST. The precise treatment of GIST guided by different primary gene mutations and secondary drug resistance mutations will replace the traditional guidelines based on the number of treatment lines.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Antineoplásicos/farmacologia , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêutico
3.
Br J Anaesth ; 125(4): 596-604, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32819621

RESUMO

BACKGROUND: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent Gi/o activator with minimal ß-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates. METHODS: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females). RESULTS: After subcutaneous administration, PZM21 (1.0-6.0 mg kg-1) and oxycodone (0.1-0.6 mg kg-1) induced dose-dependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03-0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching. CONCLUSIONS: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.


Assuntos
Analgésicos/farmacologia , Prurido/induzido quimicamente , Receptores Opioides mu/agonistas , Reforço Psicológico , Tiofenos/farmacologia , Ureia/análogos & derivados , Animais , Relação Dose-Resposta a Droga , Feminino , Macaca mulatta , Masculino , Ureia/farmacologia
4.
Life Sci ; 257: 118046, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622948

RESUMO

Orexin-A is an endogenous peptide with receptors throughout the brain. According to some recent research, learning and memory are affected by the central administration of orexin; however, no study so far has investigated the long-term inhibition of the orexinergic system. The present study has evaluated the effect of pretraining administration of orexin 1 receptor (OXR1) antagonist, SB-334867, on the acquisition of memory. The Morris water maze (MWM) task was used for training and trial purposes in all groups. Memory performance was analyzed by measuring escape latency, traveled distance, and time spent in the target quadrant. Moreover, the effect of SB-334867 on phospholipase Cß3 (PLCß3) levels in the CA1 region of hippocampus slices was examined. Hippocampus slices were prepared using an immunohistochemistry (IHC) approach. SB-334867 (20 mg/kg) increased escape latency in SB-treated rats compared to SB-vehicle group (P < 0.01). SB-treated rats spent less time in the target quadrant compared to the SB-vehicle group (P < 0.001). Distance traveled in the target quadrant was significantly more in SB-treated rats compared to the SB-vehicle group (P < 0.001). Furthermore, SB-334867 decreased PLCß3 levels in the CA1 of the hippocampus (P < 0.01 and P < 0.05, respectively). Put together, our results suggest that the long-term inhibition of OXR1 plays a prominent role in spatial learning and memory, probably by attenuating PLCß3 in CA1 neurons.


Assuntos
Memória/efeitos dos fármacos , Memória/fisiologia , Fosfolipase C beta/metabolismo , Animais , Benzoxazóis/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Fosfolipase C beta/fisiologia , Ratos , Ratos Wistar , Ureia/análogos & derivados , Ureia/farmacologia
5.
Nat Commun ; 11(1): 3405, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636378

RESUMO

Omecamtiv mecarbil (OM) is a putative positive inotropic tool for treatment of systolic heart dysfunction, based on the finding that in vivo it increases the ejection fraction and in vitro it prolongs the actin-bond life time of the cardiac and slow-skeletal muscle isoforms of myosin. OM action in situ, however, is still poorly understood as the enhanced Ca2+-sensitivity of the myofilaments is at odds with the reduction of force and rate of force development observed at saturating Ca2+. Here we show, by combining fast sarcomere-level mechanics and ATPase measurements in single slow demembranated fibres from rabbit soleus, that the depressant effect of OM on the force per attached motor is reversed, without effect on the ATPase rate, by physiological concentrations of inorganic phosphate (Pi) (1-10 mM). This mechanism could underpin an energetically efficient reduction of systolic tension cost in OM-treated patients, whenever [Pi] increases with heart-beat frequency.


Assuntos
Miosinas Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miosinas/metabolismo , Fosfatos/farmacologia , Ureia/análogos & derivados , Adenosina Trifosfatases/metabolismo , Animais , Cálcio/metabolismo , Sinergismo Farmacológico , Masculino , Músculo Esquelético/metabolismo , Coelhos , Sarcômeros/metabolismo , Estresse Mecânico , Ureia/farmacologia
6.
PLoS One ; 15(6): e0234544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555670

RESUMO

Controlled-release and slow-release fertilizers can effectively supply nitrogen (N) while mitigating N loss. To determine the suitability of these fertilizers for plants in semi-arid environments, these fertilizers need to be evaluated under varying placement and temperature conditions. Several urea fertilizers were evaluated, including: uncoated, sulfur-coated (SCU), polymer-coated-sulfur-coated (PCSCU), and polymer-coated (PCU) with projected release timings between 45 and 180 d. Nitrogen release was measured under daily fluctuating or static temperatures applied either to the surface or buried in the soil. A second experiment consisted of two PCU sources and added a hanging bag placement comparison and low and high soil moisture treatments. For the first Experiment, the N in uncoated urea released shortly after application. The SCU and PCSCU treatments released > 80% of the N before the first sampling date. With fluctuating temperatures, the PCU 45, 75, 120, and 180 incorporated into the soil released N within +9, +9, -22, and -68 d of their expected timing. However, they released their N within 35 d when surface applied. Conversely, with static temperatures, PCU products released slowly, releasing under 80% for the entire study. The second experiment verified these results and showed no difference between low and high moisture and minimal release with fertilizer not in contact with soil. Each coated fertilizer in these studies exhibited slow/control release properties, but the PCU (surface applied) and SCU/PCSCU (surface applied or incorporated in soil) release was much more rapid than expected. Our research suggests that, although the SCU and PCSCU showed minimal slow-release properties (regardless of placement), the PCU fertilizers incorporated in the soil do have a controlled release approximate to what is expected, but have a much more rapid release when surface applied.


Assuntos
Agricultura , Preparações de Ação Retardada/farmacologia , Fertilizantes , Nitrogênio/farmacologia , Preparações de Ação Retardada/química , Nitrogênio/química , Polímeros/química , Solo/química , Enxofre/química , Temperatura , Ureia/química , Ureia/farmacologia
7.
J Biosci Bioeng ; 130(2): 179-186, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32381439

RESUMO

The sediment-water interface is not only an important location for substrate conversion in a mariculture system, but also a major source of eutrophication. This study aimed to clarify the characteristics of inorganic nitrogen (ammonia, nitrite and nitrate) removal by Marichromatium gracile YL28 in the presence of both organic nitrogen and inorganic nitrogen. The results showed that, in the presence of peptone or urea, seaweed oligosaccharides (SOS) effectively enhanced the ammonia removal capacity of YL28 (6.42 mmol/L) and decreased the residual rate by 54.04% or 8.17%, respectively. With increasing peptone or urea concentrations, the removal of both ammonia and nitrate was gradually inhibited, and the residual rates of ammonia and nitrate reached 22.56-34.36% and 12.03-15.64% in the peptone system and 20.65-24.03% and 12.20-13.21% in the urea system, respectively. However, in the control group the residual rates of ammonia and nitrate reached 11.97% and 5.12%, respectively. In addition, the concentrations of peptone and urea did not affect nitrite removal, and YL28 displayed better cell growth and nitrogen removal activity in the presence of bait and SOS. Overall, the ability of YL28 to remove inorganic nitrogen was enhanced in the presence of organic nitrogen.


Assuntos
Aquicultura , Chromatiaceae/metabolismo , Nitrogênio/química , Nitrogênio/isolamento & purificação , Peptonas/farmacologia , Ureia/farmacologia , Água/química , Amônia/isolamento & purificação , Amônia/metabolismo , Desnitrificação/efeitos dos fármacos , Nitratos/isolamento & purificação , Nitratos/metabolismo , Nitritos/isolamento & purificação , Nitritos/metabolismo
8.
Biochim Biophys Acta Biomembr ; 1862(6): 183265, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32156647

RESUMO

G protein-coupled receptors (GPCRs) constitute the largest superfamily of membrane proteins in higher eukaryotes, and facilitate information transfer from the extracellular environment to the cellular interior upon activation by ligands. Their role in diverse signaling processes makes them an attractive choice as drug targets. GPCRs are coupled to heterotrimeric G-proteins which represent an important interface through which signal transduction occurs across the plasma membrane upon activation by ligands. To obtain further insight into the molecular details of interaction of G-proteins with GPCRs, in this work, we explored the selectivity of binding of specific agonists and antagonists to the serotonin1A receptor under conditions of progressive G-protein inactivation. The serotonin1A receptor is an important neurotransmitter receptor belonging to the GPCR family and is a popular drug target. By use of a number of agents to inactivate G-proteins, we show here that the serotonin1A receptor displays differential discrimination between agonist and antagonist binding. Our results show a reduction in binding sites of the receptor upon treatment with G-protein inactivating agents. In addition, G-protein coupling efficiency was enhanced when G-proteins were inactivated using urea and alkaline pH. We envision that our results could be useful in achieving multiple signaling states of the receptor by fine tuning the conditions of G-protein inactivation and in structural biology of GPCRs bound to specific ligands.


Assuntos
Descoberta de Drogas , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Sítios de Ligação , Proteínas de Ligação ao GTP/metabolismo , Concentração de Íons de Hidrogênio , Ligação Proteica , Ureia/farmacologia
9.
J Med Chem ; 63(7): 3563-3576, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32207938

RESUMO

In an effort to seek novel agents targeting prostate-specific membrane antigen (PSMA), 16 ligands (L1-L16) with structural modifications in S1' binding pocket were synthesized and evaluated for PSMA inhibition. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acids proved to be potent PSMA ligands with Ki values ranging from 0.08 nM to 8.98 nM, which are in the range of or are higher in potency compared to previously published urea-based ligands. Computational docking was performed to study the binding mode of the two most potent ligands discovered. FITC-conjugated L14 could selectively stain PSMA+ LNCaP cells over PSMA- PC3 cells. IRDye800CW conjugated L16 can effectively image tumors in a murine xenograft model of prostate cancer.


Assuntos
Corantes Fluorescentes/farmacologia , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Imagem Óptica/métodos , Estudo de Prova de Conceito , Ligação Proteica , Ureia/metabolismo
10.
Pak J Biol Sci ; 23(2): 173-180, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31944077

RESUMO

BACKGROUND AND OBJECTIVE: In spite of therapeutic effect of tamoxifen on the breast cancer, it has some side effects on the liver including non-alcoholic fatty liver disease. In this study the effects of Rosa canina distilled water on the tamoxifen-induced fatty liver and oxidative stress status in male rats were investigated. MATERIALS AND METHODS: Twenty four adult male Wistar rats were randomly divided into 4 groups of 6: 1st group: Untreated control rats (C), 2nd group (T): The rats received tamoxifen, 3rd group (T+R): Rats received tamoxifen and Rosa canina distilled water and 4th group (R): Rats received only Rosa canina distilled water. Tamoxifen at 1 mg kg-1/day was injected subcutaneously for 7 days and the rats received orally Rosa canina distilled water at 1 mL/rat/daily for 14 days. At the end of the study, animals were studied for serum biochemical parameters (glucose, lipid profile, BUN, creatinine, uric acid, urea, ALT, AST, ALP, total protein, bilirubin, oxidative stress indices, sperm analysis and histology of the liver. The data were analyzed with SPSS software version 20 and expressed as Mean±SD. RESULTS: Rosa canina distilled water improved liver enzyme and renal function indices which disturbed due to tamoxifen treatment. While tamoxifen enhanced lipid peroxidation, Rosa canina distilled water reduced it. In addition, tamoxifen reduced the mobility, morphology and viability of sperms, but the Rosa canina distilled water enhanced the sperm parameters. Histological results also confirmed the adverse effect of tamoxifen and the favorable impact of the Rosa canina distilled water on the liver structures of animals. CONCLUSION: Rosa canina distilled water could modulate tamoxifen-induced fatty liver as well as improving the sperm parameters.


Assuntos
Fígado Gorduroso/terapia , Extratos Vegetais/farmacologia , Rosa/química , Tamoxifeno/efeitos adversos , Água/química , Animais , Antioxidantes/farmacologia , Glicemia/análise , Fígado Gorduroso/induzido quimicamente , Rim/efeitos dos fármacos , Peroxidação de Lipídeos , Masculino , Estresse Oxidativo , Plantas Medicinais , Ratos , Ratos Wistar , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Ureia/farmacologia
11.
BMC Ophthalmol ; 20(1): 28, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941474

RESUMO

BACKGROUND: Corneal infections with antibiotic-resistant microorganisms are an increasingly difficult management challenge and chemically or photochemically cross-linking the cornea for therapy presents a unique approach to managing such infections since both direct microbial pathogens killing and matrix stabilization can occur simultaneously. The present study was undertaken in order to compare the anti-microbial efficacy, in vitro, of 5 candidate cross-linking solutions against 5 different microbial pathogens with relevance to infectious keratitis. METHODS: In vitro bactericidal efficacy studies were carried out using 5 different FARs [diazolidinyl urea (DAU), 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDM), sodium hydroxymethylglycinate (SMG), 2-(hydroxymethyl)-2-nitro-1,3-propanediol (NT = nitrotriol), 2-nitro-1-propanol (NP)] against 5 different microbial pathogens including two antibiotic-resistant species [methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Pseudomonas aeruginosa (PA), and Candida albicans (CA)]. Standard in vitro antimicrobial testing methods were used. RESULTS: The results for MSSA were similar to those for MRSA. DAU, DMDM, and SMG all showed effectiveness with greater effects generally observed with longer incubation times and higher concentrations. Against MRSA, 40 mM SMG at 120 min showed a > 95% kill rate, p < 0.02. Against VRE, 40 mM DAU for 120 min showed a > 94% kill rate, p < 0.001. All FARs showed bactericidal effect against Pseudomonas aeruginosa, making PA the most susceptible of the strains tested. Candida showed relative resistance to these compounds, requiring high concentrations (100 mM) to achieve kill rates greater than 50%. CONCLUSION: Our results show that each FAR compound has different effects against different cultures. Our antimicrobial armamentarium could potentially be broadened by DAU, DMDM, SMG and other FARs for antibiotic-resistant keratitis. Further testing in live animal models are indicated.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Formaldeído/metabolismo , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Resistência a Medicamentos , Farmacorresistência Bacteriana , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Testes de Sensibilidade Microbiana , Nitrocompostos/farmacologia , Propanóis/farmacologia , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Trometamina/análogos & derivados , Trometamina/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
12.
J Recept Signal Transduct Res ; 40(1): 34-41, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910703

RESUMO

Synthesis of a series of new urea and thiourea compounds have been accomplished by the reaction of 2,3-dihydro-1H-inden-1-amine with various phenyl isocyanates and isothiocyanates. These compounds were evaluated for their antioxidant activity by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and nitric oxide (NO) radical scavenging assay methods including IC50 values. Some of the compounds exhibited potential activity in the two tested methods. Among the series of compounds, urea derivative linked with 4-bromo phenyl ring (4b), and thiourea derivatives bonded with phenyl ring (4e), 4-fluoro phenyl ring (4f) and 4-nitro pheyl ring (4h) were found to exhibit promising anti oxidant activity with low IC50 values. Where four of the title comounds exhibited higher bindig energies than the reference compound (Imatinib) in in silico molecular docking studies with Aromatase. All the synthesized compounds were characterized by IR, 1H, 13C NMR and mass spectral data.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Simulação por Computador , Tioureia/farmacologia , Ureia/farmacologia , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/química , Depuradores de Radicais Livres/química , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Óxido Nítrico/química , Picratos/química , Tioureia/síntese química , Tioureia/química , Ureia/síntese química , Ureia/química
13.
Cancer Sci ; 111(2): 429-440, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808966

RESUMO

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3ß, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3ß in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3ß (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3ß activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3ß inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3ß in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3ß as a new and promising therapeutic target for these STS types.


Assuntos
Fibrossarcoma/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Indóis/administração & dosagem , Maleimidas/administração & dosagem , Sarcoma Sinovial/tratamento farmacológico , Tiazóis/administração & dosagem , Ureia/análogos & derivados , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Indóis/farmacologia , Injeções Intraperitoneais , Maleimidas/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Tiazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Eur J Med Chem ; 186: 111896, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31784185

RESUMO

We report here a thorough structure-activity relationship (SAR) with piperazinylureido sulfamates as inhibitors of human (h) carbonic anhydrase (CA, EC 4.2.1.1). A SAR investigation over the structure of reported anti-cancer zinc-binder CAIs such as SLC-0111 and S4 was carried out by including the urea outer nitrogen atom into a substituted piperazine ring reducing the linker flexibility. The derivatives were assessed for the inhibition of CA I, II and IV (off-target isoforms) and the tumor-associated CA IX (anticancer drug target). CA I and IV were not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against CA II (KIs in the range of 1.0-705.5 nM), and IX (KIs in the range of 0.91-155.9 nM). Interestingly, a subset of CA II/IX selective inhibitors was detected which might represent interesting lead for the development of new anticancer strategies.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Ácidos Sulfônicos/farmacologia , Ureia/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Ácidos Sulfônicos/química , Ureia/análogos & derivados , Ureia/química
15.
Am J Physiol Renal Physiol ; 318(2): F375-F387, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813251

RESUMO

Protein arginine methyltransferase 1 (PRMT1), which primarily causes asymmetric arginine methylation of histone and nonhistone proteins, has been found to activate gene expression and mediate multiple pathological processes. Its role in renal fibrosis, however, remains unclear. In the present study, we observed that PRMT1 and its specific epigenetic marker, asymmetric di-methylated histone 4 arginine 3 (H4R3Me2a), were highly expressed in cultured renal interstitial fibroblasts. Treatment of PRMT1 with AMI-1, a selective inhibitor of PRMT1, or silencing PRMT1 with siRNA inhibited serum-induced and transforming growth factor (TGF)-ß1-induced expression of α-smooth muscle actin (α-SMA) and collagen type I, two hallmarks of renal fibroblast activation, in a dose-dependent and time-dependent manner. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, PRMT1 expression and H4R3Me2a were also upregulated, which was coincident with increased expression of α-SMA, collagen type I, and fibronectin. Administration of AMI-1 reduced PRMT1 and H4R3Me2a expression, attenuated extracellular matrix protein deposition, and inhibited renal fibroblast activation and proliferation. Moreover, AMI-1 treatment inhibited Smad3 phosphorylation and TGF-ß receptor I expression but prevented Smad7 downregulation both in the kidney after unilateral ureteral obstruction injury and in cultured renal interstitial fibroblasts exposed to TGF-ß1. Collectively, these results demonstrate that PRMT1 may mediate renal fibroblast activation and renal fibrosis development through activation of the TGF-ß/Smad3 signaling pathway. They also suggest that PRMT1 inhibition may be a potential therapeutic approach for the treatment of fibrotic kidney disease.


Assuntos
Desdiferenciação Celular , Fibroblastos/enzimologia , Nefropatias/enzimologia , Rim/enzimologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína Smad3/metabolismo , Animais , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/enzimologia , Miofibroblastos/patologia , Naftalenossulfonatos/farmacologia , Fosforilação , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Obstrução Ureteral/complicações
16.
J Cell Physiol ; 235(1): 254-266, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237697

RESUMO

Accumulated evidence suggested the importance of the Rho/Rho-kinase (ROCK) signaling pathway in cancer proliferation and invasion. However, its role in colorectal carcinoma (CRC) is not well understood. This study evaluated the effect of ROCK signaling pathway on CRC behavior on the basis of a novel Rho/ROCK inhibitor RKI-1447. Here, we found RKI-1447 could drastically suppress HCT-8 and HCT-116 cell growth and promoted apoptosis. Our in vitro data indicated suppressed cytoskeletal dynamics induced by RKI-1447 inhibition on mitochondrial respiration, which was evidenced by basal and maximal respiration rates, and ATP production. Simultaneously, cellular basal and maximal glycolytic rates, and glycolytic capacity were also reduced in response to RKI-1447. Moreover, RKI-1447 caused excessive reactive oxygen species generation and membrane depolarization as well as activated ER-stress. We also demonstrated CHOP is essential for RKI-1447 induced cell apoptosis. Finally, we proved inhibition of ROCK by RKI-1447 could effectively inhibit CRC growth in vivo. Taken together, this study demonstrated that inhibition of ROCK signaling pathway by RKI-1447 could suppress CRC via cytoskeleton associated mitochondrial dysfunction and cellular bioenergetics disruption. Our data suggest RKI-1447 may be an attractive antitumor drug candidate for the treatment of CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Tiazóis/farmacologia , Ureia/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Invasividade Neoplásica/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Associadas a rho/antagonistas & inibidores
17.
Eur J Med Chem ; 187: 111973, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881453

RESUMO

Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including ß-thalassemia. Small molecule activators of HRI are essential for studying normal- and patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2α may be beneficial. We previously reported development of 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2α phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2α phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.


Assuntos
Antineoplásicos/farmacologia , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Heme/antagonistas & inibidores , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Iniciação 2 em Eucariotos/metabolismo , Heme/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
18.
Eur J Med Chem ; 187: 111971, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881457

RESUMO

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Fármacos , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
19.
Eur J Med Chem ; 185: 111840, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711794

RESUMO

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 µM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs.


Assuntos
Adenovírus Humanos/efeitos dos fármacos , Antivirais/farmacologia , Piperazinas/farmacologia , Ureia/farmacologia , Células A549 , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
20.
J Enzyme Inhib Med Chem ; 35(1): 404-413, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880473

RESUMO

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.


Assuntos
Helicobacter pylori/efeitos dos fármacos , Ureia/farmacologia , Urease/antagonistas & inibidores , Antibacterianos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Helicobacter pylori/citologia , Helicobacter pylori/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Urease/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA