Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.255
Filtrar
1.
Phys Chem Chem Phys ; 22(10): 5487-5499, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32101223

RESUMO

Ubiquitin specific protease 7 (USP7) has attracted increasing attention because of its multifaceted roles in different tumor types. The crystal structures of USP7-inhibitor complexes resolved recently provide reliable models for computational structure-based drug design (SBDD) towards USP7. How to accurately estimate USP7-ligand binding affinity is quite critical to guarantee the reliability of SBDD. In this study, we assessed the reliability of multiple computational methods to the binding affinity prediction for a series of USP7 inhibitors with the pyrimidinone scaffold, including molecular docking scoring, MM/PB(GB)SA, and umbrella sampling (US). It was found that the accuracy of the evaluated computational methods for binding affinity prediction follows the order: US-based method > MM/PB(GB)SA > Glide XP scoring. The calculation results demonstrate that incorporating protein flexibility through induced-fit docking or ensemble docking cannot improve the performance of the Glide scoring based on rigid-receptor docking. For the MM/PB(GB)SA methods, the choice of the protein structure and the calculation procedure has a marked impact on the predictions. More importantly, we discovered for the first time that there are significant differences in the dissociation pathways of strong-binding inhibitors and weak-binding inhibitors of USP7, which may be used as a new criterion to judge whether an inhibitor is a strong binder or not. It is expected that our work can provide valuable guidance on the design and discovery of potent USP7 inhibitors.


Assuntos
Inibidores Enzimáticos/metabolismo , Pirimidinonas/química , Peptidase 7 Específica de Ubiquitina/metabolismo , Desenho de Drogas , Inibidores Enzimáticos/química , Ligação Proteica
3.
J Asian Nat Prod Res ; 22(1): 69-82, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30588834

RESUMO

Dozens of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones were synthesized in a straightforward method by condensation of substituted 2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-diones or N-methyl-2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-dione with 3,4-dihydro-ß-carbolines. In vitro cytotoxic assay discovered that compounds 9a, 10e, 11a, 11d, 11f, and 12a could induce antiproliferation against four different types of human cancer cells while compounds 10f and 12e were inactive. Notably, compound 11a displayed potent cell cytotoxicity for human non-small cell lung cancer cells A549, PC-9, human prostate cancer cells PC-3, and human breast cancer cell line MCF-7. Furthermore, compound 11a exhibited strong colony formation inhibition to A549 cells. These results unfold potential anticancer therapeutic applications of hybrids of thieno[2,3-d]pyrimidinones and quinazolinones.


Assuntos
Alcaloides , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Alcaloides Indólicos , Estrutura Molecular , Pirimidinonas , Quinazolinas , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 68(2): 471-484, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31841334

RESUMO

Plant diseases seriously affect crop yield and quality and are difficult to control. Marine natural products (MNPs) have become an important source of drug candidates with new biological mechanisms. Marine natural product essramycin (1) was found to have good anti-tobacco mosaic virus (TMV) and anti-phytopathogenic fungus activities for the first time. A series of essramycin derivatives were designed, synthesized, and evaluated for their bioactivity. Most of these compounds exhibited antiviral effects that are greater than that of the control ribavirin. Compounds 7e and 8f displayed antiviral activities that are greater than that of ningnanmycin (the most widely used antiviral agent at present), thus emerging as novel antiviral lead compounds. As the lead compound, 7e was selected for further antiviral mechanism research. The results indicated that 7e could inhibit virus assembly and promote 20S disk protein aggregation. Fungicidal activity tests against 14 kinds of phytopathogenic fungi revealed that essramycin analogues displayed broad-spectrum fungicidal activities. Compound 5b displayed more than 50% inhibition rate against most of the 14 kinds of phytopathogenic fungi at 50 µg/mL. The current research lays a solid foundation for the application of essramycin alkaloids in crop protection.


Assuntos
Alcaloides/química , Antivirais/química , Fungicidas Industriais/química , Pirimidinonas/química , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Triazóis/química , Alcaloides/farmacologia , Antivirais/farmacologia , Fungos/efeitos dos fármacos , Fungos/fisiologia , Fungicidas Industriais/farmacologia , Estrutura Molecular , Doenças das Plantas/microbiologia , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/fisiologia , Triazóis/farmacologia , Montagem de Vírus/efeitos dos fármacos
5.
Chem Commun (Camb) ; 56(2): 201-204, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31799554

RESUMO

Dark nπ* states were shown to have substantial contribution to the destructive photochemistry of pyrimidine nucleobases. Based on quantum-chemical calculations, we demonstrate that the characteristic hydrogen bonding pattern of the GC base pair could facilitate the formation of a wobble excited-state charge-transfer complex. This entails a barrierless electron-driven proton transfer (EDPT) process which enables damageless photodeactivation of the base pair. These photostabilizing properties are retained even when guanine is exchanged to hypoxanthine. The inaccessibility of this process in the AT base pair sheds further light on the reasons why cytosine is less susceptible to the formation of photodimers in double-stranded DNA.


Assuntos
Pareamento de Bases , DNA/química , Prótons , Pareamento de Bases/efeitos da radiação , DNA/genética , DNA/efeitos da radiação , Ligações de Hidrogênio , Modelos Químicos , Conformação de Ácido Nucleico , Purinonas/química , Pirimidinonas/química , Teoria Quântica , Raios Ultravioleta
6.
Pharm Res ; 37(1): 5, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823112

RESUMO

PURPOSE: To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965. METHODS: Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. RESULTS: AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. CONCLUSIONS: The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.


Assuntos
Pirimidinonas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Circulação Êntero-Hepática , Feminino , Glucuronídeos/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinonas/administração & dosagem , Espectrometria de Massas em Tandem , Tiofenos/administração & dosagem , Distribuição Tecidual
7.
Cancer Treat Rev ; 81: 101907, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715422

RESUMO

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.


Assuntos
Antineoplásicos/uso terapêutico , MAP Quinase Quinase 1/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Antineoplásicos/farmacologia , Grupo com Ancestrais do Continente Asiático/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , Camundongos , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia
8.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614517

RESUMO

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 µM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Pirimidinonas/química , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Piperazina/síntese química , Piperazina/química , Piperazina/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Receptor A2A de Adenosina/química , Relação Estrutura-Atividade
9.
Plant Mol Biol ; 101(6): 561-574, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621006

RESUMO

KEY MESSAGE: We investigated the functions of two cyanobacterial HemY protoporphyrinogen IX oxidase (PPO) genes with in vitro and in vivo assays and evaluated their applicability as resistance traits to PPO-inhibiting herbicides. We isolated HemY-type protoporphyrinogen IX oxidase (PPO) genes from cyanobacteria, OnPPO gene from Oscillatoria nigro-viridis PCC7112 and HaPPO gene from Halothece sp. PCC7418. The alignment of amino acid sequences as well as phylogenetic analyses conducted showed that OnPPO and HaPPO are classified as HemY-type PPO and are more closely related to plastidic PPOs than to mitochondrial PPOs. The PPO-deficient Escherichia coli BT3 strain, which requires heme supplementation, could obtain normal growth in the absence of heme supplementation when complemented with OnPPO and HaPPO. The enzyme assays of OnPPO, HaPPO, and Arabidopsis thaliana PPO1 (AtPPO1) proteins each revealed different kinetic properties in terms of catalytic efficiency, substrate affinity, and the degree of inhibition by PPO inhibitors. In particular, the catalytic efficiencies (kcat/Km) of OnPPO and HaPPO were approximately twofold higher than that of AtPPO1. The elution profiles of all three PPOs, acquired by size-exclusion chromatography, showed only a single peak with a molecular weight of approximately 52-54 kDa, which corresponds to a monomeric form. Moreover, functional complementation with OnPPO and HaPPO in AtPPO1-silenced Arabidopsis resulted in restored growth, whereas AtPPO1-silenced wild type Arabidopsis suffered necrotic death. In addition, we observed that overexpression of OnPPO and HaPPO in Arabidopsis conferred resistance to the PPO-inhibiting herbicides tiafenacil and saflufenacil. These results suggest that two HemY-type PPOs of cyanobacteria can functionally substitute for plastidic PPO activity in Arabidopsis and can enhance resistance to tiafenacil and saflufenacil.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/enzimologia , Protoporfirinogênio Oxidase/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Resistência a Herbicidas/genética , Resistência a Herbicidas/fisiologia , Protoporfirinogênio Oxidase/genética , Pirimidinonas/farmacologia , Sulfonamidas/farmacologia , Tiagabina/farmacologia
10.
Gynecol Oncol ; 155(3): 420-428, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623857

RESUMO

OBJECTIVE: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diaminas/administração & dosagem , Diaminas/efeitos adversos , Neoplasias do Endométrio/enzimologia , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos
11.
World J Gastroenterol ; 25(33): 4835-4849, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543677

RESUMO

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Cirrose Hepática/imunologia , Fígado/patologia , Transdução de Sinais/imunologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Fígado/citologia , Fígado/imunologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
12.
Expert Opin Investig Drugs ; 28(10): 827-833, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474120

RESUMO

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.


Assuntos
Asma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinonas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Humanos , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Pirimidinonas/farmacologia
13.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470659

RESUMO

Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/prevenção & controle , Melanoma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Aminopiridinas/administração & dosagem , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Melanoma/metabolismo , Melanoma/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Morfolinas/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Agric Food Chem ; 67(43): 11860-11866, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31532652

RESUMO

Plant bacterial diseases cause tremendous decreases in crop yield and quality, and there is a lack of highly effective and low-risk antibacterial agents. A series of novel pyrido[1,2-a]pyrimidinone mesoionic compounds containing vanillin moieties were synthesized, and the application of these mesoionic compounds as plant antibacterial agents was reported here for the first time. The bioassay results revealed that the mesoionic compounds had good antibacterial activity. Of these compounds, compound 11 showed excellent in vitro activity against Xanthomonas oryzae pv. oryzae, with an EC50 value of 1.1 µg/mL, which was substantially better than that of bismerthiazol (92.7 µg/mL) and thiodiazole copper (105.4 µg/mL). Moreover, greenhouse condition trials indicated that the protective and curative activities of compound 11 against rice bacterial leaf blight were 75.12 and 72.04%, respectively, which were better than those of bismerthiazol (62.24 and 50.83%, respectively) and thiodiazole copper (53.35 and 65.04%, respectively). These results provide a basis for the application of mesoionic vanillin moieties as new antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Pirimidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Desenho de Drogas , Testes de Sensibilidade Microbiana , Oryza/microbiologia , Doenças das Plantas/microbiologia , Pirimidinonas/química , Relação Estrutura-Atividade , Xanthomonas/efeitos dos fármacos
16.
Drug Des Devel Ther ; 13: 2393-2404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409973

RESUMO

Purpose: To evaluate the antihepatotoxic activity of dihydropyrimidinone derivative linked with 1,4-benzodioxane. Methods: A series of novel dihydropyrimidinone derivatives linked with 1,4-benzodioxane moiety were synthesized in good yield. Modern spectroscopic techniques and elemental analysis were used for the identification of the synthesized compounds. The hepatoprotective properties of compound 2, 4-(4-nitrophenyl)-5-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-3,4-dihydropyrimidin-2(1H)-one, was evaluated in a carbon tetrachloride (CCl4)-induced hepatotoxicity rat model. Results: Administration of compound 2 prior to CCl4 exposure produced a dose-dependent decrease in the levels of elevated biochemical parameters compared with the standard drug silymarin. CCl4 induced oxidative stress, increased lipid profile, and decreased high-density lipoprotein (HDL) levels. Compound 2 (20 mg/kg) significantly reduced the lipid profile and significantly improved HDL levels in a dose-dependent manner. CCl4 treatment increased malondialdehyde (MDA) level and decreased nonprotein thiol (NP-SH) and total protein (TP) in liver tissues. Pretreatment of rats with compound 2 (20 mg/kg) decreased MDA level and increased NP-SH and TP in liver tissues. Histopathological examination of liver tissues also confirmed the hepatoprotective activity of compound 2. Conclusion: These results demonstrate the antihepatotoxic activity of compound 2 in CCl4-induced hepatotoxicity model.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Dioxanos/farmacologia , Substâncias Protetoras/farmacologia , Pirimidinonas/farmacologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dioxanos/administração & dosagem , Dioxanos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
18.
Nat Med ; 25(9): 1422-1427, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406350

RESUMO

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Adolescente , Adulto , Animais , Benzamidas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Criança , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
19.
Int J Mol Sci ; 20(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461993

RESUMO

Cancer cell phenotype largely depends on oxygen availability. The atmospheric oxygen concentration (21%) used in in vitro studies is much higher than in any human tissue. Using well-characterized patient-derived melanoma cell lines, we compared: (i) activities of several signaling pathways, and (ii) the effects of vemurafenib and trametinib in hyperoxia (21% O2), normoxia (6% O2) and hypoxia (1% O2). A high plasticity of melanoma cells in response to changes in oxygen supplementation and drug treatment was observed, and the transcriptional reprograming and phenotypic changes varied between cell lines. Normoxia enhanced the expression of vascular endothelial growth factor (VEGF), glucose metabolism/transport-related genes, and changed percentages of NGFR- and MITF-positive cells in cell line-dependent manner. Increased protein stability might be responsible for high PGC1α level in MITFlow melanoma cells. Vemurafenib and trametinib while targeting the activity of MAPK/ERK pathway irrespective of oxygen concentration, were less effective in normoxia than hyperoxia in reducing levels of VEGF, PGC1α, SLC7A11 and Ki-67-positive cells in cell line-dependent manner. In conclusion, in vitro studies performed in atmospheric oxygen concentration provide different information on melanoma cell phenotype and response to drugs than performed in normoxia, which might partially explain the discrepancies between results obtained in vitro and in clinical settings.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma/metabolismo , Oxigênio/metabolismo , Hipóxia Tumoral , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Transcrição Associado à Microftalmia/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vemurafenib/farmacologia
20.
J Microbiol ; 57(9): 781-794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452043

RESUMO

The phytopathogenic Burkholderia species B. glumae and B. plantarii are the causal agents of bacterial wilt, grain rot, and seedling blight, which threaten the rice industry globally. Toxoflavin and tropolone are produced by these phytopathogens and are considered the most hostile biohazards with a broad spectrum of target organisms. However, despite their nonspecific toxicity, the effects of toxoflavin and tropolone on bacteria remain unknown. RNA-seq based transcriptome analysis was employed to determine the genome-wide expression patterns under phytotoxin treatment. Expression of 2327 and 830 genes was differentially changed by toxoflavin and tropolone, respectively. Enriched biological pathways reflected the down-regulation of oxidative phosphorylation and ribosome function, beginning with the inhibition of membrane biosynthesis and nitrogen metabolism under oxidative stress or iron starvation. Conversely, several systems such as bacterial chemotaxis, flagellar assembly, biofilm formation, and sulfur/taurine transporters were highly expressed as countermeasures against the phytotoxins. In addition, our findings revealed that three hub genes commonly induced by both phytotoxins function as the siderophore enterobactin, an iron-chelator. Our study provides new insights into the effects of phytotoxins on bacteria for better understanding of the interactions between phytopathogens and other microorganisms. These data will also be applied as a valuable source in subsequent applications against phytotoxins, the major virulence factor.


Assuntos
Antibacterianos/toxicidade , Burkholderia/química , Proteínas de Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Doenças das Plantas/microbiologia , Pirimidinonas/toxicidade , Triazinas/toxicidade , Tropolona/toxicidade , Antibacterianos/metabolismo , Burkholderia/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Oryza/microbiologia , Pirimidinonas/metabolismo , Transcriptoma/efeitos dos fármacos , Triazinas/metabolismo , Tropolona/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA