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1.
Pestic Biochem Physiol ; 159: 80-84, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400787

RESUMO

The plastid acetyl coenzyme carboxylase (ACCase) Trp1999Leu mutation was identified in a Beckmannia syzigachne population resistant to fenoxaprop-p-ethyl. The pattern of cross-resistance for the Trp1999Leu mutation is still ambiguous. In this paper, mutant homozygote (1999Leu/Leu, RR) and wild type (1999Trp/Trp, SS) B. syzigachne plants with the same genetic background were purified from the JS-26 population using the dCAPS method. The activity of ACCase in RR and SS was determined. Then, the cross-resistance pattern to ACCase inhibiting herbicides of the Trp1999Leu mutation was determined using the whole-plant method. ACCase activity showed that the Trp1999Leu mutation decreased ACCase sensitivity to fenoxaprop-p-ethyl by 2.73-fold. A dose-response experiment indicated that the Trp1999Leu mutation conferred high resistance to quizalofop-p-ethyl (20.29-fold), metamifop (12.22-fold) and pinoxaden (18.60-fold), moderate resistance to fenoxaprop-p-ethyl (8.20-fold) and sethoxydim (6.38-fold), low resistance to cyhalofop-butyl (2.73-fold) and no resistance to clodinafop-propargyl (1.42 fold) and clethodim (1.59-fold). This is the first report of the role of Trp1999Leu in fenoxaprop-p-ethyl resistance and of the patterns of cross-resistance to ACCase-inhibiting herbicides in B. syzigachne.


Assuntos
Acetil-CoA Carboxilase/genética , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Poaceae/genética , Anilidas/farmacologia , Benzoxazóis/farmacologia , Cicloexanonas/farmacologia , Resistência a Herbicidas/genética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Mutação/genética , Propionatos/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia
2.
Acta Pharm ; 69(2): 177-196, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259731

RESUMO

Surpassing heart diseases, cancer is taking the lead as the deadliest disease because of its fast rate of spreading in all parts of the world. Tireless commitment to searching for novel therapeutic medicines is a worthwhile adventure in synthetic chemistry because of the drug resistance predicament and regular outbreak of new diseases due to abnormal cell growth and proliferation. Medicinal chemistry researchers and pharmacists have unveiled quinoxaline templates as precursors of importance and valuable intermediates in drug discovery because they have been established to possess diverse pharmacological potentials. Hence, this review highlights the current versatile routes to accessing functionalized quinoxaline motifs and harnessing their documented therapeutic potentials for anticancer drug development.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Quinoxalinas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Quinoxalinas/química , Quinoxalinas/farmacologia
3.
Malar J ; 18(1): 201, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217011

RESUMO

BACKGROUND: The challenge in anti-malarial chemotherapy is based on the emergence of resistance to drugs and the search for medicines against all stages of the life cycle of Plasmodium spp. as a therapeutic target. Nowadays, many molecules with anti-malarial activity are reported. However, few studies about the cellular and molecular mechanisms to understand their mode of action have been explored. Recently, new primaquine-based hybrids as new molecules with potential multi-acting anti-malarial activity were reported and two hybrids of primaquine linked to quinoxaline 1,4-di-N-oxide (PQ-QdNO) were identified as the most active against erythrocytic, exoerythrocytic and sporogonic stages. METHODS: To further understand the anti-malarial mode of action (MA) of these hybrids, hepg2-CD81 were infected with Plasmodium yoelii 17XNL and treated with PQ-QdNO hybrids during 48 h. After were evaluated the production of ROS, the mitochondrial depolarization, the total glutathione content, the DNA damage and proteins related to oxidative stress and death cell. RESULTS: In a preliminary analysis as tissue schizonticidals, these hybrids showed a mode of action dependent on peroxides production, but independent of the activation of transcription factor p53, mitochondrial depolarization and arrest cell cycle. CONCLUSIONS: Primaquine-quinoxaline 1,4-di-N-oxide hybrids exert their antiplasmodial activity in the exoerythrocytic phase by generating high levels of oxidative stress which promotes the increase of total glutathione levels, through oxidation stress sensor protein DJ-1. In addition, the role of HIF1a in the mode of action of quinoxaline 1,4-di-N-oxide is independent of biological activity.


Assuntos
Antimaláricos/farmacologia , Plasmodium yoelii/efeitos dos fármacos , Primaquina/farmacologia , Quinoxalinas/farmacologia , Combinação de Medicamentos , Eritrócitos/parasitologia , Células Hep G2 , Humanos , Esporozoítos/efeitos dos fármacos
4.
Molecules ; 24(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083328

RESUMO

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/ß (GSK-3α/ß), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.


Assuntos
Fatores Imunológicos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Compostos Orgânicos/farmacologia , Compostos de Enxofre/farmacologia , Compostos Alílicos/farmacologia , Antioxidantes/metabolismo , Dissulfetos/farmacologia , Alho/química , Células HL-60 , Compostos Heterocíclicos/farmacologia , Humanos , Proteínas Quinases Ativadas por Mitógeno , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/farmacologia , Tiazolidinedionas/farmacologia
5.
Neoplasia ; 21(6): 615-626, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31078067

RESUMO

Heterogeneous populations within a tumor have varying metabolic profiles, which can muddle the interpretation of bulk tumor imaging studies of treatment response. Although methods to study tumor metabolism at the cellular level are emerging, these methods provide a single time point "snapshot" of tumor metabolism and require a significant time and animal burden while failing to capture the longitudinal metabolic response of a single tumor to treatment. Here, we investigated a novel method for longitudinal, single-cell tracking of metabolism across heterogeneous tumor cell populations using optical metabolic imaging (OMI), which measures autofluorescence of metabolic coenzymes as a report of metabolic activity. We also investigated whether in vivo cellular metabolic heterogeneity can be accurately captured using tumor-derived three-dimensional organoids in a genetically engineered mouse model of breast cancer. OMI measurements of response to paclitaxel and the phosphatidylinositol-3-kinase inhibitor XL147 in tumors and organoids taken at single cell resolution revealed parallel shifts in metaboltruic heterogeneity. Interestingly, these previously unappreciated heterogeneous metabolic responses in tumors and organoids could not be attributed to tumor cell fate or varying leukocyte content within the microenvironment, suggesting that heightened metabolic heterogeneity upon treatment is largely due to heterogeneous metabolic shifts within tumor cells. Together, these studies show that OMI revealed remarkable heterogeneity in response to treatment, which could provide a novel approach to predict the presence of potentially unresponsive tumor cell subpopulations lurking within a largely responsive bulk tumor population, which might otherwise be overlooked by traditional measurements.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Organoides/diagnóstico por imagem , Análise de Célula Única , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Imagem Óptica , Organoides/metabolismo , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Microambiente Tumoral/genética
6.
Molecules ; 24(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121813

RESUMO

An expedient synthesis of hitherto unexplored novel hybrid heterocycles comprising dispiropyrrolidine, N-styrylpiperidone and indeno[1,2-b]quinoxaline units has been developed via domino multicomponent 1,3-dipolar cycloaddition strategy employing a new class of azomethine ylide in ionic liquid, 1-butyl-3-methylimidazolium bromide. This domino protocol involves, 1,3-dipolar cycloaddition and concomitant enamine reaction affording the dispiropyrrolidine tethered N-styrylpiperidone hybrid heterocycles in moderate to good yield in a single step. These compounds were evaluated for their antimicrobial activity against bacterial and fungal pathogens, therein compounds 8f, 8h, and 8l displayed significant activity against tested microbial pathogens. The synergistic effect revealed that the combination of compound 8h with streptomycin and vancomycin exhibited potent synergistic activity against E. coli ATCC 25922. In addition, molecular docking simulation has also been studied for the most active compound.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antibacterianos/química , Reação de Cicloadição , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Imidazóis/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinoxalinas/química , Estreptomicina/farmacologia , Relação Estrutura-Atividade , Vancomicina/farmacologia
7.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058815

RESUMO

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 µM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.


Assuntos
Isquemia Encefálica/prevenção & controle , Citidina Difosfato Colina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oximas/administração & dosagem , Quinoxalinas/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/metabolismo , Circulação Cerebrovascular , Citidina Difosfato Colina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Oximas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento
8.
Molecules ; 24(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934622

RESUMO

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Drogas , Quinoxalinas/química , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinoxalinas/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
9.
J Agric Food Chem ; 67(28): 7977-7985, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30932489

RESUMO

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant heterocyclic aromatic amines (HAAs) found in the human diet, is primarily produced during high-temperature meat or fish cooking. While MeIQx has been investigated as a potential carcinogen, the cytotoxicity and related molecular mechanisms remain unclear. Here, we demonstrate that autophagosome maturation is blocked by MeIQx. Mechanistically, MeIQx inhibits acidification of lysosomes rather than prevents autophagosome-lysosome fusion. Moreover, cellular lipid profiles are altered by MeIQx treatment. Notably, many phospholipids and sphingolipids are significantly upregulated after exposure to MeIQx. Furthermore, MeIQx decreases expression of pluripotency-associated proteins in mouse embryonic stem cells (ESCs). Together, MeIQx blocks autophagosome maturation through inhibiting acidification of lysosomes, alters lipid metabolism, and decreases expression of pluripotent factors. Our studies provide more cytotoxic evidence and elucidate related mechanisms on the risk of HAA exposure and are expected to promote supervision of food safety and human health.


Assuntos
Autofagossomos/efeitos dos fármacos , Lipídeos/química , Quinoxalinas/farmacologia , Fatores de Transcrição/metabolismo , Animais , Autofagossomos/metabolismo , Linhagem Celular , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Transcrição/genética
10.
Molecules ; 24(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871147

RESUMO

We have synthesized quinoxaline analogs (1⁻25), characterized by ¹H-NMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent compound among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21 and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure-activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.


Assuntos
Inibidores Enzimáticos/síntese química , Quinoxalinas/síntese química , Timidina Fosforilase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 171: 255-264, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30925340

RESUMO

Anticancer anthracyclines are cytotoxic drugs that can induce antitumor immune response as a secondary effect through immunogenic cell death (ICD) mechanism. However, the immunogenic potency is quite limited, possibly due to that these chemotherapeutic agents are not specifically developed as ICD inducers. Thus, new drug entities through studies focusing on enhanced ICD induction would significantly promote antitumor immune response in the vaccination application. We report here a naphthyl quinoxaline thymidine conjugate as a new class of cytotoxic compounds that effectively induced in vivo antitumor activity through the vaccination application. Synthesized naphthyl quinoxaline conjugates were weak fluorescent thymidine analog yet exhibited a pronounced anticancer activity in the low nanomolar range post UVA activation. The potent activity of naphthyl conjugate was able to induce the marked detection of ICD markers including ATP and HMGB1 extracellular and calreticulin intracellularly at 2 h post UVA activation. Most importantly, mice vaccinated with cells treated with naphthyl conjugate plus UVA exhibited complete tumor growth inhibition in the tumor challenge study, and the induced immunogenic inhibition was much more effective than that of mitoxantrone anthracycline drug. All these results demonstrate the high potential of naphthyl quinoxaline conjugate for the cancer cell vaccine against tumor.


Assuntos
Antineoplásicos/farmacologia , Quinoxalinas/farmacologia , Timidina/farmacologia , Raios Ultravioleta , Animais , 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 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Quinoxalinas/química , Relação Estrutura-Atividade , Timidina/química , Vacinação
12.
Nat Commun ; 10(1): 1373, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914635

RESUMO

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fulvestranto/administração & dosagem , Fulvestranto/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Camundongos , Mutação , Naftalenos/farmacologia , Piperazinas/farmacologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Purinas/administração & dosagem , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Quinoxalinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Artigo em Inglês | MEDLINE | ID: mdl-30814933

RESUMO

In natural environments our auditory system is exposed to multiple and diverse signals of fluctuating amplitudes. Therefore, to detect, localize, and single out individual sounds the auditory system has to process and filter spectral and temporal information from both ears. It is known that the overall sound pressure level affects sensory signal transduction and therefore the temporal response pattern of auditory neurons. We hypothesize that the mammalian binaural system utilizes a dynamic mechanism to adjust the temporal filters in neuronal circuits to different overall sound pressure levels. Previous studies proposed an inhibitory mechanism generated by the reciprocally coupled dorsal nuclei of the lateral lemniscus (DNLL) as a temporal neuronal-network filter that suppresses rapid binaural fluctuations. Here we investigated the consequence of different sound levels on this filter during binaural processing. Our in vivo and in vitro electrophysiology in Mongolian gerbils shows that the integration of ascending excitation and contralateral inhibition defines the temporal properties of this inhibitory filter. The time course of this filter depends on the synaptic drive, which is modulated by the overall sound pressure level and N-methyl-D-aspartate receptor (NMDAR) signaling. In psychophysical experiments we tested the temporal perception of humans and show that detection and localization of two subsequent tones changes with the sound pressure level consistent with our physiological results. Together our data support the hypothesis that mammals dynamically adjust their time window for sound detection and localization within the binaural system in a sound level dependent manner.


Assuntos
Audição/fisiologia , Localização de Som/fisiologia , Som , 2-Amino-5-fosfonovalerato/farmacologia , Estimulação Acústica , Potenciais de Ação/efeitos dos fármacos , Animais , Vias Auditivas/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Gerbillinae , Colículos Inferiores/fisiologia , Masculino , Inibição Neural , Neurônios/efeitos dos fármacos , Psicofísica , Quinoxalinas/farmacologia , Fatores de Tempo
14.
Pulm Pharmacol Ther ; 55: 75-83, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776489

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with incompletely understood pathophysiology. Effectiveness of available medicines is limited and the need for new and improved therapies remains. Due to complexity of the disease, it is difficult to develop predictable in vitro models. In this study we have described precision-cut lung slices (PCLS) prepared from bleomycin treated mice as an in vitro model for testing of novel compounds with antifibrotic activity. We have shown that PCLS during in vitro incubation retain characteristics of bleomycin model with increased expression of fibrosis related genes ACTA2 (α-smooth muscle actin), COL1A1 (collagen 1), FN1 (fibronectin 1), MMP12 (matrix metalloproteinase 12) and TIMP1 (tissue inhibitor of metalloproteinases). To further evaluate PCLS as an in vitro model, we have tested ALK5 inhibitor SB525334 which was previously shown to attenuate fibrosis in in vivo bleomycin model and nintedanib which is the FDA approved treatment for IPF. SB525334 and nintedanib inhibited expression of fibrosis related genes in PCLS from bleomycin treated mice. In addition, comparable activity profile of SB525334 was achieved in PCLS and in vivo model. Altogether these results suggest that PCLS may be a suitable in vitro model for compound testing during drug development process.


Assuntos
Modelos Animais de Doenças , Fibrose Pulmonar Idiopática/fisiopatologia , Imidazóis/farmacologia , Indóis/farmacologia , Quinoxalinas/farmacologia , Animais , Bleomicina/toxicidade , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Int J Mol Sci ; 20(3)2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691132

RESUMO

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8⁻3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1⁻38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Mieloma Múltiplo/metabolismo , Compostos Organosselênicos/farmacologia , Quinoxalinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mutação , Compostos Organosselênicos/química , Fosforilação/efeitos dos fármacos , Conformação Proteica , Proteínas Proto-Oncogênicas B-raf/genética , Quinoxalinas/química , Fator de Transcrição STAT3/química , Transdução de Sinais/efeitos dos fármacos
16.
Molecules ; 24(3)2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678061

RESUMO

Despite major advancements in the development of various chemotherapeutic agents, treatment for lung cancer remains costly, ineffective, toxic to normal non-cancerous cells, and still hampered by a high level of remissions. A novel cohort of quinoxaline derivatives designed to possess a wide spectrum of biological activities was synthesized with promising targeted and selective anticancer drug activity. Hence, this study was aimed at determining in vitro anticancer activity effects of a newly synthesized class of 3-(quinoxaline-3-yl) prop-2-ynyl quinoxaline derivatives on A549 lung cancer cells. An assessment of the quinoxaline derivatives ferric reducing power, free radical scavenging activity, cytotoxic activity, and ability to induce reactive oxygen species (ROS) production was performed using the Ferric Reducing Antioxidant Power (FRAP), 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assays, respectively. The ability of the quinoxaline derivatives to induce apoptosis in A549 cells was assessed using the Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell Assay. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) displayed a dose-dependent reducing power, free-radical scavenging activity, inhibition of cell viability, and stimulation of ROS production which was accompanied by induction of apoptosis in A549 lung cancer cells. None of the quinoxaline derivatives induced cell death or ROS production in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer, and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop-2-yn-1-ol induce apoptotic cell death in A549 lung cancer cells.


Assuntos
Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quinoxalinas/farmacologia , Células A549 , Antioxidantes/síntese química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Quinoxalinas/síntese química , Quinoxalinas/química , Espécies Reativas de Oxigênio/química
17.
Artigo em Inglês | MEDLINE | ID: mdl-30690282

RESUMO

In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC50 values ranged from 3.5 to 52.0 µM for inhibition of larval motility or development. Cytotoxicity IC50 against human MCF10A cells was generally higher than 50 µM. Microscopic studies revealed that this eviscerated (Evi) phenotype occurs rapidly (<20 min) and relates to a protrusion of internal tissues and organs (evisceration) through the excretory pore in xL3s; severe pathological damage in L4s as well as a suppression of larval growth in both stages were also observed. Using a relatively low concentration (12.5 µM) of compound m10, it was established that the inhibitor has to be present for a relatively short time (between 30 h and 42 h) during in vitro development from xL3 to L4, to induce the Evi phenotype. Increasing external osmotic pressure prevented evisceration and moulting, and xL3s remained unaffected by the test compound. These results point to a mode of action involving a dysregulation of morphogenetic processes during a critical time-frame, in agreement with the expected behaviour of a tyrosine kinase inhibitor, and suggest potential for development of this compound class as nematocidal drugs.


Assuntos
Antinematódeos/farmacologia , Haemonchus/efeitos dos fármacos , Quinoxalinas/farmacologia , Tirfostinas/farmacologia , Animais , Bioensaio , Descoberta de Drogas , Haemonchus/fisiologia , Concentração Inibidora 50 , Larva/efeitos dos fármacos , Larva/fisiologia , Muda/efeitos dos fármacos , Fenótipo
18.
Hypertension ; 73(1): 206-216, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571560

RESUMO

Genetic and pharmacological inhibition of the PI3Kγ (phosphoinositide 3-kinase-γ) exerts anti-inflammatory and protective effects in a number of inflammatory and autoimmune diseases. SHRs (spontaneously hypertensive rats) subjected to embolic middle cerebral occlusion were treated with AS605240 (30 mg/kg) at 2 or 4 hours, tPA (tissue-type plasminogen activator; 10 mg/kg) at 2 or 6 hours, or AS605240 at 4 hours plus tPA at 6 hours. Infarct volume, brain hemorrhage, neurological function, microvascular thrombosis, and cerebral microvessel patency were examined. We found that treatment with AS605240 alone at 2 hours or the combination treatment with AS605240 at 4 hours and tPA at 6 hours significantly reduced infarct volume and neurological deficits at 3 days after stroke compared with ischemic rats treated with saline, AS605240 alone at 4 hours, and tPA alone at 6 hours. Moreover, the combination treatment effectively prevented the delayed tPA-induced cerebral hemorrhage. These protective effects are associated with reduced disruption of the blood-brain barrier, reduced downstream microvascular thrombosis, and improved microvascular patency by AS605240. Inhibition of the NF-κB (nuclear transcription factor-κB)-dependent MMP (matrix metalloproteinase)-9 and PAI-1 (plasminogen activator inhibitor-1) in the ischemic brain endothelium may underlie the neurovascular protective effect of AS605240. In addition, the combination treatment significantly reduced circulating platelet P-selectin expression and platelet-leukocyte aggregation compared with ischemic rats treated with saline or tPA alone at 6 hours. In conclusion, inhibition of PI3Kγ with AS605240 reduces delayed tPA-induced intracerebral hemorrhage and improves microvascular patency, which likely contributes to neuroprotective effect of the combination treatment.


Assuntos
Hemorragia Cerebral , Embolia Intracraniana , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/microbiologia , Hemorragia Cerebral/fisiopatologia , Fibrinolíticos/farmacologia , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/metabolismo , Embolia Intracraniana/fisiopatologia , Microvasos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Endogâmicos SHR , Ativador de Plasminogênio Tecidual/farmacologia , Grau de Desobstrução Vascular/efeitos dos fármacos
19.
J Med Chem ; 62(2): 893-907, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30543421

RESUMO

Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective κ-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.


Assuntos
Antineoplásicos/química , Quinoxalinas/química , Receptores Opioides kappa/agonistas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Células HEK293 , Humanos , Interferon gama/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Receptores Opioides kappa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo
20.
Eur J Med Chem ; 158: 68-81, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30199706

RESUMO

Emergence of drug resistance and targeting all stages of the parasite life cycle are currently the major challenges in antimalarial chemotherapy. Molecular hybridization combining two scaffolds in a single molecule is an innovative strategy for achieving these goals. In this work, a series of novel quinoxaline 1,4-di-N-oxide hybrids containing either chloroquine or primaquine pharmacophores was designed, synthesized and tested against both chloroquine sensitive and multidrug resistant strains of Plasmodium falciparum. Only chloroquine-based compounds exhibited potent blood stage activity with compounds 4b and 4e being the most active and selective hybrids at this parasite stage. Based on their intraerythrocytic activity and selectivity or their chemical nature, seven hybrids were then evaluated against the liver stage of Plasmodium yoelii, Plasmodium berghei and Plasmodium falciparum infections. Compound 4b was the only chloroquine-quinoxaline 1,4-di-N-oxide hybrid with a moderate liver activity, whereas compound 6a and 6b were identified as the most active primaquine-based hybrids against exoerythrocytic stages, displaying enhanced liver activity against P. yoelii and P. berghei, respectively, and better SI values than primaquine. Although both primaquine-quinoxaline 1,4-di-N-oxide hybrids slightly reduced the infection of mosquitoes, they inhibited sporogony of P. berghei and compound 6a showed 92% blocking of transmission. In vivo liver efficacy assays revealed that compound 6a showed causal prophylactic activity affording parasitaemia reduction of up to 95% on day 4. Absence of genotoxicity and in vivo acute toxicity were also determined. These results suggest the approach of primaquine-quinoxaline 1,4-di-N-oxide hybrids as new potential dual-acting antimalarials for further investigation.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Cloroquina/análogos & derivados , Cloroquina/farmacologia , Plasmodium/efeitos dos fármacos , Primaquina/análogos & derivados , Primaquina/farmacologia , Animais , Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Feminino , Células Hep G2 , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/prevenção & controle , Camundongos Endogâmicos BALB C , Plasmodium/fisiologia , Primaquina/uso terapêutico , Quinoxalinas/química , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico
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