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1.
Chemistry ; 26(1): 139-142, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31680317

RESUMO

Cyclic naphthalene diimides (cNDIs), with a ferrocene moiety (cFNDs) and different linker lengths between the ferrocene and cNDI moieties, were designed and synthesized as redox-active, tetraplex-DNA ligands. Intramolecular stacking was observed between ferrocene and the NDI planes, which could affect the binding properties for G-quadruplexes. Interestingly, the circular dichroism spectrum of one of these compounds clearly shows new Cotton effects around 320-380 and 240 nm, which can be considered a direct evidence of intramolecular stacking of ferrocene and the NDI. Regarding recognition of hybrid G-quadruplexes, the less rigid structures (longer linkers) show higher binding affinity (106 m-1 order of magnitude). All new compounds show higher selectivity for G4 during electrochemical detection than noncyclic FND derivatives, which further identifies the redox-active potentiality of the cFNDs. Two of the three compounds tested even show preferential inhibition of cell growth in cancer cells over normal cells in a low concentration range, highlighting the potential for bioapplications of these cFNDs.


Assuntos
Compostos Ferrosos/química , Quadruplex G , Imidas/química , Metalocenos/química , Naftalenos/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Células HeLa , Humanos , Imidas/farmacologia , Ligantes , Naftalenos/farmacologia , Oxirredução , Telômero/química
2.
Eur J Med Chem ; 188: 111986, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884407

RESUMO

Breast cancer is the second leading cause of deaths in women globally. Present communication deals with design and synthesis of a few diarylnaphthyls as possible anti-breast cancer agents. Among the thirty three representatives with significant antiproliferative activity compounds 23 and 50 were quite efficacious against human breast cancer cells. Compound 50 induced apoptosis in both MCF-7 and MDA-MB-231 cells and exerted S phase and G2/M phase arrest respectively via distinct mechanistic pathways. It showed moderate microtubule destabilization. Further, it exhibited DNA topoisomerase-II inhibition effect in MCF-7 cells. It was well tolerable and found safe up to 300 mg/kg dose in Swiss albino mice. The dual action antiproliferative effect of compound 50 is quite interesting and warrants for future development.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Pirrolidinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Naftalenos/síntese química , Naftalenos/toxicidade , Pirrolidinas/síntese química , Pirrolidinas/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/toxicidade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidade
3.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

A series of naphthalene-chalcone derivatives (3a-3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
4.
Fitoterapia ; 139: 104401, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669964

RESUMO

Three previously undescribed (±)-3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives were isolated from Juglans regia flowers. Elucidation of the 2D structures of these first-reported compounds was completed via regular spectroscopic methods. The assignment of racemic nature of these compounds was achieved using the examination of their chiral HPLC profiles. (±)-2,3-Dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one, (±)-2,3-dihydro-4',5,8,8'-tetrahydroxy-(1,1'-binaphthalen)-4(1H)-one, and (±)-2,3-dihydro-1',5,5',8-tetrahydroxy-(1,2'-binaphthalen)-4(1H)-one were the structures of these racemic compounds, all taking on central chirality. The resolution of all the racemic compounds was conducted and achieved using a chiral HPLC procedure. The absolute configurations of the three isolated pairs of enantiomers were assigned via time-dependent density functional theory calculations from the electronic circular dichroism data. The findings in this paper demonstrated that the relevant biochemical reactions for the construction of these 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives in the test plant are nonselective. The (±)-2,3-dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one showed selective inhibitory activity on tumor cells growth, preliminarily supporting the application of Juglans regia flowers to protect against cancers in a few Chinese folk areas.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flores/química , Juglans/química , Naftalenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Naftalenos/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
5.
Chem Commun (Camb) ; 55(87): 13140-13143, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31617528

RESUMO

In this work, we depleted glutathione (GSH) by releasing SO2 with internal stimulus GSH itself, and also selectively marked the cancer cells followed by release of anticancer drug using another orthogonal stimulus i.e., two-photon (TP) NIR light by a single naphthalene based chromophore (TP absorbance 77 GM and uncaging cross-section 21 GM). We demonstrated the improved therapeutic efficacy of chlorambucil by the stepwise dual stimuli approach and dual surveillance of both the drug uncaging process in real-time using in vitro studies.


Assuntos
Alquilantes/farmacologia , Antineoplásicos Alquilantes/farmacologia , Clorambucila/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Naftalenos/farmacologia , Fótons , Alquilantes/química , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/metabolismo , Humanos , Raios Infravermelhos , Estrutura Molecular , Naftalenos/química , Imagem Óptica , Dióxido de Enxofre/metabolismo
6.
Mol Pharmacol ; 96(4): 463-474, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399503

RESUMO

G protein-coupled receptor (GPCR) internalization is crucial for the termination of GPCR activity, and in some cases is associated with G protein-independent signaling and endosomal receptor signaling. To date, internalization has been studied in great detail for class A GPCRs; whereas it is not well established to what extent the observations can be generalized to class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). The CaSR is a prototypical class C GPCR that maintains stable blood calcium (Ca2+) levels by sensing minute changes in extracellular free Ca2+ It is thus necessary that the activity of the CaSR is tightly regulated, even while continuously being exposed to its endogenous agonist. Previous studies have used overexpression of intracellular proteins involved in GPCR trafficking, pathway inhibitors, and cell-surface expression or functional desensitization as indirect measures to investigate CaSR internalization. However, there is no general consensus on the processes involved, and the mechanism of CaSR internalization remains poorly understood. The current study provides new insights into the internalization mechanism of the CaSR. We have used a state-of-the-art time-resolved fluorescence resonance energy transfer-based internalization assay to directly measure CaSR internalization in real-time. We demonstrate that the CaSR displays both constitutive and concentration-dependent Ca2+-mediated internalization. For the first time, we conclusively show that CaSR internalization is sensitive to immediate positive and negative modulation by the CaSR-specific allosteric modulators N-(3-[2-chlorophenyl]propyl)-(R)-α-methyl-3-methoxybenzylamine (NPS R-568) and 2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile (NPS 2143), respectively. In addition, we provide compelling evidence that CaSR internalization is ß-arrestin-dependent while interestingly being largely independent of Gq/11 and Gi/o protein signaling. SIGNIFICANCE STATEMENT: A novel highly efficient cell-based real-time internalization assay to show that calcium-sensing receptor (CaSR) internalization is ß-arrestin-dependent and sensitive to modulation by allosteric ligands.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Receptores de Detecção de Cálcio/metabolismo , beta-Arrestinas/metabolismo , Regulação Alostérica , Cálcio/sangue , Transferência Ressonante de Energia de Fluorescência , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Ligantes , Mutação , Naftalenos/farmacologia , Fenetilaminas/farmacologia , Propilaminas/farmacologia , Transporte Proteico , Receptores de Detecção de Cálcio/genética
7.
Int J Radiat Oncol Biol Phys ; 105(4): 861-874, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419512

RESUMO

PURPOSE: Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC. METHODS AND MATERIALS: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association ß-galactosidase staining assay. RESULTS: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair. CONCLUSIONS: Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.


Assuntos
Aminobenzoatos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Naftalenos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Telomerase/antagonistas & inibidores , Aminobenzoatos/administração & dosagem , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Reativadores Enzimáticos/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Naftalenos/administração & dosagem , Fosforilação/efeitos dos fármacos , Sincalida , Telomerase/metabolismo , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chem Pharm Bull (Tokyo) ; 67(8): 775-777, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366826

RESUMO

Nocardia is a potent bacterial producer of bioactive compounds. From a culture of Nocardia beijingensis NBRC 16342, we isolated four aromatic compounds, named beijinchromes A-D (1-4). We purified them by silica gel chromatography and reverse phase HPLC, and identified their structures by NMR and high resolution (HR)-MS analyses. 1, 2, and 4 are novel 1,2,3,8-tetrasubstituted naphthalenes, and 3 is a novel 3,8-disubstituted ortho-naphthoquinone. 1 and 2 exert antioxidant activities, and 3 exhibits antibiotic activity. Remarkably, the putative biosynthetic gene clusters for 1-4 are widely distributed in 37 Nocardia species, implying their potential to produce this family of compounds and important biological functions of beijinchromes.


Assuntos
Naftalenos/química , Naftoquinonas/química , Nocardia/química , Estrutura Molecular , Naftalenos/isolamento & purificação , Naftalenos/farmacologia , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Estereoisomerismo
9.
Life Sci ; 232: 116670, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31330139

RESUMO

AIM: Migraine is a neurological debilitating disorder. Previous studies have shown that cannabinoid receptor agonists have analgesic effects in various models of pain. In this study, therefore, we investigated anti-nociceptive effects of WIN 55,212-2, and the role of either CB1 or CB2 receptors in nitroglycerine (NTG)-induced animal model of migraine. METHODS: The present study was conducted on both male and female rats receiving NTG (10 mg/kg, i.p.) to induce acute (single dose of NTG) and chronic (repetitive doses of NTG) models of migraine. Additionally, three groups received WIN 55,212-2 (0.33, 1, 3 mg/kg, i.p.) 45 min before behavioral tests. Additionally, AM251 and AM630 (CB1 and CB2 receptor antagonist, respectively, 1 mg/kg, i.p.) were used to evaluate the possible involvement of CB1 and CB2 receptors during the protective effects of WIN 55,212-2. KEY FINDINGS: We found that NTG (10 mg/kg, i.p.) in both acute and chronic models increased sensitivity to pain. In acute model, we found that WIN 55,212-2 (almost high doses) decreases the level of pain mainly through CB1 receptor due to CB1 antagonist abrogates its protective effects, however, in formalin test CB2 receptors also had crucial roles in both phases at 3 mg/kg of WIN 55,212-2. In chronic model, WIN 55,212-2 (0.33, 1 and 3 mg/kg) significantly attenuated NTG-induced hyperalgesia through both CB1 and CB2 receptors. SIGNIFICANCE: Our data supported the argument that activation of CB1 and CB2 receptors by WIN 55,212-2 may be considered a new medication for migraine, however in lack of each receptor leads to different responses from deletion to the reduction of analgesic effects.


Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/prevenção & controle , Morfolinas/farmacologia , Naftalenos/farmacologia , Nitroglicerina/toxicidade , Animais , Benzoxazinas/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Ratos
10.
Eur J Med Chem ; 180: 224-237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306909

RESUMO

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM+/CD133+ cancer stem cells. IC50 of (R)-4'-methylklavuzon was found as 1.25 µM for HuH-7 parental cells while it was found as 2.50 µM for HuH-7 EpCAM+/CD133+ cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC50 values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'-methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM+/CD133+ cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels.


Assuntos
Antígeno AC133/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Naftalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Antígeno AC133/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Molécula de Adesão da Célula Epitelial/metabolismo , Células Hep G2 , Humanos , Carioferinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Nihon Yakurigaku Zasshi ; 154(1): 35-43, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31308348

RESUMO

Calcimimetics allosterically activate the calcium receptor (CaR) and inhibit the secretion of parathyroid hormone (PTH). Cinacalcet hydrochloride (cinacalcet) has been approved as the first calcimimetic drug for the treatment of secondary hyperparathyroidism (SHPT) in patients with hemodialysis. Cinacalcet improved the achievement of target serum PTH and Ca levels and helped drastically reduce the number of parathyroidectomies. However, cinacalcet has side effects involving the gastrointestinal tract, such as nausea and vomiting, which makes it difficult to increase the dose and may result in reduced compliance. Evocalcet has been developed to improve defects of cinacalcet for management of SHPT. Evocalcet acts as an allosteric modulator of CaR, just like cinacalcet. However, its metabolic pathway is different from that of cinacalcet. The metabolism of evocalcet by cytochrome P450 is very low, so evocalcet has higher bioavailability. As a result, its pharmacologically effective dose for the inhibition of PTH secretion is lower than that of cinacalcet. Evocalcet had less of an effect on the gastrointestinal tract than cinacalcet because of the reduced dose required. In a clinical trial with a randomized, double-blind, head-to-head comparison study, it was also confirmed that the incidence of gastrointestinal-related adverse events was lower in the evocalcet group than in the cinacalcet group. Evocalcet may thus be a potent option for the management of SHPT.


Assuntos
Cinacalcete/farmacologia , Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/farmacologia , Pirrolidinas/farmacologia , Cálcio , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Med Sci Monit ; 25: 4225-4232, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31171764

RESUMO

BACKGROUND The aim of this study was to assess the efficacy and safety of "on-demand" dapoxetine in the treatment of premature ejaculation (PE). MATERIAL AND METHODS We performed a meta-analysis of intravaginal ejaculatory latency time (IELT), patient-reported global impression of change (PGIC), perceived control over ejaculation (PCOE), and drug-related adverse effects (AEs). We searched Medline, PubMed, Embase, CNKI, Wanfang, and VIP databases up to May 30, 2018 with the following search terms: "dapoxetine" or "SSRIs" and "premature ejaculation" or "sexual dysfunction". RESULTS Our analysis included 11 RCTs (8521 cases and 4338 controls). We found that IELT, PGIC, and PCOE in PE patients with "on-demand" dapoxetine were significantly higher than in the control group, and we observed higher proportions in 60 mg vs. 30 mg dapoxetine. The AEs were mild and tolerable. CONCLUSIONS "On-demand" dapoxetine is effective and safe for patients with PE, and a dose of 60 mg may be more effective than 30 mg.


Assuntos
Benzilaminas/administração & dosagem , Naftalenos/administração & dosagem , Ejaculação Precoce/tratamento farmacológico , Adulto , Benzilaminas/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ejaculação/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
13.
Front Neural Circuits ; 13: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164809

RESUMO

The sole output of the retina to the brain is a signal that results from the integration of excitatory and inhibitory synaptic inputs at the level of retinal ganglion cells (RGCs). Endogenous cannabinoids (eCBs) are found throughout the central nervous system where they modulate synaptic excitability. Cannabinoid receptors and their ligands have been localized to most retinal neurons in mammals, yet their impact on retinal processing is not well known. Here, we set out to investigate the role of the cannabinoid system in retinal signaling using electrophysiological recordings from ON-sustained (ON-S) RGCs that displayed morphological and physiological signatures of ON alpha RGCs in dark adapted mouse retina. We studied the effect of the cannabinoid agonist WIN55212-2 and the inverse agonist AM251 on the spatial tuning of ON-S RGCs. WIN55212-2 significantly reduced their spontaneous spiking activity and responses to optimal spot size as well as altered their spatial tuning by reducing light driven excitatory and inhibitory inputs to RGCs. AM251 produced the opposite effect, increasing spontaneous spiking activity and peak response as well as increasing inhibitory and excitatory inputs. In addition, AM251 sharpened the spatial tuning of ON-S RGCs by increasing the inhibitory effect of the surround. These results demonstrate the presence of a functional cannabinergic system in the retina as well as sensitivity of ON-RGCs to cannabinoids. These results reveal a neuromodulatory system that can regulate the sensitivity and excitability of retinal synapses in a dynamic, activity dependent manner and that endocannabinoids may play a significant role in retinal processing.


Assuntos
Canabinoides/metabolismo , Potenciais Evocados Visuais/fisiologia , Células Ganglionares da Retina/metabolismo , Transmissão Sináptica/fisiologia , Animais , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Potenciais Evocados Visuais/efeitos dos fármacos , Luz , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
14.
Chin J Nat Med ; 17(5): 394-400, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31171275

RESUMO

Six novel monacolin analogs, monacolins V1-V6 (1-6), together with seven known ones (7-13), were isolated from the ethyl acetate extract of red yeast rice. Their structures and absolute configurations were determined by spectroscopic methods, especially 2D NMR (1H-1HCOSY, HSQC, HMBC, and NOESY/ROESY) and CD spectroscopic analyses as well as chemical derivation. Monacolins V2 (2) and V3 (3) represent the first examples of monacolins with 3-hydroxybutyrate substitute. The anti-inflammatory inhibitory activities against the lipopolysaccharide (LPS) induced NO production in BV-2 cells as well as antioxidant activities against rat liver microsomal lipid peroxidation were evaluated.


Assuntos
Produtos Biológicos/química , Hidroxibutiratos/química , Naftalenos/química , Acetatos/química , Animais , Linhagem Celular Transformada , Hidroxibutiratos/isolamento & purificação , Hidroxibutiratos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Naftalenos/isolamento & purificação , Naftalenos/farmacologia
15.
Psychopharmacology (Berl) ; 236(5): 1583-1596, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31147734

RESUMO

RATIONALE: Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS). OBJECTIVES: The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS. METHODS: Male Wistar rats were exposed to MS (3 h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5 mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed. RESULTS: ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward-seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood. CONCLUSIONS: Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain-gut axis communication in a context of stress.


Assuntos
Azepinas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Privação Materna , Naftalenos/farmacologia , Estresse Psicológico/metabolismo , Animais , Animais Recém-Nascidos , Azepinas/uso terapêutico , Corticosterona/metabolismo , Relação Dose-Resposta a Droga , Feminino , Microbioma Gastrointestinal/fisiologia , Masculino , Quinase de Cadeia Leve de Miosina/farmacologia , Quinase de Cadeia Leve de Miosina/uso terapêutico , Naftalenos/uso terapêutico , Gravidez , Ratos , Ratos Wistar , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia , Fatores de Tempo
16.
Biomed Pharmacother ; 117: 109056, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31181441

RESUMO

Chronic low back pain (LBP) ranks among the most common reasons for patient visits to healthcare providers. Drug treatments often provide only partial pain relief and are associated with considerable side-effects. J-2156 [(1'S,2S)-4amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4"-methyl-1"-naphthalenesulfonylamino)butanamide] is an agonist that binds with nanomolar affinity to the rat and human somatostatin receptor type 4 (SST4 receptor). Hence, our aim was to assess the efficacy of J-2156 for relief of chronic mechanical LBP in a rat model. Male Sprague Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but without disc puncture. For LBP-rats, noxious pressure hyperalgesia developed in the lumbar axial deep tissues from day 7 to day 21 post-surgery, which was maintained until study completion. Importantly, mechanical hyperalgesia did not develop in the lumbar axial deep tissues of sham-rats. In LBP-rats, single intraperitoneal (i.p.) injection of J-2156 (3, 10, 30 mg kg-1) alleviated primary and secondary hyperalgesia in the lumbar axial deep tissues at L4/L5 and L1, respectively. This was accompanied by a reduction in the otherwise augmented lumbar (L4-L6) dorsal root ganglia expression levels of the pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK and a reduction in pp38 MAPK in the lumbar enlargement of the spinal cord. The SST4 receptor is worthy of further investigation as a target for discovery of novel analgesics for the relief of chronic LBP.


Assuntos
Butanos/uso terapêutico , Dor Crônica/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Naftalenos/uso terapêutico , Receptores de Somatostatina/agonistas , Sulfonas/uso terapêutico , Animais , Butanos/química , Butanos/farmacologia , Modelos Animais de Doenças , Masculino , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Naftalenos/química , Naftalenos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Sulfonas/química , Sulfonas/farmacologia , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248140

RESUMO

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Ácidos Carboxílicos/farmacologia , MicroRNAs/genética , Naftalenos/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Acetilação , Biomarcadores , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunofluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Naftalenos/química , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Proteólise , Interferência de RNA
18.
Chemistry ; 25(47): 11085-11097, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31219221

RESUMO

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C7 linker exhibit extremely low IC50 values, below 10 nm, on different cancer cell lines. Contrary, the dyads with the shorter C4 linker were much less effective, with IC values increasing up to 1 µm. Among the three dyads with the longest linker, small differences in the IC50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Quadruplex G , Imidas/farmacologia , Naftalenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidas/síntese química , Imidas/química , Ligantes , Metáfase/efeitos dos fármacos , Microscopia de Fluorescência , Naftalenos/síntese química , Naftalenos/química , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo
19.
Eur J Med Chem ; 178: 571-588, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220675

RESUMO

In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 µg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.


Assuntos
Analgésicos Opioides/farmacologia , Encefalinas/farmacologia , Indóis/farmacologia , Naftalenos/farmacologia , Oxicodona/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Encefalinas/química , Indóis/química , Camundongos , Estrutura Molecular , Naftalenos/química , Oxicodona/química , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 178: 648-666, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226656

RESUMO

Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B.


Assuntos
Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Lactamas/farmacologia , Naftalenos/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
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