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1.
World J Gastroenterol ; 25(39): 5936-5952, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660031

RESUMO

BACKGROUND: The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM: To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS: The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS: The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION: We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

2.
Org Biomol Chem ; 17(35): 8067-8070, 2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31451812

RESUMO

Biologically important quinazolinones have been synthesized from 2-aminobenzamides and DMSO. The key feature of the reaction is the utilization of DMSO as a methine source for intramolecular oxidative annulation. The CNS depressant drug methaqualone has also been synthesized by our methodology. The present method involves the synthesis of quinazolinones with a broad substrate scope and a good yield.

3.
Bioorg Med Chem Lett ; 29(18): 2604-2608, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31387790

RESUMO

We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control arbutin. From the SAR studies, we identified 3k and 6g as lead compounds which displayed almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively than the reference arbutin. It is also evident the presence of electron withdrawing group at para position (R3) for the compounds (3a-p) and presence of +M group at ortho position (R5) for the compounds (6a-j) were crucial for their excellent inhibition activities of α-MSH-stimulated melanogenesis.

4.
J Transl Med ; 17(1): 195, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182117

RESUMO

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

5.
Theranostics ; 9(3): 646-660, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809299

RESUMO

Rationale: SOX10 (SRY-related HMG-box 10) and MITF-M (microphthalmia-associated transcription factor M) restrict the expression of melanogenic genes, such as TYR (tyrosinase), in melanocytes. DACE (diacetylcaffeic acid cyclohexyl ester) inhibits melanin production in α-MSH (α-melanocyte stimulating hormone)-activated B16-F0 melanoma cells. In this study, we evaluated the antimelanogenic activity of DACE in vivo and elucidated the molecular basis of its action. Methods: We employed melanocyte cultures and hyperpigmented skin samples for pigmentation assays, and applied chromatin immunoprecipitation, immunoblotting, RT-PCR or siRNA-based knockdown for mechanistic analyses. Results: Topical treatment with DACE mitigated UV-B-induced hyperpigmentation in the skin with attenuated expression of MITF-M and TYR. DACE also inhibited melanin production in α-MSH- or ET-1 (endothelin 1)-activated melanocyte cultures. As a mechanism, DACE blocked the nuclear import of CRTC1 (CREB-regulated co-activator 1) in melanocytes. DACE resultantly inhibited SOX10 induction, and suppressed the transcriptional abilities of CREB/CRTC1 heterodimer and SOX10 at MITF-M promoter, thereby ameliorating facultative melanogenesis. Furthermore, this study unveiled new issues in melanocyte biology that i) KPNA1 (Impα5) escorted CRTC1 as a cargo across the nuclear envelope, ii) SOX10 was inducible in the melanogenic process, and iii) CRTC1 could direct SOX10 induction at the transcription level. Conclusion: We propose the targeting of CRTC1 as a unique strategy in the treatment of acquired pigmentary disorders.


Assuntos
Núcleo Celular/metabolismo , Hiperpigmentação/tratamento farmacológico , Melanócitos/efeitos dos fármacos , Pigmentação/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Animais , Linhagem Celular , Modelos Animais de Doenças , Camundongos , Transporte Proteico
6.
Bioorg Med Chem Lett ; 29(2): 329-333, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472026

RESUMO

Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 µM, respectively, than honokiol.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Compostos de Bifenilo/farmacologia , Compostos Heterocíclicos/farmacologia , Lignanas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
7.
J Vasc Interv Radiol ; 29(11): 1604-1612, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30293733

RESUMO

PURPOSE: To compare tumor vascularity in 4 types of rat hepatocellular carcinoma (HCC) models: N1S1, vascular endothelial growth factor (VEGF)-transfected N1S1 (VEGF-N1S1), McA-RH7777, and VEGF-transfected McA-RH7777 (VEGF-McA-RH777) tumors. MATERIALS AND METHODS: The N1S1 and McA-RH7777 cell lines were transfected with expression vectors containing cDNA for rat VEGF. Eighty-eight male Sprague-Dawley rats (weight range, 400-450 g) were randomly divided into 4 groups (ie, 22 rats per model), and 4 types of tumor models were created by using the N1S1, VEGF-N1S1, McA-RH7777, and VEGF-McA-RH777 cell lines. Tumor vascularity was evaluated by perfusion computed tomography (CT), enzyme-linked immunosorbent assay of VEGF, CD34 staining, angiography, and Lipiodol transarterial embolization. Intergroup discrepancies were evaluated by Kruskal-Wallis test. RESULTS: Arterial perfusion (P < .001), portal perfusion (P = .015), total perfusion (P < .001), tumor VEGF level (P = .002), and microvessel density (MVD; P = .007) were significantly different among groups. VEGF-McA-RH7777 tumors showed the greatest arterial perfusion (46.7 mL/min/100 mL ± 15.5), total perfusion (60.7 mL/min/100 mL ± 21.8), tumor VEGF level (3,376.7 pg/mL ± 145.8), and MVD (34.5‰ ± 7.5). Whereas most tumors in the N1S1, VEGF-N1S1, and McA-RH7777 groups showed hypovascular staining on angiography and minimal Lipiodol uptake after embolization, 5 of 6 VEGF-McA-RH7777 tumors (83.3%) presented hypervascular tumor staining and moderate to compact Lipiodol uptake. CONCLUSIONS: McA-RH7777 tumors were more hypervascular than N1S1 tumors, and tumor vascularity was enhanced further by VEGF transfection. Therefore, the VEGF-McA-RH7777 tumor is recommended to mimic hypervascular human HCC in rats.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Embolização Terapêutica/métodos , Óleo Etiodado/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Masculino , Tomografia Computadorizada Multidetectores , Neovascularização Patológica , Imagem de Perfusão/métodos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Transdução de Sinais , Fatores de Tempo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética
8.
Bioorg Med Chem ; 26(18): 5181-5193, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253887

RESUMO

A novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and IIα inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and IIα inhibition especially at 20 µM concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase IIα inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 52 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 µM concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have π-π stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIα explored that it was bound to the topo IIα DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with π-π stacking interactions and there were no hydrogen bond interactions with topo IIα.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Naftiridinas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
9.
Theranostics ; 8(16): 4409-4428, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214629

RESUMO

Rationale: Chitinase 3-like 1 (Chi3L1) protein is up-regulated in various diseases including solid cancers. According to Genome-Wide Association Study (GWAS)/Online Mendelian Inheritance in Man (OMIM)/Differentially Expressed Gene (DEG) analyses, Chi3L1 is associated with 38 cancers, and more highly associated with cancer compared to other oncogenes such as EGFR, TNFα, etc. However, the mechanisms and pathways by which Chi3L1 is associated with cancer are not clear. In current study, we investigated the role of Chi3L1 in lung metastasis. Methods: We performed the differentially expressed gene analysis to explore the genes which are associated with Chi3L1 using the web-based platform from Biomart. We investigated the metastases in lung tissues of C57BL/6 mice injected with B16F10 melanoma following treatment with Ad-shChi3L1. We also investigated the expression of USF1 and Chi3L1 in Chi3L1 KD mice lung tissues by Western blotting and IHC. We also analyzed lung cancer cells metastases induced by Chi3L1 using migration and cell proliferation assay in human lung cancer cell lines. The involvement of miR-125a-3p in Chi3L1 regulation was determined by miRNA qPCR and luciferase reporter assay. Results: We showed that melanoma metastasis in lung tissues was significantly reduced in Chi3L1 knock-down mice, accompanied by down-regulation of MMP-9, MMP-13, VEGF, and PCNA in Chi3L1 knock-down mice lung tissue, as well as in human lung cancer cell lines. We also found that USF1 was conversely expressed against Chi3L1. USF1 was increased by knock-down of Chi3L1 in mice lung tissues, as well as in human lung cancer cell lines. In addition, knock-down of USF1 increased Chi3L1 levels in addition to augmenting metastasis cell migration and proliferation in mice model, as well as in human cancer cell lines. Moreover, in human lung tumor tissues, the expression of Chi3L1 was increased but USF1 was decreased in a stage-dependent manner. Finally, Chi3L1 expression was strongly regulated by the indirect translational suppressing activity of USF1 through induction of miR-125a-3p, a target of Chi3L1. Conclusion: Metastases in mice lung tissues and human lung cancer cell lines were decreased by KD of Chi3L1. USF1 bound to the Chi3L1 promoter, however, Chi3L1 expression was decreased by USF1, despite USF1 enhancing the transcriptional activity of Chi3L1. We found that USF1 induced miR-125a-3p levels which suppressed Chi3L1 expression. Ultimately, our results suggest that lung metastasis is suppressed by knock-down of Chi3L1 through miR-125a-3p-mediated up-regulation of USF1.


Assuntos
Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Expressão Gênica , Neoplasias Pulmonares/secundário , Melanoma/patologia , MicroRNAs/biossíntese , Regulação para Cima , Fatores Estimuladores Upstream/biossíntese , Adenoviridae/genética , Adenoviridae/crescimento & desenvolvimento , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/prevenção & controle , Camundongos Endogâmicos C57BL , Transdução Genética
10.
J Neuroinflammation ; 15(1): 224, 2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30098604

RESUMO

BACKGROUND: Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aß) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aß1-42-infused mice, and microglial BV-2 cells and astrocytes. METHODS: We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aß1-42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aß1-42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aß1-42-induced memory loss. RESULTS: A memory recovery effect was found to be associated with the reduction of Aß1-42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aß1-42-induced ß-secretase activity and Aß generation. Lipopolysaccharide (LPS)-induced (1 µg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 µM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro. CONCLUSION: These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.


Assuntos
Proteína 1 Semelhante à Quitinase-3/metabolismo , Encefalite/etiologia , Encefalite/prevenção & controle , Transtornos da Memória/complicações , NF-kappa B/metabolismo , /efeitos dos fármacos , Peptídeos beta-Amiloides/toxicidade , Animais , Anti-Inflamatórios/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Transformada , Modelos Animais de Doenças , Esquema de Medicação , Sistemas de Liberação de Medicamentos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Microglia/patologia , Fragmentos de Peptídeos/toxicidade , /efeitos dos fármacos
11.
Oncogene ; 37(38): 5147-5159, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29849120

RESUMO

Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and metastasis and thus accelerates cancer progression. p21-activated kinase 4 (PAK4) is a critical regulator of prostate cancer (PC) progression. Here, we report that PAK4 activation promotes PC progression through the EMT regulator Slug. We find that phosphorylated PAK4S474 (pPAK4) levels, an index of PAK4 activation, were tightly associated with Gleason score (p < 0.001), a clinical indicator of PC progression, but not with prostate serum antigen levels or tumor stage. Stable silencing of PAK4 in PC cells reduced their potential for EMT, cellular invasion, and metastasis in vivo. PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization. The non-phosphorylatable form SlugS158A/S254A upregulated transcription of CDH1, which encodes E-cadherin, and thus suppressed EMT and invasion, to a greater extent than did wild-type Slug. The strong EMT inducer TGF-ß elevated pPAK4 and pSlugS158 levels; PAK4 knockdown or introduction of a dominant-negative form of PAK4 inhibited both TGF-ß-stimulated EMT and an increase in pSlugS158 levels. Finally, immunohistochemistry revealed a positive correlation between pPAK4 and pSlugS158 but an inverse correlation between pSlugS158 and E-cadherin. The results suggest that the PAK4-Slug axis represents a novel pathway that promotes PC progression.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias da Próstata/patologia , Fatores de Transcrição da Família Snail/metabolismo , Quinases Ativadas por p21/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Metástase Neoplásica , Fosforilação , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Fatores de Transcrição da Família Snail/química , Transcrição Genética , Fator de Crescimento Transformador beta/metabolismo , Quinases Ativadas por p21/deficiência , Quinases Ativadas por p21/genética
12.
Arch Pharm Res ; 41(3): 259-264, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29478110

RESUMO

Aminoisobutyric acid (AIB) is an important building block widely incorporated by medicinal chemists in molecular design. Owing to the steric challenge, elaborating AIB's carboxylic acid using conventional amidation protocols is often problematic. We discovered that an amidation protocol utilizing methyl Boc-aminoisobutyrate and magnesium amidates of various reactivities produces the corresponding amide derivatives in good to excellent yields.


Assuntos
Amidas/síntese química , Ácidos Aminoisobutíricos/síntese química , Química Farmacêutica/métodos
13.
Theranostics ; 7(18): 4632-4642, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158850

RESUMO

Rationale: Signal transducer and activator of transcription-3 (STAT3) plays a pivotal role in cancer biology. Many small-molecule inhibitors that target STAT3 have been developed as potential anticancer drugs. While designing small-molecule inhibitors that target the SH2 domain of STAT3 remains the leading focus for drug discovery, there has been a growing interest in targeting the DNA-binding domain (DBD) of the protein. Methods: We demonstrated the potential antitumor activity of a novel, small-molecule (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) that directly binds to the DBD of STAT3, in patient-derived non-small cell lung cancer (NSCLC) xenograft model as well as in NCI-H460 cell xenograft model in nude mice. Results: MMPP effectively inhibited the phosphorylation of STAT3 and its DNA binding activity in vitro and in vivo. It induced G1-phase cell cycle arrest and apoptosis through the regulation of cell cycle- and apoptosis-regulating genes by directly binding to the hydroxyl residue of threonine 456 in the DBD of STAT3. Furthermore, MMPP showed a similar or better antitumor activity than that of docetaxel or cisplatin. Conclusion: MMPP is suggested to be a potential candidate for further development as an anticancer drug that targets the DBD of STAT3.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Ácidos Ftálicos/farmacologia , Fator de Transcrição STAT3/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Bioorg Med Chem Lett ; 27(23): 5213-5220, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29103971

RESUMO

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.


Assuntos
Receptores Acoplados a Proteínas-G/agonistas , Tiazóis/farmacologia , Animais , Linhagem Celular , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
15.
Bioorg Med Chem Lett ; 27(21): 4854-4857, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28964634

RESUMO

A series of catechol and dioxolane analogs containing thiazole CGA derivatives have been synthesized and evaluated for their inhibitory activity against α-MSH. The inhibitory activity was improved by replacing an α,ß-unsaturated carbonyl of previously reported caffeamides with thiazole motif. Surprisingly, compound 7d, one of the derivatives of dioxolane analogs, displayed the most potent inhibitory activity with an IC50 of 0.90µM. Further studies on metabolic stability and bioactivation potential were also accomplished.


Assuntos
Ácido Clorogênico/química , Melaninas/metabolismo , Tiazóis/química , alfa-MSH/metabolismo , Animais , Catecóis/síntese química , Catecóis/química , Catecóis/metabolismo , Linhagem Celular Tumoral , Ácido Clorogênico/síntese química , Ácido Clorogênico/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/metabolismo , Melaninas/antagonistas & inibidores , Camundongos , Microssomos Hepáticos/metabolismo , Relação Estrutura-Atividade , alfa-MSH/antagonistas & inibidores
16.
Bioorg Med Chem ; 25(20): 5586-5597, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28870801

RESUMO

A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIα inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIα inhibition than the reference drug etoposide in both 100µM and 20µM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIα DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site.


Assuntos
Alcanos/química , Desenho de Drogas , Piridinas/síntese química , Piridinas/farmacologia , Alcanos/síntese química , Alcanos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Piridinas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
17.
Bioorg Med Chem Lett ; 27(15): 3374-3377, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28619537

RESUMO

We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.


Assuntos
Ácidos Cafeicos/farmacologia , Preparações Clareadoras de Pele/farmacologia , Pigmentação da Pele/efeitos dos fármacos , alfa-MSH/antagonistas & inibidores , Animais , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Preparações Clareadoras de Pele/síntese química , Preparações Clareadoras de Pele/química , Relação Estrutura-Atividade , alfa-MSH/metabolismo
18.
Mol Carcinog ; 56(9): 2003-2013, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28277616

RESUMO

In the present study, we synthesized several non-aldehyde analogues of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal which showed anti-cancer effect. Interestingly, among the 16 compounds, we found that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) showed the most significant anti-proliferative effect on PA-1 and SK-OV-3 ovarian epithelial cancer cells. MMPP treatment (0-15 µg/mL) induced apoptotic cell death, enhanced the expression of cleaved caspase-3, and cleaved caspase-9 in a concentration dependent manner. Notably, DNA binding activity of STAT3, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was significantly decreased by MMPP treatment. However, ERK siRNA augmented MMPP-induced inhibitory effect on cell growth rather than p38 siRNA or JNK siRNA. Moreover, combination treatment of MMPP with ERK inhibitor U0126 (10 µM) augmented MMPP-induced inhibitory effect on cell growth and DNA binding activity of STAT3, and enhanced expression of cleaved caspase-3 and cleaved caspase-9. In addition, STAT3 siRNA transfection augmented MMPP-induced cell growth inhibition. In PA-1 bearing xenograft mice model, MMPP (5 mg/kg) suppressed tumor growth significantly. Immunohistochemistry staining showed that the expression levels of p-ERK, PCNA, p-STAT3 were decreased while the expression level of caspase-3 was increased by MMPP treatment. Thus, MMPP may be a promising anti-cancer agent in ovarian epithelial cancer treatment.


Assuntos
Aldeídos/química , Antineoplásicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Guaiacol/análogos & derivados , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Fenóis/química , Fator de Transcrição STAT3/antagonistas & inibidores , Aldeídos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Feminino , Guaiacol/química , Guaiacol/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fenóis/farmacologia , Ligação Proteica/efeitos dos fármacos
19.
Sci Rep ; 7: 41180, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28145460

RESUMO

Targeting myeloid differentiation protein 2 (MD-2) or Toll-like receptor 4 (TLR4) with small molecule inhibitor rescues the systemic inflammatory response syndrome (SIRS) in sepsis due to infection with Gram-negative bacteria but not other microbes. Herein, we provided IκB kinase ß (IKKß) in innate immune process as a molecular target of caffeic acid cyclohexylamide (CGA-JK3) in the treatment of polymicrobial TLR agonists-induced lethal inflammation. CGA-JK3 ameliorated E. coli lipopolysaccharide (LPS, MD-2/TLR4 agonist)-induced endotoxic shock, cecal ligation and puncture (CLP)-challenged septic shock or LPS plus D-galactosamine (GalN)-induced acute liver failure (ALF) in C57BL/6J mice. As a molecular basis, CGA-JK3 inhibited IKKß-catalyzed kinase activity in a competitive mechanism with respect to ATP, displaced fluorescent ATP probe from the complex with IKKß, and docked at the ATP-binding active site on the crystal structure of human IKKß. Furthermore, CGA-JK3 inhibited IKKß-catalyzed IκB phosphorylation, which is an axis leading to IκB degradation in the activating pathway of nuclear factor-κB (NF-κB), in macrophages stimulated with TLR (1/2, 2/6, 4, 5, 7, 9) agonists from Gram-positive/negative bacteria and viruses. CGA-JK3 consequently interrupted IKKß-inducible NF-κB activation and NF-κB-regulated expression of TNF-α, IL-1α or HMGB-1 gene, thereby improving TLRs-associated redundant inflammatory responses in endotoxemia, polymicrobial sepsis and ALF.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Cafeicos/administração & dosagem , Cicloexilaminas/administração & dosagem , Galactosamina/efeitos adversos , Quinase I-kappa B/metabolismo , Lipopolissacarídeos/administração & dosagem , Falência Hepática Aguda/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/química , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia
20.
Sci Rep ; 6: 26357, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27198178

RESUMO

Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0-15 µM) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-κB (NF-κB) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently. Moreover, co-treatment of PL with NF-κB inhibitor phenylarsine oxide (0.1 µM) or p50 siRNA (100 nM) augmented PL-induced inhibitory effect on cell growth and activation of Fas and DR4. Notably, co-treatment of PL with p50 mutant plasmid (C62S) partially abolished PL-induced cell growth inhibition and decreased the enhanced expression of Fas and DR4. In xenograft mice model, PL (2.5-5 mg/kg) suppressed tumor growth of NSCLC dose-dependently. Therefore, these results indicated that PL could inhibit lung cancer cell growth via inhibition of NF-κB signaling pathway in vitro and in vivo.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dioxolanos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , NF-kappa B/metabolismo , Células A549 , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dioxolanos/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , NF-kappa B/química , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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