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1.
Eur J Med Chem ; 180: 62-71, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301564

RESUMO

Oxidative stress and inflammation are major causes of numerous life-threatening human diseases. In the present study, we synthesized a series of phenylacrylamide derivatives as novel anti-oxidant and anti-inflammatory agents. Biological evaluation showed that compound 6a could more potently protect HBZY-1 mesangial cells from H2O2-caused oxidative stress than positive controls resveratrol and sulforaphane by dose- and time-dependently impairing the ROS accumulation. Preliminary anti-oxidant mechanism studies indicated that compound 6a could activate Nrf2 and increase the protein and mRNA expression of downstream anti-oxidant enzymes, ie. NQO-1, HO-1, GCLM and GCLC. Notably, 6a could inhibit the production of NO and the activity of NF-κB in LPS-stimulated HBZY-1 mesangial cells, indicating its potential anti-inflammatory activity. Interestingly, both effects could be significantly attenuated by Nrf2 inhibitor TRG, HO-1 inhibitor ZnPP or GCL inhibitor BSO at non-toxic concentrations, confirming that the anti-oxidant and anti-inflammatory activity of 6a is related to the activation of Nrf2 signaling pathway. These results, together with the relatively safety profile, indicated that compound 6a could be a promising lead to develop novel anti-oxidant and anti-inflammatory agents, thus preventing diseases induced by oxidative stress and inflammation.


Assuntos
Acrilamida/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Acrilamida/síntese química , Acrilamida/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 176: 41-49, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091479

RESUMO

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 µM and 0.71 µM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 µM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Replicação do DNA/efeitos dos fármacos , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 162: 59-69, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30408749

RESUMO

Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against H2O2-induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity. Interestingly, the Nrf2 activating effect of 6e is achieved, at least partly, in Michael acceptor and Keap1-dependent manners. These results, together with the low intrinsic cytotoxicity, suggested that compound 6e might be a promising lead for the development of novel anti-oxidant agents to prevent diseases induced by oxidative stress.

4.
PLoS One ; 13(10): e0205317, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30304004

RESUMO

Based on carbon spot prices selected from seven carbon pilots, we assess the financial performances related to carbon volatility in China on the overall perspective. According to the results, the Chinese carbon market fluctuated severely at the beginning of carbon trading, but has stabilised in general, despite several dramatic changes related to 'yearly compliance events'. Long-term memory exists in the volatility series. Moreover, asymmetry exists in the Chinese carbon market, and volatility reacts more severely to good news than to bad news. Finally, we discuss our empirical results, and make certain suggestions regarding firms' awareness, international cooperation and individual investors not only for policy makers in China but also for other developing countries who are contemplating either commencing carbon trading or improving the current market.

5.
Eur J Med Chem ; 144: 424-434, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29288943

RESUMO

As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 µM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 µM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Desenho de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
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