- Synthesis and Evaluation of Novel Quinazolinone Derivatives as Potential Anti-HCC Agents
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Hepatocellular carcinoma (HCC), a common malignancy worldwide, has a high mortality rate and limited effective therapeutic options. In this work, a series of quinazolinone compounds (6a–t and 7a–i) were synthesized as potential anti-HCC agents. Among them, compound 7b more potently inhibited HepG2, HUH7 and SK-Hep-1 cells proliferation than classical anti-HCC drug sorafenib, indicating its potential anti-HCC effect. Interestingly, 7b could dose-dependently decrease Cyclin D1 and CDK2 levels, and increase p21 protein expression, thus inducing HepG2 cells cycle arrest at G0/G1 phase. In addition, 7b also displayed potent apoptosis-induced effect on HepG2 cells by interfering Bad, Bax, Bcl-2 and Bcl-xl proteins expression. Notably, 7b could efficiently block the activity of PI3K pathway by dose-dependently reducing the phosphorylation of PI3K (Y607) and AKT (S473). Moreover, predicted ADME properties indicated that 7b possessed a good pharmacokinetic profile. Collectively, compound 7b might be a promising lead to the development of novel therapeutic agents towards HCC.
- Chen, Wang,Gu, Xiaoke,Jiang, Chunyu,Li, Shuqiong,Li, Zheng,Liu, Qingchuan,Qiu, Jingying,Zhou, Qingqing,Zou, Yueting
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- Discovery of novel quinazolinone derivatives as potential anti-HBV and anti-HCC agents
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As a continuation of earlier works, a series of novel quinazolinone derivatives (5a-s) were synthesized and evaluated for their in vitro anti-HBV and anti-hepatocellular carcinoma cell (HCC) activities. Among them, compounds 5j and 5k exhibited most potent inhibitory effect on HBV DNA replication in both drug sensitive and resistant (lamivudine and entecavir) HBV strains. Interestingly, besides the anti-HBV effect, compound 5k could significantly inhibit the proliferation of HepG2, HUH7 and SK- cells, with IC50 values of 5.44, 6.42 and 6.75 μM, respectively, indicating its potential anti-HCC activity. Notably, the in vitro anti-HCC activity of 5k were more potent than that of positive control 5-fluorouracil and sorafenib. Further studies revealed that compound 5k could induce HepG2 cells apoptosis by dose-dependently upregulating Bad and Bax expression and decreasing Bcl-2 and Bcl-xl protein level. Considering the potent anti-HBV and anti-HCC effect, compound 5k might be a promising lead to develop novel therapeutic agents towards HBV infection and HBV-induced HCC.
- Qiu, Jingying,Zhou, Qingqing,Zhang, Yinpeng,Guan, Mingyu,Li, Xin,Zou, Yueting,Huang, Xuan,Zhao, Yali,Chen, Wang,Gu, Xiaoke
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- Assessment of quinazolinone derivatives as novel non-nucleoside hepatitis B virus inhibitors
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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.
- Qiu, Jingying,Chen, Wang,Zhang, Yinpeng,Zhou, Qingqing,Chen, Jing,Yang, Lihua,Gao, Jian,Gu, Xiaoke,Tang, Daoquan
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- Pyridopyrimidine Or Pyrimidopyrimidine Compound, Prepration Method, Pharmaceutical Composition, And Use Thereof
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The present invention belongs to the field of pharmaceutical Chemistry. In particular, the present invention relates to a pyridopyrimidine or pyrimidopyrimidine compound as represented by general formula (I), or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, a preparation method, a pharmaceutical composition and uses thereof in preparing a mTOR inhibitor. As a mTOR inhibitor, the compound or the pharmaceutical composition thereof can be used for treating a disease or condition due to PI3K-AKT-mTOR signalling pathway malfunction.
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Paragraph 0063-0066
(2016/01/15)
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- A photoactivated molecular gate
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An o-nitrobenzyl ester derivative bearing a cyclodextrin moiety that was selectively opened by the addition of specific enzymes and by UV irradiation was prepared. On methoxybenzylamine fragment, a compound, which , other than the photo-cleavable group, c
- Agostini, Alessandro,Sancenon, Felix,Martinez-Manez, Ramon,Marcos, Maria D.,Soto, Juan,Amoros, Pedro
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supporting information
p. 12218 - 12221
(2012/11/07)
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- A SIMPLE AND INEXPENSIVE PROCEDURE FOR CHLOROMETHYLATION OF CERTAIN AROMATIC COMPOUNDS
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Reaction of a range of aromatic compounds with methoxyacetyl chloride and aluminium chloride in either nitromethane or carbon disulphide results in chloromethylation in good to excellent yield.
- McKillop, Alexander,Madjdabadi, Fereidon Abbasi,Long, David A.
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p. 1933 - 1936
(2007/10/02)
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