- Discovery of quinolone derivatives as antimycobacterial agents
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Tuberculosis (TB), an infectious disease caused byMycobacterium tuberculosis(M. tuberculosis), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound1with antituberculosis activity and a minimal inhibitory concentration (MIC) againstM. tuberculosisof 20 μg mL?1. Structure optimization and the structure-activity relationship of1as the lead compound enabled the design and synthesis of a series of quinolone derivatives,6a1-6a2,6b1-6b36,6c1,6d1-6d14,7a1-7a2,7b1-7b2,7c1,8a1-8a5,9a1-9a4and10a1-10a6. These compounds were evaluatedin vitrofor anti-tubercular activity against theM. tuberculosisH37Rv strain. Among them, compounds6b6,6b12and6b21exhibited MIC values in the range of 1.2-3 μg mL?1and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 μg mL?1, respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 μg mL?1, respectively). In addition, an antibacterial spectrum test carried out using compound6b21showed that this compound specifically inhibitsM. tuberculosis. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.
- Gao, Chao,Li, Xiao,Liu, Kun-Lin,Teng, Fei,Xiong, Lu,Yu, Luo-Ting
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p. 24095 - 24115
(2021/07/29)
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- 5-Hydroxyindole-based EZH2 inhibitors assembled via TCCA-catalyzed condensation and Nenitzescu reactions
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5-Hydroxyindole derivatives have various demonstrated biological activities. Herein, we used 5-hydroxyindole as a synthetic starting point for structural alterations in a combinatorial process to synthesize 22 different compounds with EZH2 inhibitor pharmacophores. A series of 5-hydroxyindole-derived compounds were screened inhibitory activities against K562 cells. According to molecular modeling and in vitro biological activity assays, the preliminary structure-activity relationship was summarized. Compound L–04 improved both the H3K27Me3 reduction and antiproliferation parameters (IC50 = 52.6 μM). These findings revealed that compound L–04 is worthy of consideration as a lead compound to design more potent EZH2 inhibitors. During the preparation of compounds, we discovered that trichloroisocyanuric acid (TCCA) is a novel catalyst which demonstrates condensation-promoting effects. To gain insight into the reaction, in situ React IR technology was used to confirm the reactivity. Different amines were condensed in high yields with β-diketones or β-ketoesters in the presence of TCCA to afford the corresponding products in a short time (10~20 min), which displayed some advantages and provided an alternative condensation strategy.
- Chen, Guoliang,Du, Fangyu,Sun, Wenjiao,Wang, Lihui,Wu, Chunfu,Yang, Cheng,Zhou, Qifan
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supporting information
(2020/05/16)
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- Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents
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Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure-activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.
- Zhou, Qifan,Jia, Lina,Du, Fangyu,Dong, Xiaoyu,Sun, Wanyu,Wang, Lihui,Chen, Guoliang
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supporting information
p. 2247 - 2255
(2020/02/20)
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- Pyrrole-3-formamide compound as well as preparation method and application thereof
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The invention belongs to the technical field of medicines, and relates to a pyrrole-3-formamide compound as well as a preparation method and application thereof, in particular to a pyrrole-3-formamidecompound shown as a formula (I) or (II) and a pharmaceutically-acceptable salt thereof, wherein R to R and X are defined in the claims and description. The preparation of the compound mainly comprises performing Knorr pyrrole synthesis, Hantzsch pyrrole synthesis, decarboxylation, alkylation, hydrolysis, condensation, cyclization and reduction on ethyl acetoacetate or tert-butyl acetoacetate serving as the raw material. The pyrrole-3-formamide compound and the pharmaceutically-acceptable salt thereof have good treatment effects on tumors, and can be applied to the preparation of anti-tumor drugs. (The formulas (I) and (II) are shown in the description).
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Paragraph 0124; 0129; 0131; 0132; 0141; 0142
(2019/02/25)
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- Zinc (II)-mediated selective O-benzylation of 2-Oxo-1,2-dihydropyridines systems
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The selective O-benzylation of 2-oxo-1,2-dihydropyridines plays a critical role in organic synthesis of natural products and biological active molecules. Herein we report a novel ternary system of ZnO, ZnCl2 and N,N-diisopropylethylamine (DIEA), that is highly effective for selective O-benzylation of 2-oxo-1,2-dihydropyridines using abundant substituted benzyl halides and related substituted 2-oxo-1,2-dihydropyridines compounds. This process allows access to a variety of O-benzyl products under mild reaction conditions, which are important synthetic intermediates in the protection of functional groups, and represents a new method toward the development for the O-benzylation of 2-oxo-1,2-dihydropyridines.
- Zhou, Qifan,Du, Fangyu,Liang, Xinjie,Liu, Wenqiang,Fang, Ting,Chen, Guoliang
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- Structure-activity relationship studies for enhancer of zeste homologue 2 (EZH2) and enhancer of zeste homologue 1 (EZH1) inhibitors
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EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.
- Yang, Xiaobao,Li, Fengling,Konze, Kyle D.,Meslamani, Jamel,Ma, Anqi,Brown, Peter J.,Zhou, Ming-Ming,Arrowsmith, Cheryl H.,ümit Kaniskan,Vedadi, Masoud,Jin, Jian
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supporting information
p. 7617 - 7633
(2016/09/04)
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- METHOD OF TREATMENT
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The present invention relates to a method of treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases, which comprises administering to a human in need thereof an effective amount of a compound which inhibits EZH2 and/or EZH1, or a pharmaceutically acceptable salt thereof.
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Paragraph 0761
(2014/09/29)
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- AZAINDAZOLES
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Herein are disclosed azaindazoles of formula (I), (I), where the various groups are defined herein, and which are useful for treating cancer.
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Page/Page column 190
(2013/03/28)
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- ENHANCER OF ZESTE HOMOLOG 2 INHIBITORS
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This invention relates to novel substituted benzamide according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.
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Page/Page column 53; 54
(2013/12/03)
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- The Reaction of β-Aminoenones with Substituted Acetonitriles. Regiospecific Synthesis of 2(1H)-Pyridones
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Unsymmetrically substituted β-aminoenones react with malononitrile, cyanomethylphenylsulfone, benzoylacetonitrile and ethyl cyanoacetate, in very mild conditions, to yield regiospecifically 3-functionalized 2(1H)-pyridones in high yields.
- Alberola, Angel,Andres, Celia,Ortega, Alfonso Gonzalez,Pedrosa, Rafael,Vicente, Martina
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p. 709 - 713
(2007/10/02)
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