- Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
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Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 12089 - 12108
(2021/09/06)
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- Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents
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The naturally occurring flavone 8-(6″-umbelliferyl)apigenin, a hybrid structure of apigenin and coumarin, as well as seven of its analogues were synthesized for the first time by using iodination and Suzuki coupling reactions as key steps. The synthesis of 8-(6″-umbelliferyl)-apigenin was achieved in seven linear steps from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one and 7-hydroxyl coumarine with 31% overall yield. Effects of these compounds on glucose disposal were investigated in adipocytes. All of the flavonoid and coumarin hydrids were found to have better bioactivities than their corresponding flavonoid cores. The most potent compound 15 (10?μΜ) could promote glucose consumption by 57% which exhibited similar effect as the positive control metformin at 1?mM. Moreover, fluorescence microscopy showed that four 8-(6″-umbelliferyl)apigenin analogues 2, 15, 30 and 31 could promote the 2-NBDG uptake into 3T3-L1 cells, which consist with those observed in the regulation of glucose.
- Pan, Guojun,Zhao, Lianbo,Xiao, Na,Yang, Ke,Ma, Yantao,Zhao, Xia,Fan, Zhenchuan,Zhang, Yongmin,Yao, Qingwei,Lu, Kui,Yu, Peng
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p. 674 - 683
(2016/07/21)
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- BENZOTHIOPHENE DERIVATIVE HAVING ANTI-CANCER EFFECT
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PROBLEM TO BE SOLVED: To provide a novel compound that has an excellent anti-cancer effect. SOLUTION: Provided is a benzothiophene derivative represented by formula (1), or a pharmaceutically acceptable salt thereof. [R1 is H, OH, a halogeno group, a C1 to 12 alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylamino group or an alkylthio group, a substituted/unsubstituted aryl group, a substituted/unsubstituted benzyl group, or a substituted/unsubstituted carbon ring or heterocyclic ring condensed to 5-6 position; R2 is H, OH, a halogeno group, a C1 to 12 alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylamino group or an alkylthio group; a substituted/unsubstituted aryl group or a substituted/unsubstituted benzyl group.] SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 0012
(2018/09/25)
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- Huazhongilexone is not 3′,5,5′,7-tetrahydroxyflavanone. Preparation of 3′,5′-dimethoxy-5,7-dihydroxyflavanone
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Huazhongilexone, isolated from Ilex centrochinensis, was originally assigned the structure 3′,5,5′,7-tetrahydroxyflavanone. The racemic flavanone has been synthezised. Huazhongilexone is different from the synthetic compound and thus must have a different structure. In addition the new (±)-3′,5′-dimethoxy-5,7- dihydroxyflavanone has been prepared and characterized. Acta Chemica Scandinavica 1998.
- Anthoni, Uffe,Encarnacion D., Rosalba,Nielsen, Per H.,Christophersen, Garsten
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p. 1243 - 1246
(2007/10/03)
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