- Discovery of polymethoxyflavones as potential cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and phosphodiesterase 4B (PDE4B) inhibitors
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Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat inflammatory-related diseases, pain and fever. However, the prolong use of traditional NSAIDs leads to undesirable side effects such as gastric, ulceration, and renal toxicity due to lack of selectivity toward respective targets for COX-2, 5-LOX, and PDE4B. Thus, targeting multiple sites can reduce these adverse effects of the drugs and increase its potency. A series of methoxyflavones (F1–F5) were synthesized and investigated for their anti-inflammatory properties through molecular docking and inhibition assays. Among these flavones, only F2 exhibited selectivity toward COX-2 (Selectivity Index, SI: 3.90, COX-2 inhibition: 98.96 ± 1.47%) in comparison with celecoxib (SI: 7.54, COX-2 inhibition: 98.20 ± 2.55%). For PDEs, F3 possessed better selectivity to PDE4B (SI: 4.67) than rolipram (SI: 0.78). F5 had the best 5-LOX inhibitory activity among the flavones (33.65 ± 4.74%) but less than zileuton (90.81 ± 0.19%). Docking analysis indicated that the position of methoxy group and the substitution of halogen play role in determining the bioactivities of flavones. Interestingly, F1–F5 displayed favorable pharmacokinetic profiles and acceptable range of toxicity (IC50>70 μM) in cell lines with the exception for F1 (IC50: 16.02 ± 1.165 μM). This study generated valuable insight in designing new anti-inflammatory drug based on flavone scaffold. The newly synthesized flavones can be further developed as future therapeutic agents against inflammation.
- Hamzah, Ahmad Sazali,Md Idris, Muhd Hanis,Mohd Amin, Siti Norhidayah,Mohd Amin, Siti Norhidayu,Salleh, Mohd Zaki,Selvaraj, Manikandan,Shaameri, Zurina,Teh, Lay Kek,Wibowo, Agustono,Zakaria, Zainul Amiruddin
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- Discovery of human TyrRS inhibitors by structure-based virtual screening, structural optimization, and bioassays
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The human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS), which is well known for its essential aminoacylation function in protein synthesis, has been shown to translocate to the nucleus and protect against DNA damage caused by external stimuli. Small molecules that can fit into the active site pocket of TyrRS are thought to affect the nuclear role. The exploitation of TyrRS inhibitors has attracted attention recently. In this investigation, we adopted a structure-based virtual screening strategy and subsequent structure-activity relationship analysis to discover new TyrRS inhibitors, and identified a potent compound 5,7-dihydroxy-6,8-bis((3-hydroxyphenyl)thio)-2-phenyl-4H-chromen-4-one (compound 11, Ki = 8.8 μM). In intact HeLa cells, this compound showed a protective effect against DNA damage. Compound 11 is a good lead compound for the further development of drugs against disorders caused by DNA damage.
- Huang, Shenzhen,Wang, Xiang,Lin, Guifeng,Cheng, Jie,Chen, Xiuli,Sun, Weining,Xiang, Rong,Yu, Yamei,Li, Linli,Yang, Shengyong
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p. 9323 - 9330
(2019/03/28)
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- Substituted 6,8-dimercapto-2-phenyl-4H-chromen-4-one derivative and preparation method and application thereof
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The invention belongs to the field of organic synthetic medicine and particularly relates to a substituted 6,8-dimercapto-2-phenyl-4H-chromen-4-one derivative, having the structure that is shown in the description. Embodiments of the substituted 6,8-dimercapto-2-phenyl-4H-chromen-4-one derivative prove that the derivative can activate TyrRS-PARP-1 signal pathway such that activation of PARP-1 viaTyrRS leads to a series of protective genes, including tumor inhibiting gene p53 and longevity genes FOXO3A and SIRT6 to be activated; the derivative has good medicinal potential in age defying and DNA restoration drugs, and a new potential option is provided for clinical medication; in addition, a preparation method of a new compound herein is simple, the preparation method has mild reaction conditions, is convenient to perform and control, has low energy consumption, high yield and low cost, and is suitable for industrial production, and the compound produced has high bioactivity, high activity and selectivity, significant drug-likeness, and promising market prospect.
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Paragraph 0120; 0133; 0134
(2018/11/03)
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- Unveiling the 6,8-Rearrangement in 8-Phenyl-5,7-dihydroxyflavylium and 8-Methyl-5,7-dihydroxyflavylium through Host–Guest Complexation
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8-Phenyl-5,7-dihydroxyflavylium and 8-methyl-5,7-dihydroxyflavylium were synthesized to observe the 6,8-rearrangement. 8-Phenyl and 8-methyl residues were introduced by Suzuki–Miyaura reaction of 8-iodochrysin, then reduced by LiAlH4 to give the corresponding 3-deoxyanthocyanidins. At pH 1.0 the stable form is the 8-substituted flavylium cation in both compounds. At higher pH values the quinoidal bases are the stable species and some evidence for the 6,8-rearrangement was obtained, but the respective spectral variations are very small. This was overcome by using a modified cyclodextrin (captisol), which favors the formation of the trans-chalcone at the expense of the quinoidal bases. The trans-chalcone was isolated and dissolved in CD3OD/DCl (pD + m/z 253). The 6-isomer slowly reverts to the most stable 8-isomer. The 6,8-rearrangement was also observed after irradiation of the trans-chalcone (in the presence of captisol) at pH 5. Acidification of this photostationary state gave a mixture of both flavylium cations. The UV/Vis absorption of the flavylium cation (6-isomer) was blueshifted in comparison to the 8-isomer.
- Basílio, Nuno,Lima, Jo?o Carlos,Cruz, Luís,de Freitas, Victor,Pina, Fernando,Ando, Hiroki,Kimura, Yuki,Oyama, Kin-Ichi,Yoshida, Kumi
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supporting information
p. 5617 - 5626
(2017/10/13)
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- Regioselective iodination of flavonoids by N-iodosuccinimide under neutral conditions
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Regioselective synthesis of C-6 and C-8 monoiodo flavonoids, which are important intermediates for the synthesis of flavonoid natural products and drug molecules, was achieved by iodination of suitably alkylated flavonoids with N-iodosuccinimide (NIS) in DMF. The iodination gives either a C-6 or C-8 iodo flavonoid in high yield, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions render this novel protocol particularly useful for the regioselective iodination of acid-sensitive substrates.
- Lu, Kui,Chu, Jie,Wang, Haomeng,Fu, Xiaoli,Quan, Dewu,Ding, Hongxia,Yao, Qingwei,Yu, Peng
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supporting information
p. 6345 - 6348
(2013/11/06)
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- Synthesis and anticancer effect of chrysin derivatives
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A series of chrysin derivatives, prepared by alkylation, halogenation, nitration, methylation, acetylation and trifluoromethylation, were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma (HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3 and 8-bromo-5-hydroxy-7-methoxychrysin 11 have the strongest activities against SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were found to have strong activities against both SGC-7901 and HT-29 cells.
- Zheng, Xing,Meng, Wei-Dong,Xu, Yang-Yan,Cao, Jian-Guo,Qing, Feng-Ling
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p. 881 - 884
(2007/10/03)
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- BIFLAVONOIDS. SYNTHESIS OF TWO PARTIAL METHYL ETHERS OF CUPRESSUFLAVONE AND OF 8,8'%'-BICHRYSINYL TETRAMETHYL ETHER
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Cupressuflavone 7,7'%'-dimethyl ether has been prepared by controlled demethylation of cupressuflavone hexamethyl ether with hydriodic acid. Partial methylation of cupressuflavone with 5. 5 moles od dimethyl sulfate yields 5,7,4',7'%',4'%'%'-pentamethyl ether. Bichrysinyl tetramethyl ether has also been synthesized by the Ullmann condensation of 8-iodochrysin dimethyl ether, obtained from 2-hydroxy- 3- iodo- 4,6- dimethoxyacetophenone. The UV and NMR data for these compounds are given.
- NATARAJAN S,MURTI VVS,SESHADRI TR
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p. 113 - 115
(2007/10/08)
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