- Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors
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The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC50 of 72 ± 2 nM and its 8-C-glucoside orientin with an IC50 of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 ? resolution and quambalarine B at 2.5 ? resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells.
- Albi?ana, Carlos Berenguer,Brynda, Ji?í,Fanfrlík, Jind?ich,Flieger, Miroslav,Hodek, Jan,Karlukova, Elena,Ko?í?ek, Milan,Konvalinka, Jan,Machara, Ale?,Majer, Pavel,Radilová, Kate?ina,Weber, Jan,Zima, Václav
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- Natural product-based design, synthesis and biological evaluation of 2′,3,4,4′-tetrahydrochalcone analogues as antivitiligo agents
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A bioactive component, 2′,3,4,4′-tetrahydrochalcone (RY3-a) was first isolated from Vernohia anthelmintica (L.) willd seeds, and a set of its analogs, RY3-a-1–RY3-a-15 and RY3-c were designed and synthesized. Biological activity assays showed that RY3-c exhibited better melanogenesis and antioxidant activity and lower toxicity in comparison with RY3-a and butin. Further study tests showed that RY3-c exhibited better melanogenesis activity compared with the positive control 8-methoxypsoralan (8-MOP) in a vitiligo mouse model, suggesting that RY3-c is a good candidate antivitiligo agent. Mechanistic studies showed that RY3-c could repair cell damage induced by excessive oxidative stress and may exert melanin synthesis activity in the mouse melanoma B16F10 cell line by activating the mitogen-activated protein kinase (MAPK) pathway and the upregulation of c-kit.
- Zhong, Hui,Zhou, Jia,An, Xiao-Hong,Hua, Ying-Rong,Lai, Yi-Fan,Zhang, Rui,Ahmad, Owais,Zhang, Ye,Shang, Jing
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p. 523 - 533
(2019/04/01)
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- Novel flavonoids
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Novel flavonoids of formula (I) 1where A and E form together a C—C or C=C bond; R1, R2, R3, and R4 are H, OH, O(CH2)n— aromatic group, n=0-8; O(CH2)n N(CH3)q with n=0-8, q=0-3; O(CH2)n OH with n=1-8; O(CH2)n-halide with n=1-8; O(CH2)n COOH with n=0-8; O(CH2)n COOR′ with n=0-8 and R′ is C1-C8 alkyl or an aromatic group; O(CH2)n CONH R″ with n=0-8 and R″ is C1-C8 alkyl or an aromatic group, and sugars in mono-, di- or trimeric form or analogues thereof, with the proviso that R1 is not H, at least two of R2, R3 and R4 are H, and at most one of R1, R2, R3 and R4 is OH, are useful for the treatment of drug-induced toxicity, doxorubicin-induced cardiotoxicity, free radical mediated diseases, lung diseases, cancer, diabetes mellitus, cardiovascular disease, or arteriosclerosis.
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- Synthesis of novel 3,7-substituted-2-(3',4'-dihydroxyphenyl)flavones with improved antioxidant activity
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A series of 3,7-disubstituted-2-(3',4'-dihydroxyphenyl)flavones was synthesized as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 positions of the flavone nucleus on radical scavenging and
- Van Acker,Hageman,Haenen,Van der Vijgh,Bast,Menge
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p. 3752 - 3760
(2007/10/03)
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- Synthesis of 3-Acyl- and 3-Carbamoylflavones
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Routes to 3-acyl-, 3-carboxamido- and polyhydroxylated flavones have been devised by application of isoxazole methodology and Heck-Stille couplings.Reductive ring opening of 3-alkoxyisoxazoles gives β-keto carboxamides in contrast with 3-alkoxy-2-isoxazolines, which give β-hydroxy esters.
- Ellemose, Steen,Kure, Niels,Torsell, Kurt B. G.
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p. 524 - 529
(2007/10/02)
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