57601-14-6Relevant articles and documents
Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors
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
, (2020/09/09)
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.
Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds
Borsari, Chiara,Santarem, Nuno,Torrado, Juan,Olías, Ana Isabel,Corral, María Jesús,Baptista, Catarina,Gul, Sheraz,Wolf, Markus,Kuzikov, Maria,Ellinger, Bernhard,Witt, Gesa,Gribbon, Philip,Reinshagen, Jeanette,Linciano, Pasquale,Tait, Annalisa,Costantino, Luca,Freitas-Junior, Lucio H.,Moraes, Carolina B.,Bruno dos Santos, Pascoalino,Alcantara, Laura Maria,Franco, Caio Haddad,Bertolacini, Claudia Danielli,Fontana, Vanessa,Tejera Nevado, Paloma,Clos, Joachim,Alunda, José María,Cordeiro-da-Silva, Anabela,Ferrari, Stefania,Costi, Maria Paola
supporting information, p. 1129 - 1135 (2017/01/12)
Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2’-hydroxy methoxylated chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, com
Profiling of flavonol derivatives for the development of antitrypanosomatidic drugs
Borsari, Chiara,Lucian, Rosaria,Pozzi, Cecilia,Poehner, Ina,Henrich, Stefan,Trande, Matteo,Cordeiro-Da-silva, Anabela,Santarem, Nuno,Baptista, Catarina,Tait, Annalisa,Di Pisa, Flavio,Iacono, Lucia Dello,Landi, Giacomo,Gul, Sheraz,Wolf, Markus,Kuzikov, Maria,Ellinger, Bernhard,Reinshagen, Jeanette,Witt, Gesa,Gribbon, Philip,Kohler, Manfred,Keminer, Oliver,Behrens, Birte,Costantino, Luca,Nevado, Paloma Tejera,Bifeld, Eugenia,Eick, Julia,Clos, Joachim,Torrado, Juan,Jiménez-Antón, María D.,Corral, María J.,Alunda, José Ma,Pellati, Federica,Wade, Rebecca C.,Ferrari, Stefania,Mangani, Stefano,Costi, Maria Paola
, p. 7598 - 7616 (2016/09/04)
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.
