- Profiling of flavonol derivatives for the development of antitrypanosomatidic drugs
-
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.
- 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)
-
- MICROBIAL PRODUCTION OF THE FLAVONOIDS GARBANZOL, RESOKAEMPFEROL AND FISETIN
-
The invention provides a genetically modified micro-organism comprising one or more transgene for the production of one or more of the flavonoids garbanzol, resokaempferol and fisetin. The micro-organism may be a bacterial or yeast cell engineered to express a metabolic pathway for garbanzol, resokaempferol and/or fisetin biosynthesis. The invention further provides a method for producing garbanzol, resokaempferol and/or fisetin employing the genetically modified micro-organism of the invention. The genetically modified micro- organism may be used to convert a number of substrates and/or co-substrates into fisetin via a fisetin biosynthetic pathway.
- -
-
Page/Page column 40; 41
(2016/06/01)
-
- Selective synthesis of functional alkynylmono- and -trisilanes
-
The selective synthesis of functional alkynylsllanes RC=C(SiMe 2)m,-X (m = 1, 3) was investigated. Monofunctionalization with or without protecting groups gave moderate to good yields of alkynyldimethylmonosilanes RC=CMe2SiX [R = Ph, X = Cl. (1), NEt 2 (2), OMe (3), H (4), Br (5), I (6), Cp (8), C5H 4Li (10), Ph (11); R = Pr, X = Ph (12)]. Compounds 4 and 8 were converted into the (alkyne)transition-metal complexes 4-Cp2Mo 2(CO)4 (13) and 8-Co2(CO)6 (14), respectively, which were characterized by X-ray diffraction. Stepwise extension and functionalization of the silane chain starting from 1chloro-2-(diethylamino) tetramethyldisilane (Et2NMe2Si-SiMe2Cl) yielded the trisilanes Ph-(SiMe2J3-X [X = NEt2 (18), OMe (19), Cl (20), H (21), C=CPh (22), C=CPr (23)]. The synthesized compounds were characterized by NMR and IR spectroscopy, 4, 11, 13, and 14 also by UV/Vis spectroscopy.
- Hoffmann, Florian,Wagler, Joerg,Roewer, Gerhard
-
experimental part
p. 1133 - 1142
(2010/06/20)
-
- PHOTOOXYGENATION OF 2',4,4'-TRIHYDROXYCHALCONE: IDENTITY WITH PRODUCTS FROM ENZYMIC OXIDATION
-
The dioxetane derivative of 2',4,4'-trihydroxychalcone, previously known as a product from peroxidase-catalysed oxidation, has now been detected in the dye-sensitized photooxygenation of the same chalcone and shown to be accountable for the host of other products formed. - Key Word Index: Dioxetanes; chalcones; photooxygenation.
- Wong, Edmon
-
p. 1544 - 1545
(2007/10/02)
-
