490-31-3Relevant academic research and scientific papers
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.
Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation
Bennett, Christopher J.,Caldwell, Stuart T.,McPhail, Donald B.,Morrice, Philip C.,Duthie, Garry G.,Hartley, Richard C.
, p. 2079 - 2098 (2007/10/03)
The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6-C12 alkyl chains are attached to the A-ring of either a 3,3′,4 ′,5′-tetrahydroxyflavone or a 3,2 ′,4′,5′-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
