TY  - JOUR
A1  - Hofmann, Julian
A1  - Spatz, Philipp
A1  - Walther, Rasmus
A1  - Gutmann, Marcus
A1  - Maurice, Tangui
A1  - Decker, Michael
T1  - Synthesis and Biological Evaluation of Flavonoid-Cinnamic Acid Amide Hybrids with Distinct Activity against Neurodegeneration in Vitro and in Vivo
JF  - Chemistry-A European Journal
N2  - Flavonoids are polyphenolic natural products and have shown significant potential as disease-modifying agents against neurodegenerative disorders like Alzheimer's disease (AD), with activities even in vivo. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in several phenotypic screening assays related to neurodegeneration and AD. Therefore, we have exchanged the flavonoid part of the hybrids with different flavonoids, which show higher efficacy than taxifolin or silibinin, to improve the activity of the respective hybrids. Chemical connection between the flavonoid and cinnamic acid was realized by an amide instead of a labile ester bond to improve stability towards hydrolysis. To investigate the influence of a double bond at the C-ring of the flavonoid, the dehydro analogues of the respective hybrids were also synthesized. All compounds obtained show neuroprotection against oxytosis, ferroptosis and ATP-depletion, respectively, in the murine hippocampal cell line HT22. Interestingly, the taxifolin and the quercetin derivatives are the most active compounds, whereby the quercetin derivate shows even more pronounced activity than the taxifolin one in all assays applied. As aimed for, no hydrolysis product was found in cellular uptake experiments after 4 h whereas different metabolites were detected. Furthermore, the quercetin-cinnamic acid amide showed pronounced activity in an in vivo AD mouse model at a remarkably low dose of 0.3 mg/kg.
KW  - AD mouse modele
KW  - oxytosis/ferroptosis
KW  - natural product hybrids
KW  - Alzheimer's diseas
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318878
VL  - 28
IS  - 39
ER  - 
TY  - JOUR
A1  - Hofmann, Julian
A1  - Ginex, Tiziana
A1  - Espargaró, Alba
A1  - Scheiner, Matthias
A1  - Gunesch, Sandra
A1  - Aragó, Marc
A1  - Stigloher, Christian
A1  - Sabaté, Raimon
A1  - Luque, F. Javier
A1  - Decker, Michael
T1  - Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation, Intracellular Oxidative Stress, and Neuroinflammation
JF  - Chemistry – A European Journal
N2  - Many (poly‐)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid‐β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril‐like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate‐induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV‐2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival).
KW  - amyloid beta
KW  - bioisosterism
KW  - natural products
KW  - neuroprotectivity
KW  - replica-exchange molecular dynamics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238988
VL  - 27
IS  - 19
SP  - 6015
EP  - 6027
ER  - 
TY  - JOUR
A1  - Hofmann, Julian
A1  - Fayez, Shaimaa
A1  - Scheiner, Matthias
A1  - Hoffmann, Matthias
A1  - Oerter, Sabrina
A1  - Appelt‐Menzel, Antje
A1  - Maher, Pamela
A1  - Maurice, Tangui
A1  - Bringmann, Gerhard
A1  - Decker, Michael
T1  - Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo
JF  - Chemistry – A European Journal
N2  - Alzheimer′s disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)‐1 and (S)‐1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC‐ECD coupling. (R)‐1 and (S)‐1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)‐enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short‐ and long‐term memory at low dosages.
KW  - Alzheimer′s disease
KW  - chiral resolution
KW  - circular dichroism
KW  - Eriodictyon californicum
KW  - flavonoids
KW  - sterubin
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215993
VL  - 26
IS  - 32
SP  - 7299
EP  - 7308
ER  -