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  - 
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  - Scheiner, Matthias
A1  - Sink, Alexandra
A1  - Spatz, Philipp
A1  - Endres, Erik
A1  - Decker, Michael
T1  - Photopharmacology on Acetylcholinesterase: Novel Photoswitchable Inhibitors with Improved Pharmacological Profiles
JF  - ChemPhotoChem
N2  - Considerable effort has previously been invested in a light‐controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene‐based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo‐controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light‐controlled tacrine‐based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis‐enriched form showed an 8.4‐fold higher inhibition of hAChE compared with its trans‐enriched form and was about 30‐fold more active than the reference compound tacrine with a single‐digit nanomolar inhibition. We went beyond proof‐of‐concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, “cis‐on” effect, and pronounces differences between the photoisomers.
KW  - azobenzenes
KW  - enzymes
KW  - kinetics
KW  - photopharmacology
KW  - tacrine
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218445
VL  - 5
IS  - 2
SP  - 149
EP  - 159
ER  -