@article{HofmannFayezScheineretal.2020, author = {Hofmann, Julian and Fayez, Shaimaa and Scheiner, Matthias and Hoffmann, Matthias and Oerter, Sabrina and Appelt-Menzel, Antje and Maher, Pamela and Maurice, Tangui and Bringmann, Gerhard and Decker, Michael}, title = {Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo}, series = {Chemistry - A European Journal}, volume = {26}, journal = {Chemistry - A European Journal}, number = {32}, doi = {10.1002/chem.202001264}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215993}, pages = {7299 -- 7308}, year = {2020}, abstract = {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.}, language = {en} } @article{HofmannGinexEspargaroetal.2021, author = {Hofmann, Julian and Ginex, Tiziana and Espargar{\´o}, Alba and Scheiner, Matthias and Gunesch, Sandra and Arag{\´o}, Marc and Stigloher, Christian and Sabat{\´e}, Raimon and Luque, F. Javier and Decker, Michael}, title = {Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation, Intracellular Oxidative Stress, and Neuroinflammation}, series = {Chemistry - A European Journal}, volume = {27}, journal = {Chemistry - A European Journal}, number = {19}, doi = {10.1002/chem.202005263}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238988}, pages = {6015 -- 6027}, year = {2021}, abstract = {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).}, language = {en} } @article{HofmannSpatzWaltheretal.2022, author = {Hofmann, Julian and Spatz, Philipp and Walther, Rasmus and Gutmann, Marcus and Maurice, Tangui and Decker, Michael}, title = {Synthesis and Biological Evaluation of Flavonoid-Cinnamic Acid Amide Hybrids with Distinct Activity against Neurodegeneration in Vitro and in Vivo}, series = {Chemistry-A European Journal}, volume = {28}, journal = {Chemistry-A European Journal}, number = {39}, doi = {10.1002/chem.202200786}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318878}, year = {2022}, abstract = {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.}, language = {en} } @phdthesis{Hofmann2023, author = {Hofmann, Julian}, title = {Synthesis of Sterubin, Flavonoid Hybrids, and Curcumin Bioisosteres and Characterization of their Neuroprotective Effects}, doi = {10.25972/OPUS-26664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266641}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Alzheimer´s disease (AD) is a neurodegenerative disease and the most common form of dementia with still no preventive or curative treatment. Besides several risk factors, age is one of the major risks for AD and with an aging society, there is an urgent need for disease modifying agents. The strategy to address only one target within the intertwined network of AD failed so far. Natural products especially the phytochemical flavonoids, which are poly-phenolic natural products, have shown great potential as disease modifying agents against neurodegenerative disorders like Alzheimer´s disease (AD) with activities even in vivo. Flavonoids are produced by many plants and the native Californian plant Eriodictyon californicum is particularly rich in flavonoids. One of the major flavonoids of E. californicum is sterubin, a very potent agent against oxidative stress and inflammation, two hallmarks and drivers of AD and neurodegeneration. Herein, racemic sterubin was synthesized and separated into its pure (R)- and (S)-enantiomer by chiral HPLC. The pure enantiomers showed comparable neuroprotection in vitro with no significant differences. The stereoisomers were configurationally stable in methanol, but fast racemization was observed in culture medium. Moreover, the activity of sterubin was investigated in vivo, in an AD mouse model. Sterubin showed a significant positive impact on short- and long-term memory at low dosages. A promising concept for the increase of activity of single flavonoids is hybridization with aromatic acids like cinnamic or ferulic acids. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in phenotypic screening assays related to neurodegeneration and AD. Because there are more potent agents as taxifolin or silibinin, the hybrids were further developed, and different flavonoid cinnamic acid hybrids were synthesized. The connection between flavonoids and cinnamic acid was achieved by an amide instead of a labile ester to improve the stability towards hydrolysis to gain better "druggability" of the compounds. To investigate the oxidation state of the C-ring of the flavonoid part, the dehydro analogues of the respective hybrids were also synthesized. The compounds show neuroprotection against oxytosis, ferroptosis and ATP-depletion in the murine hippocampal cell line HT22. While no overall trend within the flavanones compared to the flavones could be assigned, the taxifolin and the quercetin derivative were the most active compounds in course of all assays. The quercetin derivate even shows greater activity than the taxifolin derivate in every assay. As desired no hydrolysis product was found in cellular uptake experiments after 4h, whereas different metabolites were found. The last part of this work focused on synthetic bioisoteres of the natural product curcumin. Due to the drawbacks of curcumin and flavonoids arising from poor pharmacokinetics, rapid metabolism and sometimes instability in aqueous medium, we have examined the biological activity of azobenzene compounds designed as bioisoteres of curcumin, carrying the pharmacophoric catechol group of flavonoids. These bioisosteres exceeded their parent compounds in counteracting intracellular oxidative stress, neuroinflammation and amyloid-beta aggregation. By incorporating an azobenzene moiety and the isosteric behaviour to the natural parent compounds, these compounds may act as molecular tools for further investigation towards the molecular mode of action of natural products.}, subject = {Organische Synthese}, language = {en} }