The flavonoid class encompasses over 700 distinct structural variants, all of which have been demonstrated to confer a multitude of beneficial effects on human health. Given the correlation between oxidative stress and over 100 diseases, including neurodegenerative, cardiovascular, and inflammatory diseases, it is a valuable target for the development of therapeutic agents. This study examined the effects of prenylated chalcones and flavanones derived from hops (Humulus lupulus L.), including xanthohumol, xanthohumol A, and C, as well as isoxanthohumol, 6- and 8-prenylnaringenin, and 8-geranylnaringenin, on cell viability and on revising the effect of sodium nitroprusside (SNP) on cell viability in the neuroblastoma cell line SH-SY5Y. The lowest IC50 (10.14-20.42 mu M) was observed in treatment with chalcones. With regard to the protective effect against SNP, a structure-activity relationship of prenylated and geranylated flavanones indicated that the extension of the prenyl side chain is beneficial for the protective effect of prenylated flavanones against SNP treatment. In accordance with the aforementioned methodology, 8-farnesylnaringenin, comprising a chain of three isoprene units, was synthesized and the effect on cell viability and protection against SNP-induced reduction of cell viability was subsequently evaluated. The strongest impact on cell viability (IC50) was observed for 8-farnesylnaringenin, which also demonstrated the most robust protective effect (25 %).

Chalcones represent a privileged scaffold in medicinal chemistry, with pyranochalcones, featuring an additional chromane-like ring, identified as neurogenic and neuroprotective. Reporter gene assays, often used to study these and other effects, can produce false positives due to firefly luciferase stabilisation by inhibitors. The present study demonstrates that pyranochalcones inhibit firefly luciferase activity, with inhibition levels ranging from none to 100% and IC50 values of 7.82 µM to 92.99 µM. Furthermore, molecular docking offers potential structure-based explanations for the observed selectivity of compounds towards firefly luciferase inhibition. Even slight modifications in the molecular structure lead to significant changes in luciferase inhibition, underscoring the importance of these findings for understanding structure-activity relationships in reporter gene assays. Accordingly, caution is advised when using reporter gene assays based on firefly luciferase and pyranochalcones, as the IC50 values are within the range of concentrations commonly used in both in vivo and in vitro assays.

Flavonoids and chalcones are known for their manifold biological activities, of which many affect the central nervous system. Pyranochalcones were recently shown to have a great neurogenic potential, which is partly due to a specific structural motif-the pyran ring. Accordingly, we questioned if other flavonoid backbones with a pyran ring as structural moiety would also show neurogenic potential. Different semi-synthetic approaches starting with the prenylated chalcone xanthohumol, isolated from hops, led to pyranoflavanoids with different backbones. We identified the chalcone backbone as the most active backbone with pyran ring using a reporter gene assay based on the promoter activity of doublecortin, an early neuronal marker. Pyranochalcones therefore appear to be promising compounds for further development as a treatment strategy for neurodegenerative diseases.

Humulus lupulus L. - Hopfen - ist eine seit langem verwendete Arzneipflanze. Die traditionelle Anwendung bei Schlaflosigkeit hängt mit den Bittersäuren zusammen, welche den Hopfen auch für die Brauindustrie wertvoll machen. Mit Hilfe einer aktivitätsgeführten Fraktionierung zur Bestimmung der differenzierungsinduzierenden Aktivität in neuronalen Vorläuferzellen der Maus wurde Xanthohumol C als potentes neuroregeneratives Chalkon identifiziert. Substanzen mit diesem Wirkprofil eignen sich zur Behandlung von neurodegenerativen Erkankungen, welche aufgrund des demogaphischen Wandels eine zunehmende Bürde der westlichen Gesellschaft darstellen. Der Chroman-Ring des Xanthohumol C wurde als wichtiges Strukturmerkmal für die Wirksamkeit identifiziert. Ein auf Cyclodextrinen basiertes Extraktionsverfahren, welches zu einer besser wasserlöslichen und bioverfügbaren Formulierung führt, ebnet den Weg für mögliche phytopharmazeutische Anwendungen des Hopfens im Bereich der Neuroregeneration.

Economically feasible biorefinery concepts rely on the production of multiple high-value products and valorization even of residual side streams. This generally holds true for biomass from agriculture, forestry, and aquaculture. Cyanobacteria are seen as promising organisms for this purpose. The potential for commercialization, however, strongly depends on the strain being used and the range of products it offers. The cyanobacterial strain Cylindrospermum alatosporum CCALA 988 was reported to produce high amounts of the cyclic lipopeptides puwainaphycins (PUWs) and minutisamides (MINs) as high-value products. Hence, this study investigated the biomass of the cyanobacterial strain as a potential feedstock for a biorefinery concept. The study also explored the enzymatic hydrolysis of the residual biomass and its utilization as a medium supplement for appA E. coli phytase expression with Pichia pastoris. Analysis of the cyanobacterial biomass revealed the following composition: ash 1.9 %, lipids 4.1 %, starch 2.4 %, structural saccharides 8.7 %, and protein 52.4 %. Further, a sequential extraction concept and a bench-scale mass balance were investigated, and products were proposed with 56.2 % of biomass being utilized and 43.8 % being left as residue. PUWs (21.6 mg/g), MINs (101.5 mg/g), phycobiliproteins (34.5 mg/g), and pigments (6.4 mg/g) were selected as products and quantified. The utilization of hydrolysate by fermentation of P. pastoris for appA E. coli phytase expression was studied in a 1 L system. In batch mode, the hydrolysate allowed to achieve comparable results to a rich complex medium, with over 500 U/mL of appA E. coli phytase. The obtained results provide a basis for further development of this biorefinery concept.

Isatis tinctoria contains many complicated condensed aromatic compounds – some indigoids and indolochinazolins have shown promising anti-cancer and anti-inflammatory properties, also anti-malaria activity is there [1]. In anti-cancer research, not only the cytotoxic activity of a compound is important, much more counts the therapeutic index and resistance breaking properties. Among Isatis metabolites, quingdainones (Indigo brown) have received less attention. These are cross breeds between tryptanthrines being indoloquinazolines and indoxyl. An active dihydroxyquingdainone AC50 7.5 µmol, has been found and further characterized and compared to synthetic derivatives. No other compound of this family including the unsubstituted quingdainone was active. Finding its apoptosis inducing ability (in a caspase 3 dependent manner) it was further characterized using Nalm-6 cells. Reduced mitochondrial membrane potential was determined using JC-1 staining and flow cytometric measurement, 6.3 µmol dihydroxyquingdainone showed 50% cell number with low mitochondrial membrane potential. BeKa cells (Vincristine resistant Nalm 6 cells), show an increased expression of the p-glycoprotein. Substances can be actively secreted from the cell via this protein [2], [3], whereby they become multidrug resistant (MDR) [4], which has also been demonstrated for BeKa cells. BeKa cells show a co-resistance to anthracyclines (Idarubicine, Daunorubicine, Doxorubicine, Epirubicine), Mitoxanthrone, Fludarabine, Vincristine or Vinblastin and Etoposide in vitro. Nalm-6 and BeKa cells had been treated with dihydroxyquingdainone for 72 h. The comparison of the percentage of apoptotic cells in these treated cell lines showed no significant differences. Thus, it is no substrate of the p-glycoprotein and explains a prominent effect in vincristine resistant leukaemia cells.

Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression.

Innovative Natural Health Products (NHP) – including herbal medicinal products as well as natural food supplements – show growing demand in Germany. In recent years researchers scrutineered by-products of the hops processing industry and found secondary plant compounds (prenyl flavonoids) having the potential to stimulate the formation of neurons [1], [2], [3]. These herbal extracts have the potential to extend the use of hops (Humulus lupulus L.) as a medicinal plant from sleep aids to modern therapeutic approaches in the fields of neurodegenerative diseases (e.g., dementia, depression) and neuroprotection (e.g., cognition enhancers).

By coupling of oligomerization reactions of ethene by neutral nickel salicylaldiminato catalysts with solvent alkylation using AlEt2Cl and AlEtCl2 as cocatalysts, we were able to generate long chain alkyltoluenes suited for the use as a diesel fuel component. Currently such complexes are designed as polymerization catalysts. Six new nickel(II) complexes bearing varying electron-withdrawing and electron-donating substituents at the N-phenyl moiety were checked as catalysts for the moderate oligomerization of ethylene under mild reaction conditions. The complexes showed activities up to 7.01·104 g(Prod.)/mol(Ni)·h in reactions at normal conditions without temperature control and excess ethylene pressure. Oligomers with 4 to 14 carbon atoms were produced with butenes being the major products. With AlEtCl2 as the activator, obviously, this organoaluminium compound acted as a Friedel-Crafts catalyst for the alkylation of the aromatic solvent toluene with the olefins present in the reaction solution.

Sideritis L. genus finds great ethnomedical importance in the regions of the Mediterranean basin and Balkan peninsula [1], [2]. In folk medicine, herbal preparations of Sideritis plants are widely used for various diseases in Greece and Cyprus. Specifically, their infusions are consumed as diaphoretic, diuretic, tonic agents, as well as to treat inflammation of the respiratory tract, stomach disorders, and common cold [1], [2]. Previous studies reported the rich phytochemical profiles of Sideritis taxa [2]. In continuation of our studies on the genus Sideritis [3], [4], we focused on the metabolite fingerprinting of the infusions of different Sideritis taxa. The samples originated from wild or/and cultivated populations from Cyprus (Sideritis cypria Post. and S. perfoliata L. subsp. perfoliata) and different areas of Greece (S. euboea Heldr., S. scardica Griseb., S. clandestina (Bory & Chaub.) Hayek subsp. clandestina, S. raeseri subsp. attica (Heldr.) Pap. et Kok., S. raeseri Boiss. & Heldr. subsp. raeseri and S. sipylea Boiss.). The chemical fingerprints of the samples were explored by GC-MS and LC-UV and MS/MS techniques. For GC-MS analysis of the infusions silylated derivatives were produced by using derivatisation reagent. The present study revealed differences in the chemical profiles of the infusions based on different geographical origins and environmental conditions.

Recently, a unique class of flavonoids, characterized by the presence of prenylated side chains, called prenylated flavanones, gain more and more attention in research. Since this group defines the second most abundant class of flavonoids, they may have a huge potential as therapeutic agents against multiple diseases [1]. Possibly prenylation of those substances could be related to an improved neuro-regenerative potential [2]. Anti-oxidative activity is a major issue related to neuroprotection. Therefore, the influence of the substitution of a prenyl, geranyl, or farnesyl group at position C-8 of the flavanone naringenin concerning cytotoxic and neuroprotective effects against oxidative stress in neuronal SH-SY5Y cells was investigated. Extension of the prenyl side chain revealed an increasing cytotoxic effect against SH-SY5Y cells. However, a neuroprotective effect was determined, when cells were preconditioned with those flavanones four hours before oxidative stress was induced by NO, released from sodium nitroprusside (SNP). Since neither pretreatment with naringenin nor 8-prenylnaringenin, but treatment with 10 µM 8-geranylnaringenin and 5 µM 8-farnesylnaringenin could prevent cell death after oxidative insult, the anti-oxidative effect of prenylated Flavanones may be related to the length of prenyl side chain. Consequently, the extension of the prenyl side chain of prenylated Flavanones is supposed to have major effects on the biological activity, which could be explained by changes in the substances lipophilicity, membrane attachment and transmembrane transport capability [3], [4].

Loss of neuronal tissue is a hallmark of age-related neurodegenerative diseases. Since adult neurogenesis has been confirmed in the human brain, great interest has arisen in substances stimulating the endogenous neuronal regeneration mechanism based on adult neural stem cells. Medicinal plants are a valuable source of neuroactive small molecules. In the structure-activity study presented here, the activities of prenyl- and pyranochalcones were compared to each other, using a differentiation assay based on the doublecortin promoter sequences. The latter revealed that the pyrano ring is a crucial structural element for the induction of neuronal differentiation of adult neural stem cells, while compounds with a prenyl group show significantly lower activities. Furthermore, a decrease of pro-differentiation activity was observed following structural modifications, such as substitutions on the pyrano ring and on the B-ring of the chalcone. We also initiated the elucidation of the structural characteristics of the newly discovered lead substance xanthohumol C, which correlated with the activation of the doublecortin promoter during neuronal differentiation.

Humulus lupulus L. – Hops - is a well known medicinal plant. The traditional use for insomnia is related to bitter acids and furthermore an effect on “melancholy” was mentioned in monastic medicine. Since it is known that anti-depressive medication can regulate neuro-regenerative processes concerning adult neuronal stem cells in the human brain, hops was a promising candidate for further investigations.

It is a desireable reaction to shift the double bond of the naturally abundant oleic acid from plant oils to the terminal position to enable suitable hydrosilylation or other hydrometallations to obtain intermediates of polymer manufacture. The catalyst [Ir(OMe)(1,5-cod)]2 is able to catalyze the 8-fold isomerisation using simple alkyl silanes as reactant, but technically more interesting alkoxysilanes do not react. It was found that combined application of HCo(N2)(PPh3)3 and Wilkinson´s catalyst isomerize and hydrosilylate oleic acid to the desired ω-triethoxysilyloctadecanoic acid ethylester but with still poor yield. Considerable improvement was found when the phosphanes are changed, i.e. tris-p-tolylphosphane being the most effective yielding nearly 50% terminally hydrosilylated oleic acid ester.

Both the substitution of free hydroxyl substituents and extending/branching of the fatty acid moiety improved the antifungal potency and limits the cytotoxicity of cyanobacterial cyclic lipopeptides puwainaphycin/minutissamides.

Cyclic lipopeptides from cyanobacteria represent an important class of compounds with antifungal properties. Their medical uses are frequently accompanied by cytotoxicity on host cells, so application as antifungal drugs is hampered [1]. In this study we demonstrate that natural lipopeptides known as puwainaphycins (sometimes called Minutissamides) isolated from Cylindrospermum alatosporum [2] with attached variable fatty acid (C10+n) chain length differ in the kinetics of their cytotoxic effect on human cells and their antifungal effect. Lipopeptides with an extended FA tail showed improved strain-specific antifungal activity against facultative pathogen Aspergillus fumigatus (MIC=0.5–3.8 µM) and plant pathogen Alternaria alternate (MIC=0.1–0.5 µM) but their cytotoxic effect was partially retained (~10 µM). Esterified at position 1’ lipopeptides possessed substantially higher antifungal potencies (MIC=0.2–0.6 µM against A. alternate) and greatly reduced (>20 µM) or abolished cytotoxic activity.