Prenylated Flavonoids Research Articles

Involvement of mTOR-related signaling in antidepressant effects of Sophoraflavanone G on chronically stressed mice.

SophoraflavanoneG (SG), an important prenylated flavonoid isolated from Sophoraalopecuroides.L, is effective for many illnesses. The present study was designed to investigate whether the compound could reverse depressive-like symptoms and investigate its possible mechanisms. Chronic Unpredictable Mild Stress (CUMS) mice were treated with fluoxetine and SG. The immobility time in forced swimming test (FST) and tail suspension test (TST) were recorded. The levels of pro-inflammatory cytokines and neurotransmitters in the hippocampus were evaluated. Furthermore, the protein expressions of PI3K, AKT, mTOR, p70S6K, BDNF, and Trkb in hippocampus were detected. Rapamycin, the selective mTOR inhibitor, was used to estimate the potential mechanism. As a result, after 7 days of SG treatment, the immobility time in FST and TST was declined obviously. The levels of IL-6, IL-1β, and TNF-α in the hippocampus were significantly reduced, and the quantity of 5-HT and NE was raised considerably in SG-treated group compared with the CUMS-exposed group. Additionally, SG could up-regulate the expressions of PI3K, AKT, mTOR, 70S6K, BDNF, and Trkb. The blockade of mammalian target of rapamycin signaling blunted the antidepressant effect and reversed the up-regulation of BDNF expression caused by SG. These findings suggested that SG treatment alleviated depressive-like symptoms via mTOR-mediated BDNF/Trkb signaling.

Prenylated Flavonoids as Antioxidant and Melanin Inhibitors From Stingless Bee (Wallacetrigona incisa) Propolis

Propolis from 4 stingless bees ( Homotrigona apicalis, Wallacetrigona incisa, Tetragonula fuscobalteata, and Tetragonula fuscibasis) was investigated in the search for medicinal and cosmetic materials from tropical rainforest resources. Methanol extracts of the propolis were screened using antioxidant and antimelanogenesis assays (tyrosinase enzyme activity and melanin inhibitor in B16 melanoma). The extract of H. apicalis showed the strongest antioxidant activity, both in the 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays, with half-maximal inhibitory concentration values of 0.72 ± 0.01 (mg/mL) and 0.26 ± 0.00 (mg/mL), respectively. The H. apicalis extract also displayed the strongest inhibition of tyrosinase (53% at 100 µg/mL). In the B16 melanoma cell assay, the W. incisa extract showed the strongest inhibition of melanin (21%) and was less cytotoxic. The W. incisa extract was fractioned to isolate the compounds with biological activities. Two prenylated flavonoids were obtained, named broussoflavonol F and glyasperin A. Both showed potent antioxidant activities, as well as inhibiting melanin in B16 melanoma, but not tyrosinase activity. These results indicated the potential of methanol extract of W. incisa to be developed for cosmetic material, but further experiments are needed to verify the function.

Flavonoid Profile of the Genista tridentata L., a Species Used Traditionally to Treat Inflammatory Processes.

Ethnopharmacological surveys on Portuguese flora reveal that Genista tridentata L. is a shrub used in traditional medicine for the treatment of various inflammation-related health problems, although scientific support of its benefits is still necessary. In order to establish the anti-inflammatory potential of G. tridentata and support its traditional use, ethanolic extracts of three sections of the plant (root, stem, and leaves) were subjected to in vitro evaluation of anti-inflammatory activity using lipopolysaccharide (LPS)-stimulates macrophages as an inflammation model. Simultaneously, we also aimed to establish the extracts’ flavonoids profile. The ethanolic extracts, obtained by Soxhlet extraction, profile of the three sections confirmed their richness in flavonoids, being three prenylated flavonoids isolated and characterized in the root, including a new natural compound, the 3-methoxymundulin. The extracts from the three plant sections showed strong antioxidant activity at the cellular level and significantly inhibit the LPS-triggered NO production by downregulating Nos2 gene transcription and consequently iNOS expression. Additionally, root and stem extracts also decreased the LPS-induced transcription of the pro-inflammatory genes Il1b, Il6, and Ptgs2. Thus, the results support the anti-inflammatory properties attributed to G. tridentate preparations. Relevantly, the roots of the shrub, plant part not used, is an unexplored source of compounds with pharmacological and nutraceutical value.

Isolation of Dihydrostilbenes from Macaranga Heynei and their Bioactivities

Macaranga is known to contain abundant sources of prenylated flavonoids and stilbenoids which possessed broad spectrum of biological activities including anti-inflammatory, antimicrobial, antioxidant and cytotoxicity. These species are widely distributed in New Guinea, Borneo and from West Africa to the south Pacific islands. Although Macaranga comprises a large number of species, this genus has not been widely investigated which prompted us to conduct a study on Macaranga heynei. This research is conducted to isolate and characterise the compounds from M. heynei as well as to access the antibacterial and cytotoxicity of the isolates. The purification from the leaves of M. heynei has successfully yielded three dihydrostilbenes which were analysed by means of NMR, UV-Vis, FTIR, MS and comparison with the literature data. These compounds were characterised as laevifolins A (1) and B (2) as well as macarubiginosin C (3). Laevifolin A (1) exhibited good activity against S.cohnii subsp. urealyticum and moderate activity against S.aureus ATCC 25923 with the IC50 values of 11.65 and 27.13 M respectively. It also displayed pronounced inhibition against HT-29 cells with an IC50 value of 21.20 M. Meanwhile, laevifolin B (2) displayed moderate activity on S.cohnii subsp. urealyticum but strong inhibition against S.aureus ATCC 25923 with the IC50 values of 20.71 and 1.64 M respectively.

Characterization and Identification of Prenylated Flavonoids from Artocarpus heterophyllus Lam. Roots by Quadrupole Time-Of-Flight and Linear Trap Quadrupole Orbitrap Mass Spectrometry

In this study, a combination of quadrupole time-of-flight mass spectrometry (Q-TOF-MS) and linear trap quadrupole orbitrap mass spectrometry (LTQ-Orbitrap-MS) was performed to investigate the fragmentation behaviors of prenylated flavonoids (PFs) from Artocarpus plants. Fifteen PFs were selected as the model molecules and divided into five types (groups A–E) according to their structural characteristics in terms of the position and existing form of prenyl substitution in the flavone skeleton. The LTQ-Orbitrap-MSn spectra of the [M − H]− ions for these compounds provided a wealth of structural information on the five different types of compounds. The main fragmentation pathways of group A were the ortho effect and retro Diels–Alder (RDA), and common losses of C4H10, CO, and CO2. The compounds in group B easily lose C6H12, forming a stable structure of a 1,4-dienyl group, unlike those in group A. The fragmentation pathway for group C is characterized by obvious 1,4A−, 1,4B− cracking of the C ring. The diagnostic fragmentation for group D is obvious RDA cracking of the C ring and the successive loss of CH3 and H2O in the LTQ-Orbitrap-MSn spectra. Fragmentation with successive loss of CO or CO2, ·CH3, and CH4 in the LTQ-Orbitrap-MSn spectra formed the characteristics of group E. The summarized fragmentation rules were successfully exploited to identify PFs from Artocarpus heterophyllus, a well-known Artocarpus plant, which led to the identification of a total of 47 PFs in this plant.

Inhibitory Effects and Kinetic-Docking Studies of Xanthohumol FromHumulus lupulusCones Against Carbonic Anhydrase, Acetylcholinesterase, and Butyrylcholinesterase

Xanthohumol is an essential prenyl flavonoid of Humulus lupulus L. cones, and the taste of beer is due to this compound. Lately, xanthohumol has earned significant interest due to its potential anticancer, antigenotoxic, and adipogenesis effects. In this paper, the inhibitory effects of xanthohumol on human carbonic anhydrase isozymes (hCAI and hCAII), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) were studied. Also, molecular docking studies were used to investigate ligand interaction diagrams of xanthohumol at the binding cavities of hCAI and II. Xanthohumol was isolated from hop cones by silica gel column chromatography. Carbonic anhydrase enzyme activities were determined spectrophotometrically. In addition, molecular modeling approaches were used for the hCAI and hCAII isoenzymes. Ellman’s method was used for the inhibitor activities of AChE and BChE. The KIvalues of xanthohumol were detected as 0.085 µM for hCAI, 0.049 µM for hCAII, 95.5 nM for AChE, and 124.9 nM for BChE. In conclusion, xanthohumol can pleiotropically exert health promoting effects. It has antiglaucoma, anticonvulsant, antiepileptic, and anticancer activities due to its potent inhibitory effects on hCAI and hCAII. These findings may open new avenues for the design and development of novel hCAI, hCAII, AChE, and BChE inhibitors compared with sulfonamide/sulfamate.

Cytotoxic prenylated flavonoids from the leaves of Macaranga indica

Three new prenylated flavonoids, macarindicins D–F (1-3) together with eight known compounds, macadenathin B (4), glyasperin A (5), kaempferol (6), quercetin (7), quercitrin (8), (+)-isolariciresinol (9), (–)-woonenoside XI (10), and (+)-lyoniresinol 4-O-β-d-glucopyranoside (11) were isolated from the leaves of Macaranga indica Wight. Their structures were determined on the basis of extensive spectroscopic methods, including 1D-, 2D-NMR and MS data. All the isolated compounds were evaluated for their cytotoxic activities against KB, MCF-7, HepG-2, and LU human cancer cell lines. As results, compound 2 showed significant cytotoxic activity on all human cancer cell lines with IC50 values ranging from 11.0 to 17.0 μM. Compounds 3-5, exhibited moderate cytotoxic activity against all human cancer cell lines with IC50 values ranging from 15.0 to 38.2 μM.

Prenylated flavonoids and other constituents from Macaranga indica

Four new prenylated flavonoids, macarindicins I-IV (1-4) together with ten known compounds, broussoflavonol F (5), vedelianin (6), schweinfurthin E (7), vitexin (8), 2″-rhamnosyl vitexin (9), isovitexin (10), (6R,7E,9R)-9-hydroxy-megastigman-4,7-dien-3-one-9-O-β-D-glucopyranoside (11), 6S,9R)-roseoside (12), (6S,9S)-roseoside (13), and bridelionoside B (14) were isolated from the leaves of Macaranga indica. Their structures were determined on the basis of extensive spectroscopic methods, including 1D-, 2D-NMR, and MS data. All the isolated compounds were evaluated for their cytotoxic activities against four human cancer cell lines including KB, MCF-7, HepG-2, and LU. As a result, compound 6 significantly exhibited cytotoxic activity against all tested human cancer cell lines with IC50 values ranging from 4.7 to 11.0 μM. Compounds 2, 5, and 7 showed moderate cytotoxic activity with IC50 values ranging from 7.0 to 38.7 μM.

Sanggenon D from root bark of mulberry inhibits the growth of Staphylococcus aureus by moderating the fatty acid biosynthesis system

Mulberry trees are an important crop widely cultivated in the Americas, Eurasia and Africa. Various prenylated flavonoids with different bioactivities have been identified in mulberry root bark. The objective of this study was to investigate antibacterial properties of several prenylated flavonoids from mulberry root bark and elucidate their mechanism(s) of action toward bacteria. Minimum inhibitory concentrations and time-dependent inhibiting curves of bacteria treated with mulberry root bark prenylated flavonoids were applied to identify bacteriostatic effects. Antibacterial effects were observed toward Staphylococcus aureus and Escherichia coli, the strongest effect was of sanggenon D toward Staphylococcus aureus. Scanning electron microscopy was used to observe structural changes of Staphylococcus aureus cells, gas chromatography-mass spectrometry was used to investigate the fatty acid components in cells, and assessment by quantitative real-time PCR was applied to elucidate changes in expression of fatty acid biosynthesis enzyme system-associated genes on sanggenon D treatment. The mechanism of the anti- Staphylococcus aureus activity of sanggenon D involves downregulation of expression of fatty acid biosynthesis enzyme-encoding genes, which may in turn affect biosynthesis of the Staphylococcus aureus cell membrane. Collectively, our results reveal that sanggenon D from mulberry root bark shows a potent antibacterial effect.

Sixteen New Prenylated Flavonoids from the Fruit of Sinopodophyllum hexandrum.

Sixteen new prenylated flavonoids, sinoflavonoids P–Z (1–11) and sinoflavonoids NA–NE (12–16), were isolated from the fruit of Sinopodophyllum hexandrum, along with eight known analogues (17–24). Their structures were elucidated on the basis of extensive spectroscopic data (HR-ESI-MS, 1H-NMR, 13C-NMR, HSQC, HMBC). The cytotoxic activities of compounds 1–18, 20, and 22 were evaluated by MTT assay. Compound 6 showed the most potent cytotoxicity in MCF-7, and HepG2 cell lines, with IC50 values of 6.25 and 3.83 μM, respectively.

In vitro antigenotoxic activity, in silico ADME prediction and protective effects against aflatoxin B1 induced hepatotoxicity in rats of an Erythrina latissima stem bark extract

Stem bark of Erythrina latissima E. Mey (Leguminosae) contains a wide range of prenylated flavonoids able to counteract the genotoxic properties of aflatoxin B1 (AFB1). Thus, the hypothesis was raised that E. latissima stem bark extracts (ELBE) may counteract the in vivo hepatotoxic effects of aflatoxins, contaminants in food and feed. An HPLC-DAD method was developed and validated to determine the level of flavonoid aglycones (11.82%) and glycosides (16.17%). ADME, pharmacokinetic and drug-likeness assessment of major flavonoids of ELBE, using the web tool SwissADME, showed good oral bioavailability. The protective effect of ELBE against AFB1 induced genotoxicity in the Vitotox assay after metabolic activation was confirmed (IC50 of 44.32 μg/ml), followed by evaluation of its inhibitory effect on hepatotoxicity in rats induced by the same agent. Male Wistar rats were orally treated with ELBE (20 mg/kg, 50 mg/kg and 100 mg/kg) or curcumin (500 mg/kg) combined with piperine (20 mg/kg) - positive control, for 8 days prior to AFB1 exposure (1 mg/kg). The ELBE group showed a decreased activity of ALP and γ-GT compared to the AFB1 group. Histopathological examination of the liver demonstrated ameliorative effects of ELBE. Thus, ELBE could have a protective effect against hepatotoxins such as AFB1.

Novel cannabis flavonoid, cannflavin A displays both a hormetic and neuroprotective profile against amyloid β-mediated neurotoxicity in PC12 cells: Comparison with geranylated flavonoids, mimulone and diplacone

BackgroundFlavonoids form a diverse class of naturally occurring polyphenols ascribed various biological activities, including inhibition of amyloid β (Aβ) fibrillisation and neurotoxicity of relevance to Alzheimer’s disease. Cannabis contains a unique subset of prenylated flavonoids, the cannflavins. While selected conventional flavonoids have demonstrated anti-amyloid and neuroprotective potential, any neuroprotective bioactivity of prenylated flavonoids has not been determined. We evaluated the in vitro neuroprotective and anti-aggregative properties of the novel geranylated cannabis-derived flavonoid, cannflavin A against Aβ1–42 and compared it to two similarly geranylated flavonoids, mimulone and diplacone, to compare the bioactive properties of these unique flavonoids more broadly. MethodsNeuronal viability were assessed in PC12 cells biochemically using the MTT assay in the presence of each flavonoid (1–200 µM) for 48 h. Sub-toxic threshold test concentrations of each flavonoid were then applied to cells, alone or with concomitant incubation with the lipid peroxidant tert-butyl hyrdroperoxide (t-bhp) or amyloid β (Aβ1–42; 0–2 µM). Fluorescent staining was used to indicate effects of Aβ1–42 on PC12 cellular morphology, while direct effects of each flavonoid on Aβ fibril formation and aggregation were assessed using the Thioflavin T (ThT) fluorometric kinetic assay and transmission electron microscopy (TEM) to visualise fibril and aggregate morphology. ResultsCannflavin A demonstrated intrinsic hormetic effects on cell viability, increasing viability by 40% from 1 to 10 µM but displaying neurotoxicity at higher (>10–100 µM) concentrations. Neither mimulone nor diplacone exhibited such a biphasic effect, instead showing only concentration-dependent neurotoxicity, with diplacone the more potent (from >1 µM). However at the lower concentrations (<10 µM), cannflavin A increased cell viability by up to 40%, while 10 µM cannflavin A inhibited the neurotoxicity elicited by Aβ1–42 (0–2 µM), reducing Aβ aggregate adherence to PC-12 cells and associated neurite loss. The neuroprotective effects of cannflavin A were associated with a direct inhibition of Aβ1–42 fibril and aggregate density, evidenced by attenuated ThT fluorescence kinetics and microscopic evidence of both altered and diminished density of Aβ aggregate and fibril morphology via electron microscopy. ConclusionsThese findings highlight a concentration-dependent hormetic and neuroprotective role of cannflavin A against Aβ-mediated neurotoxicity, associated with an inhibition of Aβ fibrillisation. The efficacy of the cannabis flavone may itself direct further lead development targeting neurodegeneration in Alzheimer’s disease. However, the geranylated flavonoids generally displayed a comparatively potent neurotoxicity not observed with many conventional flavonoids in vitro.

Flavanones from the rhizomes of Boesenbergia pandurata

Boesenbergia pandurata (Roxb.) Schltr. is a perennial medicinal herb belonging to the Zingiberaceae family. It is cultivated in some tropical countries in Southeast Asia including Vietnam, Thailand, Myanmar, Indonesia and Malaysia. In Vietnam, it is known as "Ngai bun", and the fresh rhizomes are mainly used as a spice. This plant contains prenylated chalcones and other flavonoids as the major bioactive constituents. From the CHCl3 extract of Boesenbergia pandurata, we had isolated six flavanones. Their structures, pinocembrin (1), pinostrobin (2), alpinetin (3), di-Omethylpinocembrin (4), naringenin (5) and 5-Omethylnaringenin (6), were determined based on extensive spectroscopic analysis and in comparison with previous works.

Highly efficient and selective extraction of minor bioactive natural products using pure ionic liquids: Application to prenylated flavonoids in licorice

Lots of minor constituents in herbal medicines have shown great potential to devolve into lead compounds, and their extraction is attracting more and more attention in pharmaceutical industry. This study provided an example that showed efficient and selective extraction of minor bioactive natural products (prenylated flavonoids with anti-cancer activities) from an herbal medicine (licorice) using pure ionic liquids as green solvents. After investigation of a variety of hydrophobic ionic liquids with ultrasonic-assisted extraction, we found that [C8MIM]BF4 (1-octyl-3-methylimidazolium tetrafluoroborate) was the most effective one for extraction of five representative compounds (isoangustone A, glycycoumarin, licoisoflavanone, licoricidin and glabridin), and solvent to solid ratio, extraction time, extraction temperature and soaking time were then optimized through single-factor experiments and response surface methodology. As a result, the established method had significantly higher extraction selectivity than conventional organic solvents, which could be attributed to significant physical change of licorice microstructures after extraction, as well as strong interactions (especially hydrogen bond interactions) between [C8MIM]BF4 and prenylated flavonoids by mechanism study. In addition, 78.92% of the extracted prenylated flavonoids could be readily recovered from [C8MIM]BF4 by using reversed-phase solid phase extraction, and the recyclability of [C8MIM]BF4 was also confirmed.

C-prenylated flavonoids with potential cytotoxic activity against solid tumor cell lines

Natural products of plant origin or their semisynthetic derivatives acting as chemopreventive or chemotherapeutic agents for various types of cancer are under study as potential new anticancer drugs. Within the huge class of plant phenolic secondary metabolites, the subclass of prenylated flavonoids is quite rich in structural variety and pharmacological activity. One of their most prominent characteristics is their potential as anticancer agents. The aim of this review is to summarize the available data about the cytotoxicity of C-prenylated flavonoids on solid tumor cell lines as shown by in vitro assays. Prenylated flavonoids are divided into groups according to the prenyl substitution of the flavonoid skeleton. Within these flavonoid groups, attention is focused on flavones, flavonols, flavanones, dihydroflavonols, and isoflavonoids. This search is limited to compounds that do not contain heteroatoms other than oxygen, and is focused only on aglycones. Attempts to compare the bioassay results obtained from the search reveal complications caused by the use of different assay protocols, different ranges of concentration studied, different times the cell cultures were exposed to the compounds being assayed, and in some cases the lack of a proper positive control. In vivo assays of the anticancer activity of prenylated flavonoids on solid tumors were also reviewed. Despite the difficulties in comparing them, it is clear that the C-prenylated flavonoid class possesses significant bioactivity, suggesting a potential role for such compounds in anticancer drug discovery and development.

Toward Developing a Yeast Cell Factory for the Production of Prenylated Flavonoids.

Prenylated flavonoids possess a wide variety of biological activities, including estrogenic, antioxidant, antimicrobial, and anticancer activities. Hence, they have potential applications in food products, medicines, or supplements with health-promoting activities. However, the low abundance of prenylated flavonoids in nature is limiting their exploitation. Therefore, we investigated the prospect of producing prenylated flavonoids in the yeast Saccharomyces cerevisiae. As a proof of concept, we focused on the production of the potent phytoestrogen 8-prenylnaringenin. Introduction of the flavonoid prenyltransferase SfFPT from Sophora flavescens in naringenin-producing yeast strains resulted in de novo production of 8-prenylnaringenin. We generated several strains with increased production of the intermediate precursor naringenin, which finally resulted in a production of 0.12 mg L–1 (0.35 μM) 8-prenylnaringenin under shake flask conditions. A number of bottlenecks in prenylated flavonoid production were identified and are discussed.

New flavonoid and stilbene derivatives from the fruits of Macaranga balansae

Two new prenylated flavonoids, 4´-methyl-8-prenyltaxifolin (1) and 6,8-diprenyl-4´-methyl-naringenin (2) and a new geranylated stilbene, 4′-deprenyl-4-methoxymappain (3) together with eight known flavonoids (4–11) were isolated from the fruits of Macaranga balansae Gagnep. Their chemical structures were determined by means of spectroscopic methods including 1D, 2D NMR, and MS data. Compound 2 showed the highest cytotoxic activity against PanC1, A549, KB and LU-1 cell lines with IC50 values range from 7.89 to 22.81 µM.

Identification of BKca channel activation effect of Kushen extract containing Kurarinone to ease urinary incontinence or overactive bladder

The large‐conductance Ca2+‐activated K+ channel (or BKCa channel) requires membrane depolarization or increased intracellular Ca2+ for its activation. This channel makes one of the most effective ways to generate membrane hyperpolarization and regulates several key physiological processes. In the bladder, BKCa channel evokes the relaxation of urinary bladder smooth muscle and thus represents a therapeutic target for urinary incontinence (UI) or overactive bladder (OAB). In our previous study, we reported that kurarinone, a prenylated flavanone from Sophora flavescens, potently activates BKCa channel and established its therapeutic potential for treating OAB (Lee et al., Mol Pharmacol. 90:140, 2016). Subsequently, we identified five more flavonoids from Kushen, the dry root of S. flavescens. including kuraridinol, a prenylated chalcone, significantly potentiating BKCa channel activity (Lee et al., Biol Pharm Bull. 41:1295, 2018). In this study, we analyzed the components of Kushen extracts isolated with differential ethanol concentrations and tested their efficacy for BKCa channel activation. We found that the potentiation effect of various extracts for BKCa channel correlates well with the concentration of kurainone in the extracts. In addition, the Kushen extracts potently relaxed acetylcholine‐induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. Our results strongly support the idea that the Kushen extract containing kurarinone as the main ingredient can be utilized as nutraceutical or functional food against lower urinary tract symptom such as UI or OAB.Support or Funding InformationThis work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry (IPET) through Agri‐Bio industry Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (317070‐4)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Potent inhibition of human carbonyl reductase 1 (CBR1) by the prenylated chalconoid xanthohumol and its related prenylflavonoids isoxanthohumol and 8-prenylnaringenin

In terms of drug disposal and metabolism SDR21C1 (carbonyl reductase 1; CBR1) exerts an assorted substrate spectrum among a large variety of clinically relevant substances. Additionally, this short-chain dehydrogenase/reductase is extensively expressed in most tissues of the human body, thus underpinning its role in xenobiotic metabolism. Reduction of the chemotherapeutic daunorubicin (DAUN) to daunorubicinol (DAUNol) is a prominent example of its metabolic properties in terms of chemoresistance and cardiotoxicity.The hop-derived prenylated chalcone xanthohumol (XN) and its physiological metabolites isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) have previously been reported to inhibit other DAUN reducing reductases and dehydrogenases including AKR1B1 and AKR1B10. Also with regard to their effects by means of interacting with cancer-related molecular pathways, XN and related prenylated flavonoids in particular have been in the focus of recent studies.In this study, inhibitory properties of these substances were examined with CBR1-mediated 2,3-hexanedione and DAUN reduction. All substances tested in this study turned out to efficiently inhibit recombinant human CBR1 within a low micromolar to submicromolar range. Among the substances tested, 8-PN turned out to be the most effective inhibitor when using 2,3-hexanedione as a substrate (Ki(app) = 180 ± 20 nM). Inhibition rates of recombinant CBR1-mediated DAUN reduction were somewhat weaker with IC50-values ranging from 11 to 20 μM. XN, IX and 8-PN also efficiently inhibited DAUN reduction by SW480 colon adenocarcinoma cytosol (IC50 = 3.71 ± 0.26 μM with 8-PN as inhibitor). This study identifies prenylated inhibitors, which might potentially interact with endogenous CBR1-driven (de-)toxication systems.

Prenylated Flavonoids from the Roots and Rhizomes of Sophora tonkinensis and Their Effects on the Expression of Inflammatory Mediators and Proprotein Convertase Subtilisin/Kexin Type 9.

Seven new prenylated flavonoids (1-7) and one new prenylated phenylpropiophenone (8) were isolated from roots and rhizomes of Sophora tonkinensis, along with nine known compounds (9-17). The structures 1-8 were elucidated by spectroscopic data analysis and comparison with reported values. Compounds 8 and 12 (7-methoxyebenosin) showed inhibitory activities against nitric oxide production in lipopolysaccharide-induced RAW264.7 cells, with IC50 values of 8.1 and 6.2 μM, respectively. They also significantly lowered expression of CSF2, TNF, and IL-1β. Lonchocarpol A (10) and erybraedin D (16) at concentrations of 20 μM downregulated proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression in HepG2 cells. Moreover, erybraedin D (16) inhibited PCSK9 protein synthesis (IC50 7.8 μM), while simultaneously activating AMP-activated protein kinase and acetyl-CoA carboxylase.