Prenylated Flavonoids Research Articles

New cytotoxic prenylated flavonoids from Commiphora opobalsamum stem bark

New cytotoxic prenylated flavonoids from Commiphora opobalsamum stem bark

Effects of biotransformation of prenylated flavonoids on antioxidative capacity

Effects of biotransformation of prenylated flavonoids on antioxidative capacity

Antidiarrhoeal activity of eriosematin E isolated from the roots of Eriosema chinense Vogel

Roots of the plant Eriosema chinense Vogel (Fabaceae) is distributed mainly over the Eastern Himalayan region of India and China. The roots of the plant are used as a vegetable by the people of Northern Australia, China and North East India and are used traditionally by the tribal people of Meghalaya (India) for the treatment of diarrhoea. It has been reported to have significant antidiarrhoeal, cytotoxic and antimycobacterial activity. The present investigation was undertaken to isolate a lead molecule responsible for the observed antidiarrhoeal activity. Eriosematin E, a prenylated flavanone, was isolated using column chromatography and was characterized by comparing its melting point and spectroscopic data (UV, IR, 1H NMR, 13C NMR, Mass Spectra) from literature. Eriosematin E (2.5, 5 and 10mg/kg p.o.) was then screened for normal faecal excretion rate and castor oil-induced diarrhoea models in rats. Further, it was examined for small intestinal transit, intestinal fluid accumulation and PGE2 induced enteropooling models in rats. Biochemical estimations and Na+ and K+ concentration in intestinal fluid were also determined along with colonic histopathological studies. The results illustrated a significant (P< 0.05) reduction in normal faecal output at 10mg/kg p.o. after 5th and 7thh of treatment and also showed maximum protection of 69.43% from diarrhoea in the castor oil-induced diarrhoea model. Significant results were also observed at the maximum effective dose of eriosematin E (10mg/kg p.o.) in inhibiting peristaltic index (small intestinal transit) and reducing intestinal fluid volume of castor oil induced and PGE2 induced enteropooling models. Further, eriosematin E restored all the alterations in biochemical parameters such as nitric oxide, protein, DNA, superoxide dismutase, catalase and lipid peroxidation. It also significantly recovered Na+ and K+ loss from body and confirmed its protective nature through the histopathological studies. The study corroborates the antidiarrhoeal potential of eriosematin E which may be attributed to its antisecretory and antioxidant potential.

Antitumoral action of icaritin in LNCaP prostate cancer cells by regulating PEA3/HER2/AR signaling.

Human epidermal growth factor receptor type 2 (HER2) and androgen receptor (AR) are critical factors for prostate cancer (PCa) progression. These factors regulate tumor cell survival and proliferation, and remain as crucial drivers of castration-resistant PCa progression. Icaritin (ICT) is a prenyl flavonoid derived from the Epimedium genus, which has many biological and pharmacological effects. Using androgen-sensitive human prostate carcinoma LNCaP cell lines, we found that 35 μg/ml of ICT could inhibit more than 50% of cell proliferation, induce cell apoptosis, and lead to a strong G1 phase arrest by targeting cyclin-related proteins and suppressing the ability of cell invasion. Moreover, ICT exerts its potent anticancer efficacy by inducing polyomavirus enhancer activator 3 (PEA3) to inhibit the aberrantly activated HER2/AR signaling. In addition, after PEA3 expression was silenced by specific small-interference RNA, we found that both the ICT-inhibited effect on LNCaP cell proliferation and the ICT-induced cell apoptosis rate decreased. These results provide alternative mechanisms for the antitumor actions of ICT, indicating that ICT might be a promising therapeutic agent, as well as a preventive agent, for hormone therapy-resistant PCa.

Two new prenylated flavonoids from the roots of Berberis thunbergii DC.

Two new prenylated flavonoids, thunbergiols A (1) and B (2), along with three known compounds, chrysin (3), quercetin (4) and berberine (5) were obtained from the methanolic extract of roots of Berberis thunbergii DC. MS, NMR and other spectroscopic techniques were employed for their structural characterisation.

α-Glucosidase and α-Amylase Inhibitors from Arcytophyllum thymifolium.

Three new coumarins (1-3), a prenylated flavanone (4), and two iridoids (5 and 6), together with 17 known secondary metabolites, were isolated from the aerial parts of Arcytophyllum thymifolium. The structures of the new compounds were elucidated on the basis of their spectroscopic data. The potential hypoglycemic properties of the new and known compounds were evaluated by measuring their α-amylase and α-glucosidase inhibitory effects. The iridoid asperulosidic acid (15) and the flavonoid rhamnetin (13) showed the highest activities versus α-amylase (IC50 = 69.4 ± 3.1 and 73.9 ± 5.9 μM, respectively). In turn, the new eriodictyol derivative 4 exhibited the most potent effect as an α-glucosidase inhibitor, with an IC50 value of 28.1 ± 2.6 μM, and was more active than acarbose, used as a positive control. Modeling studies were also performed to suggest the interaction mode of compound 4 in the α-glucosidase enzyme active site.

ChemInform Abstract: Antiinflammatory Prenylated Flavonoids from Helminthostachys zeylanica.

AbstractTwo new prenylated flavonoids, neougonins A (I) and B (II), are isolated from the whole plant of Helminthostachys zeylanica along with nine known compounds.

Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation.

Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named “angioprevention”. Several natural compounds exert their anti-tumor properties by activating 5′ adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae.

Influenza virus neuraminidase (NA) is the primary target for influenza therapeutics. Severe complications are often related to secondary pneumonia caused by Streptococcus pneumoniae (pneumococci), which also express NAs. Recently, a NA-mediated lethal synergism between influenza A viruses and pneumococci was described. Therefore, dual inhibitors of both viral and bacterial NAs are expected to be advantageous for the treatment of influenza. We investigated the traditional Chinese herbal drug sāng bái pí (mulberry root bark) as source for anti-infectives. Two prenylated flavonoid derivatives, sanggenon G (4) and sanggenol A (5) inhibited influenza A viral and pneumococcal NAs and, in contrast to the approved NA inhibitor oseltamivir, also planktonic growth and biofilm formation of pneumococci. Evaluation of 27 congeners of 5 revealed a correlation between the degree of prenylation and bioactivity. Abyssinone-V 4′-methyl ether (27) inhibited pneumococcal NA with IC50 = 2.18 μM, pneumococcal growth with MIC = 5.63 μM, and biofilm formation with MBIC = 4.21 μM, without harming lung epithelial cells. Compounds 5 and 27 also disrupt the synergism between influenza A virus and pneumococcal NA in vitro, hence functioning as dual-acting anti-infectives. The results warrant further studies on whether the observed disruption of this synergism is transferable to in vivo systems.

Regiospecific synthesis of prenylated flavonoids by a prenyltransferase cloned from Fusarium oxysporum

Due to their impressive pharmaceutical activities and safety, prenylated flavonoids have a high potent to be applied as medicines and nutraceuticals. Biocatalysis is an effective technique to synthesize prenylated flavonoids. The major concern of this technique is that the microbe-derived prenyltransferases usually have poor regiospecificity and generate multiple prenylated products. In this work, a highly regiospecific prenyltransferase (FoPT1) was found from Fusarium oxysporum. It could recognize apigenin, naringenin, genistein, dihydrogenistein, kampferol, luteolin and hesperetin as substrates, and only 6-C-prenylated flavonoids were detected as the products. The catalytic efficiency of FoPT1 on flavonoids was in a decreasing order with hesperetin >naringenin >apigenin >genistein >luteolin >dihydrogenistein >kaempferol. Chalcones, flavanols and stilbenes were not active when acting as the substrates. 5,7-Dihydroxy and 4-carbonyl groups of flavonid were required for the catalysis. 2,3-Alkenyl was beneficial to the catalysis whereas 3-hydroxy impaired the prenylation reaction. Docking studies simulated the prenyl transfer reaction of FoPT1. E186 was involved in the formation of prenyl carbonium ion. E98, F89, F182, Y197 and E246 positioned apigenin for catalysis.

Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenyl flavonoids.

Porphyromonas gingivalis is considered a major pathogen of chronic periodontitis, which also may be implicated with systemic diseases such as atherosclerosis. Secreted cysteine proteases, gingipains Rgp and Kgp, are essential for P. gingivalis virulence. Some polyphenols and flavonoids are known to inhibit gingipain activity and interfere with biofilm formation by P. gingivalis. Many bioactive compounds have been isolated from Epimedium species, but availability of these compounds on gingipains and P. gingivalis is still unclear. Therefore, the aim of this study was to evaluate natural products from medical plants to develop a new therapeutic agent against periodontal disease. Prenylated flavonoids were isolated from Epimedium species plant using column chromatographies. The inhibitory effect of the prenylated flavonoids against protease activity of gingipains were examined using purified gingipains and fluorogenic substrates. Anti-P. gingivalis activity was evaluated to analyze planktonic growth and biofilm formation in brain heart infusion medium in the presence of the prenylated flavonoids. We isolated 17 prenylated flavonoids (Limonianin, Epimedokoreanin B, etc.) from Epimedium species. We found that some prenylated flavonoids inhibited gingipain activity in a non-competitive manner with Ki values at μm order. The prenylated flavonoids also hindered growth and biofilm formation of P. gingivalis, in a manner independent of gingipain inhibition by the compounds. The results indicated an inhibitory effect of the prenylated flavonoids against P. gingivalis and would provide useful information for future development of periodontitis treatment that suppresses gingipains, P. gingivalis growth and biofilm formation.

Inhibition of α-glucosidase by new prenylated flavonoids from euphorbia hirta L. herb

Ethnopharmacological relevanceEuphorbia hirta L. (Euphorbiaceae) is a pantropical medicinal rhizomatous herb, traditionally used in the treatment of diabetes, respiratory and gastro-intestinal disorders. Aim of the studyTo isolate and characterize the constituents of Euphorbia hirta and evaluate their in-vitro α-glucosidase inhibitory activity. The study is also aimed at describing structural activity relationship, type of α-glucosidase inhibition and in-vivo potential to regulate post prandial hyperglycemia in Wistar rats. Materials and methodsMethanolic extract of whole plant was suspended in water, and sequentially fractionated with n-hexane and ethyl acetate. Further ethyl acetate fraction was subjected to medium pressure liquid chromatography (MPLC) to isolate the active molecules under the following experimental conditions, pressure (up to 5kg/cm2) and flow rate (2in./min). The structural elucidation of isolated compounds was done on the basis of detailed spectral analysis. The α-glucosidase inhibitory potential of isolated compounds was evaluated and compared with standard drug acarbose. In addition, type of inhibition was dwelled by Lineweaver-Burk plot analysis. Further, sucrose tolerance test was performed in Wistar rats pre-treated with the isolated compounds and acarbose (0.015mM) followed by a sucrose load (2g/kg, p.o.) and blood glucose level was measured up to 120min by the glucose oxidase method. ResultsThe ethyl acetate fraction afforded quercetrin (1), dimethoxy quercetrin (2), along with two new prenylated flavonosides designated as hirtacoumaroflavonoside (3) and hirtaflavonoside-B (4) characterized as 7-O-(p-coumaroyl)-5,7,4′-trihydroxy-6-(3,3-dimethyl allyl)-flavonol-3-O-β-d-glucopyranosyl-(2″→1″′)-O-α-l-rhamnopyranoside and 5, 7, 3′, 4′-trihydroxy-6-(3, 3-dimethyl allyl)-8-(iso-butenyl)-flavonol-3-C-β-d-glucopyranoside, respectively. All the isolated compounds showed dose dependent inhibition of α-glucosidase which was found to be comparable to acarbose. Maximum α-glucosidase inhibition was achieved with compound 3 (IC50 0.022mM) followed by 4 (IC50 0.071mM) in comparison to acarbose (IC50 0.092mM). The results revealed that 5,7,4′- trihydroxyflavone structure is imperative for the inhibitory activity. The prenylation in the flavonoids increase the potency and p-coumaroyl substitution at C-7 further enriched the α-glucosidase inhibition. Compound 3 exhibited non-competitive inhibition while compounds 1, 2 and 4 showed mixed non-competitive inhibitory pattern. The results of sucrose tolerance test corresponded well with the in vitro studies. Conclusionα-Glucosidase inhibitory activity and sucrose tolerance test demonstrated by the prenylated flavonoids present in E. hirta provide credence to the ethnomedicinal use of the plant in the management of diabetes in folk medicine.

Xanthohumol from Humulus lupulus L. induces glioma cell autophagy via inhibiting Akt/mTOR/S6K pathway

Xanthohumol is the major prenylated flavonoid in the hop plant (Humulus lupulus L.). The aim of our study was to determine the effects of xanthohumol on the U87 glioma cell line. In the present study, the U87 glioma cell line was treated with xanthohumol. Our results showed that xanthohumol reduced cell viability and induced apoptosis detected by the MTT assay and PI–Annexin V doubling staining, respectively, in glioma cells. In the acridine orange staining experiments, we also found that xanthohumol induced autophagy, as detected by flow cytometry and confocal microscopy. Western blot also showed that xanthohumol inhibited the Akt/mTOR/S6K pathway and promoted LC3-II formation and p62 degradation. Moreover, we found that the Erk inhibitor or JNK inhibitor could partially reversed the xanthohumol-induced LC3-II formation and cell death. Otherwise, autophagy inhibition by bafilomycin A1, Atg5 shRNA, or Atg7 shRNA partially protected xanthohumol-induced cell death. These findings indicated that xanthohumol may induce glioma cell death through induction of autophagy. In addition, we also demonstrated that xanthohumol inhibited tumour growth in a mouse xenograft model. In conclusion, xanthohumol may induce autophagy in glioma cells through both Akt/mTOR/S6K pathway and MAPK cascade and inhibit tumour growth in vivo. Our findings also support that autophagy induction may provide benefits to increasing therapeutic efficacy of anti-cancer drugs for the treatment of glioblastoma multiforme.

Cytotoxic prenylated flavonoids from Macaranga indica

Three new prenylated flavonoids, macarindicins A–C (1–3), as well as seven known compounds (4–10) were isolated from the twigs of Macaranga indica. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 2 and 3 enriched the diversity of prenyl moiety in genus Macaranga especially in the aspect of various lengths of prenyl chain. All the known compounds were isolated from M. indica for the first time and this plant was found to contain large number of ellagic acid. Compounds 1–10 were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 2.61–20.35μg/mL.

Three new prenylated flavonoids from Macaranga denticulata and their anticancer effects

One rare flavonoid–diterpene heterodimer, denticulatain C (1), one modified geranyl-type side chain substituted flavonoid, denticulatain D (2) and one geranylated flavonoid, denticulatain E (3), as well as 11 known compounds (4–14) were isolated from the fronds of Macaranga denticulata. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 4 and 8 inhibited the proliferation of A-549 cell line with IC50 values of 48.6 and 20.2μg/mL, respectively. Compounds 3, 6, and 8 exhibited significant antiangiogenic activity on a zebrafish model with IC50 values of 9.78, 0.34, and 2.55μg/mL, respectively.

Minor Prenylated Flavonoids from the Twigs of Macarangaadenantha and Their Cytotoxic Activity.

Three new minor prenylated flavonoids, named macadenanthins A–C (1–3), together with three known ones (4–6), were isolated from the twigs of Macaranga adenantha. Their structures were elucidated on the basis of extensive spectroscopic analysis including NMR, UV and MS. The prenyl moieties in compounds 1–3 were further modified by cyclization and hydroxylation. The new compounds were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 13.76–22.27 μM.Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-015-0059-1) contains supplementary material, which is available to authorized users.

Flavonoids from Artocarpus anisophyllus and their Bioactivities

Two new prenylated flavonoids, 4',5-dihydroxy-6,7-(2,2-dimethylpyrano)-2'-methoxy-8-γ,γ-dimethylallylflavone 1 and 3'-hydroxycycloartocarpin 2 along with six known flavonoids, 5,7-dihydroxy-4'-methoxy-8-prenylflavanone 3, isobavachalcone 4, pyranocycloartobiloxanthone A 5, artocarpin 6, chaplashin 7 and cycloartocarpin 8 were isolated for the first time from the leaves and the heartwoods of Artocarpus anisophyllus Miq. The structures of isolated flavonoids were elucidated spectroscopically using 1D and 2D NMR, FTIR, MS, UV and also by comparison with literature data. These flavonoids were screened for their antioxidant and tyrosinase inhibitory activities. The dichloromethane and ethyl acetate crude extracts together with 3'-hydroxycycloartocarpin 2, pyranocycloartobiloxanthone A 5 and artocarpin 6 showed DPPH (2,2-diphenyl-l-picrylhydrazyl) radical scavenging activity with SC50 values of 80.2, 40.0, 152.9, 20.2 and 140.0 μg/mL in 30 min, respectively. Pyranocycloartobiloxanthone A 5 exhibited significant tyrosinase inhibitory activity against tyrosinase from mushroom with IC50 values of 60.5 μg/mL.

Prenylated flavonoids from the fruits of Sinopodophyllum emodi and their cytotoxic activities

Thirteen new prenylated flavonoids were isolated from Sinopodophyllum emodi together with eleven known analogues. Compound 22 exhibited the most potent cytotoxicity against MCF-7 and HepG2 cell lines.

A New Flavonoid Derivative as Cytotoxic Compound Isolated from Ethyl Acetate Extract of Macaranga gigantifolia Merr. Leaves

A new prenylated flavonoid compound 5,7,3’,4’-tetrahydroxy-3,6-diprenylflavone (1) has been isolated from methanol extract of the leaves of Macaranga gigantifolia Merr. Isolation was performed using chromatography methods and their structures were elucidated based on spectroscopic data. cytotoxic activity against murine leukemia P-388 cell line conducted using MTT method. Compound 1 showed strong cytotoxic activity with IC50 value 6.19μg/mL

Flavonoid 4'-O-Methylkuwanon E from Morus alba Induces the Differentiation of THP-1 Human Leukemia Cells.

Aims. In this work we studied cytodifferentiation effects of newly characterized prenyl flavonoid 4′-O-methylkuwanon E (4ME) isolated from white mulberry (Morus alba L.). Main Methods. Cell growth and viability were measured by dye exclusion assay; cell cycle and surface antigen CD11b were monitored by flow cytometry. For the cytodifferentiation of cells the NBT reduction assay was employed. Regulatory proteins were assessed by western blotting. Key Findings. 4ME induced dose-dependent growth inhibition of THP-1 cells, which was not accompanied by toxic effect. Inhibition of cells proliferation caused by 4ME was associated with the accumulation in G1 phase and with downregulation of hyperphosphorylated pRb. Treatment with 4ME led to significant induction of NBT-reducing activity of PMA stimulated THP-1 cells and upregulation expression of differentiation-associated surface antigen CD11b. Our results suggest that monocytic differentiation induced by 4ME is connected with up-regulation of p38 kinase activity. Significance. Our study provides the first evidence that 4ME induces the differentiation of THP-1 human monocytic leukemia cells and thus is a potential cytodifferentiating anticancer agent.