http://informahealthcare.com/phb ISSN 1388-0209 print/ISSN 1744-5116 online Editor-in-Chief: John M. Pezzuto Pharm Biol, 2014; 52(5): 655–660 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2013.853809
REVIEW
A systematic review on biological activities of prenylated flavonoids Xi Chen1,2, Emmanuel Mukwaya1, Man-Sau Wong3, and Yan Zhang1,3 School of Medical Instrument and Food Engineering, Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, People’s Republic of China, 2State Key Laboratory of Biocontrol, National Engineering Center of South China Sea for Marine Biotechnology, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, College of Life Sciences, Higher Education Mega Center, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China, and 3Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, People’s Republic of China Abstract
Keywords
Context: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant’s self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. Objective: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. Methods: PubMed and WEB OF KNOWLEDGEÕ were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure–activity relationship between prenylated flavonoids and their bioactivities. Results: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. Conclusion: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure–activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.
Bioactivity, flavonoids, herb, prenyl group
Introduction Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain (prenyl, geranyl) in the flavonoid skeleton (Wang et al., 2001). They are predominantly C-prenylated, whereas a few studies reported O-prenylation (Barron & Ibrahim, 1996). The prenyl chain generally refers to the 3,3-dimethylallyl substituent (3,3-DMA), a geranyl (E-3,7-dimethyl-2,6-octadienyl), a 1,1-dimethylallyl and/or a lavandulyl (5-methyl-2-isoprophenyl-hex-4-enyl) as well as variations of this structure based on oxidation and hydroxylation moiety as part of their flavonoid backbone structure (Mukne et al., 2011). The common 2,2-dimethylchromeno substituent is often termed a pyran ring. C-prenylation at positions 6 and/or 8, as well as 30 and/or 50 , appears to be generally preferred (Figure 1) (Ibrahim, 2005). Prenylated flavanones have important roles in the plant’s defensive strategy. Most of the prenylated isoflavonoids are considered to be the products of inducible metabolites (Ibrahim, 2005; Wang et al., 2001) and comes from the Correspondence: Yan Zhang, Ph.D., Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China. Tel: (86)21-65710369. Fax: (86)21-65710108. E-mail: [email protected]
History Received 20 March 2013 Revised 14 September 2013 Accepted 6 October 2013 Published online 20 November 2013
Leguminosae subfamily Papilionoideae (Botta et al., 2005; Yazaki et al., 2009). Recently the research on prenylated flavanones becomes a hot pot due to their promising and diverse bioactivities on multitarget tissues. In this review, we summarized the bioactivities of prenylated flavonoids, such as antibacterial activity, enzyme inhibition, osteogenic activity, antioxidant activity and so on. Simultaneously, the potential structure–activity relationship for this kind of flavonoid was analyzed.
Literature search and inclusion criteria
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1
We identified a systematic literature search with a limitation of being published from 1 January 2002 to 31 December 2012 Õ in the English language in PubMed . The search terms were ‘‘prenylated flavonoids,’’ ‘‘prenylation flavonoids,’’ ‘‘prenylated isoflavonoids,’’ ‘‘prenylflavonoids’’ and the related combinations of these keywords. In addition, WEB OF KNOWLEDGEÕ was used as an alternative for fully searching the relevant references. According to the articles extracted from these two databases, we found that most of the studies focused on in vitro studies, and only a few studies investigated on insects, tissues and animal models, with rarely any clinical studies. Articles with irrelevant research directions and low level of evidence (Eaves, 2011; Oosterhuis et al., 2004) were excluded, leaving 67 articles that are mainly
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One One One/Two Various Osteogenic activity Estrogenic activity Larvicidal activity Enzyme inhibitor and enhancer
C-6# C-8" C-8" Inactive C-8"
Prenyl Prenyl Prenyl Prenyl; Lavandulyl
Unclear Unclear Prenylated flavonoids have greater binding energies than those of the non-prenylated flavonoids Unclear Unclear Unclear Prenylation increases the lipophilic chain length to enhance the function of flavonoids skeleton Prenyl Prenyl; Lavandulyl Prenyl; Isoprenyl; farnesyl; geranyl Two One Four Anti-virus activity Anti-allergy Cytotoxicity
C-5/C-6" Various" C-3" C-8"
Unclear Various Various" Various Anti-oxidant activity
Number, Position, Type describe the characters of prenyl group. Mechanism shows how these factors affect the bioactivities of prenylated flavonoids.
Zhang et al. (2008); Ming et al. (2011) Kretzschmar et al. (2010); Milligan et al. (2002) Omisore et al. (2005); Niu et al. (2010) Kene´z et al. (2007); Habtemariam, (2012); Stec and Li (2012); Cho et al. (2011); Jang et al. (2008); Oh et al. (2005); Kim et al. (2003); Jung et al. (2010, 2012)
Peluso et al. (2010); Jones et al. (1996); Huang et al. (2009); Simpson et al. (2010) Kumazawa et al. (2007); Lee et al. (2006); Dufall et al. (2003); Park et al. (2006); Jung et al. (2008); Jayasinghe et al. (2008) Feng et al. (2010); Khaomek et al. (2008) Quan et al. (2008) Dat et al. (2010); Cassidy and Serzer (2010); Ma et al. (2011); Halabalaki et al. (2006); Wu et al. (2008) Various Various Anti-inflammatory activity
Various"
Prenyl; Lavandulyl; Isoprenyl C-8"
Emerging evidence has shown that prenylated flavonoids could protect plants against diseases by strongly inhibiting bacterial and fungal activities (Inui et al., 2012; Morel et al., 2012; Mukne et al., 2011; Ruddock et al., 2011; Sasaki et al., 2012; Shen et al., 2012; Sun et al., 2012; Sutthivaiyakit et al., 2009). There was some evidence suggesting that prenylation increased the lipophilicity of flavonoids, which resulted in an increased affinity to biological membranes and an improved interaction with target proteins (Hatano et al., 2000). Sasaki’s group (2012) found that prenylated C-methylflavonoids effectively inhibited Trichophyton sp. with a minimum inhibitory concentration (MIC) value of 1.95 mg/ ml, which was much lower than that (7.8 mg/ml) of flavonoids without a prenyl group. Sohn et al. (2004) obtained a similar result that five prenylflavonoids, purified from five different medicinal plants, showed strong antibacterial activity with MIC values of 5–30 mg/ml. It was suggested that the presence and position of the prenyl group played an important role for antibacterial activity. Prenyl group on the fused pyran ring system mostly governed this activity. On the contrary, there was no
Position
Antibacterial activity
Number
Biological activities of prenylated flavonoids
Type
discussed in this review (Table 1). Moreover, narrative summaries were used as a heterogeneity study (Hemingway & Brereton, 2009). The studies on potential relationships between the number, position, the type of prenyl group and the bioactivities of flavonoids are summarized in Table 2.
Various
19 7 12 3 2 25 3 7 3 19
Antibacterial activity
Antibacterial activity Anti-inflammatory activity Anti-oxidant activity Anti-virus activity Anti-allergic Cytotoxicity Osteogenic activity Estrogenic activity Larvicidal activity Enzyme inhibition or protection
Percentage (%)
Mechanism
Bioactivity
Prenylation increases the lipophilicity of flavonoids Unclear
Table 1. Summary on bioactivities of prenylated flavonoids.
Table 2. Summary on structure–bioactivity relationship of prenylated flavonoids.
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Figure 1. Chemical structure of prenylated flavonoids: R6, R8, R30 , R50 , one or more prenyl can be found in these positions as prenylated flavonoids: R20 , R40 , R3, R5, R7, can be –H, –OH or other functional groups.
Oh et al. (2011); Hatano et al. (2000)
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DOI: 10.3109/13880209.2013.853809
mandatory requirement for the presence of the prenyl group on aryl substitution (Madan et al., 2009). The results from Oh et al. (2011) indicated that the lavandulyl or isoprenyl moieties at C-8 contributed to the antibacterial activity of prenylflavonone derivatives. These studies revealed the importance of antibacterial activity of a prenyl group attached to the flavonoid molecule. Considering their strong antibacterial activity, prenylated flavonoids could be used to treat microbial infections.
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Enzyme inhibitor and enhancer The addition of the prenyl or lavandulyl group on flavonoids and isoflavonoids showed inhibitory or enhancing effects on a number of enzymes (Cho et al., 2011; Habtemariam, 2012; Jang et al., 2008; Kene´z et al., 2007; Kim et al., 2003; Oh et al., 2005; Stec & Li, 2012). This may be caused by the prenyl group, which could increase the lipophilic chain length, consequently enhancing the function of the flavonoids skeleton (Shin et al., 2002). Thus, the prenylation on flavonols and chalcones might make predominant contributions to the inhibition on b-site APP (amyloid protein precursor) cleaving enzyme 1 (BACE1). Furthermore, the inhibition of 8-lavandulylkaempferol on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 7.10 mM and 8.11 mM, respectively, indicated that the lavandulyl group might play a predominant role in both cholinesterase inhibitions, consistent with the recent findings that 3,40 -dihydroxy flavonols with a prenyl or lavandulyl group at the C-8 position and a hydroxyl or methoxy group at the C-5 position were important for aldose reductase (AR) inhibition (Jung et al., 2012). Additionally, Togola et al. (2009) suggested prenylflavonoids to be strong inhibitors on 15-lipoxygenase. Pterocarpan, isolated from the stem and root bark of Erythrina senegalensis DC. (Leguminosae), was identified to be the most effective inhibitor on 15-lipoxygenase. Its inhibitory rate, 61% at 32 mM, was even stronger than the positive control (quercetin) with IC50 at 30 mM (Jung et al., 2010). While at micromolar concentration, 3-hydroxykenusanone B, one of the prenylated flavonoids, could enhance the activities of alcohol-metabolizing enzymes, such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), suggesting the potential of prenylated flavonoids to prevent ‘‘hangovers’’ after alcohol intake. Currently, a combination of computational prediction and enzyme kinetics has begun to emerge as an effective screening technique for the potential on regulating enzyme activity (Jung et al., 2012). However, the underlying mechanisms for the regulation of prenylflavonoids on enzyme were not elucidated in almost all of the performed studies, and the levels of evidence (LOE) in these reported articles did not reach the highest standard as well. Therefore, more related mechanism studies with high LOE are needed to identify the molecular events involved in the modulations of prenylated flavonoids on certain enzymes. Cytotoxicity Prenylated flavonoid is one group of botanical compounds with potential cytotoxicity against tumor and cancer cells (Cho et al., 2012; Choi et al., 2009; Ko et al., 2005; Li et al.,
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2009; Paoletti et al., 2009; Pedro et al., 2005; Plazar et al., 2007, 2008; Zakaria et al., 2012). Two prenylflavonoids from Amyrisins showed cytotoxicity against PC-3 and DU 145 prostate cancer cells with IC50 values of 17.5 and 23 mM, respectively (Peng et al., 2012). It was also found that 30 geranyl-3-prenyl-20 ,40 ,50 ,70 -tetrahydroxyflavone, extracted from the M. alba leaves, showed strong cytotoxicity with an IC50 value of 0.64 mM against human cervical carcinoma HeLa cells by the MTT method (Dat et al., 2010). Furthermore, a molecular docking study on the cytotoxic activity of flavonoids with and without prenyl group from Lonchocarpus haberi M. Sousa (Leguminosae) with cancerrelevant chemotherapeutic targets was presented by Cassidy and Serzer (2010). Prenylated flavonoids generally showed greater binding energies than those of the non-prenylated flavonoids. It was concluded that the prenylated flavonoids from Lonchocarpus possibly owe the cytotoxic activity by suppressing the activity of some enzymes: aromatase (CYP 19), fatty acid synthase (FAS), xanthine oxidase (XO), cyclooxygenases (COX-1 and COX-2), lipoxygenase (LOX-3), ornithine decarboxylase (ODC), protein tyrosine kinase (PTK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), topoisomerase II (ATP-binding site), ATPbinding cassette (ABC) transporter and phospholipase A(2) (PLA) (Ma et al., 2011). Other studies showed that the prenyl-like groups, such as isoprenyl, geranyl and farnesyl groups, had influences on the cytotoxic activity of the parent compounds. Geranylation induced cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells (Cho et al., 2012). By studying the isoprenylated flavonoids extracted from Onobrychis ebenoides, the results suggested that the isoprenyl substituent at C-8 rendered cytotoxic and/or estrogenic in a cell-dependent manner (Halabalaki et al., 2006). The presence of prenyl, geranyl or farnesyl group at position 6 of the A ring of baicalein derivatives would affect their cytotoxic activities by modulating apoptosisrelated proteins such as Bax and Bcl-2. The significant down-regulation by baicalein derivatives on Bax expression was observed in the compound with farnesyl group by the possible explanation that the farnesyl group is more hydrophobic than the prenyl group and the geranyl group (Wu et al., 2008). Osteogenic activity Prenylated flavonoids played an optimistic role on promoting osteogenic differentiation and maturation of osteoblasts. Ming et al. (2011) reported an in vitro study which indicated that icariin, a prenylated flavonol glycoside with a prenyl group on C-8, had more potent osteogenic activity than the soy flavonoid genistein. While the prenyl group on C-6 could lead to the suppression of the maturation and proliferation of osteoblasts (Zhang et al., 2008), suggesting that the location of prenyl group at ring A affected the osteogenic activity of flavonoids, the prenylflavonoids with C-8 prenylation may represent a class of flavonoids with a higher osteogenic activity. However, the mechanism on how the position difference of prenyl group affects osteogenic activity is still unclear.
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Estrogenic activity
anti-inflammatory, antioxidant, and cytotoxic activities, it is supposed that the prenylflavonoids might be efficient on protecting plants from attacking insects. While several studies implied that the larvicidal activity may not mainly result from this kind of compound, Omisore et al. (2005) studied several compounds extracted from Dorstenia barteri var. (Moraceae) and D. convexa against Trichomonas gallinarum, and the order of the anti-trichomonal activity at 24 h turned to be quercetin (0.121 mg/ml)4quercitrin (0.244 mg/ml) bartericin B (0.244 mg/ml)4bartericin A (0.73 mg/ml)4stigmasterol (0.98 mg/ml)46,8-diprenyleridictyol ¼ isobavachalcone ¼ dorsmanin F (31.25 mg/ml). Similar results were observed in that the prenylflavonoids seemed to be inactive (LC50430 mg/ ml) of the larvicidal activity against the fourth-instar larvae of Aedes albopictus and Culex pipens quinquefasciatus (Niu et al., 2010).
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8-Prenylnaringenin (8-PN) showed comparable binding activity to both estrogen receptor isoforms (ERa and ERb) (Simons et al., 2012); interestingly, the estrogenic activity of 8-PN in vitro was greater than that of established phytoestrogens such as coumestrol, genistein, daidzein (Milligan et al., 2002) and its backbone compound naringenin (Barron & Ibrahim, 1996). Another study on structure–estrogenicity relationships in three functionally different estrogen receptor assays, including yeast-based assay, MVLN breast cancer cells and Ishikawa endometrial cancer cells, showed strong estrogenic activities of 8-PN in all assays used, while the parent compound naringenin displayed only very weak estrogenicity (Kretzschmar et al., 2010). Antioxidant activity The prenylated Favanones were reported to have better antioxidant activity than their non-prenylated counterparts. In the Stevens group’ study (2003), the prenylated flavonoids, extracted from the inflorescences of the female hop plant Humulus lupulus, could reduce the peroxynitrite-mediated oxidation of low-density lipoproteins (LDL) to low micromolar concentration. Further research was conducted to display that the prenylated flavonoids from Sophora flavescens Ait. (Fabaceae) possessed good anti-inflammatory activity as well as antioxidant activity by detecting 2,20 -azino-bis-3ethylbenzothiazoline-6-sulfonic acid (ABTS), 1,1-diphenyl-2picrylhydrazyl (DPPH), peroxynitrite (ONOO()) and total reactive oxygen species (ROS) (Jung et al., 2008). More emerging evidences also demonstrated that the prenylflavonoids had strong radical scavenging properties toward the DPPH radical (Dufall et al., 2003; Jayasinghe et al., 2008; Kumazawa et al., 2007; Lee et al., 2006; Park et al., 2006). Anti-inflammatory activity Prenylflavonoids extracted from crude leaf of D. polyandra could inhibit an acute inflammatory response in vivo model with TPA-induced mouse ear edema (Simpson et al., 2010). Lipopolysaccharide-induced cytokine production of monocyte chemo-attractant protein-1 (MCP-1) was inhibited by xanthohumol and isoxanthohumol with IC50 values of 14.4 mM and 12.6 mM, respectively, indicating that the position, number and length of the prenyl group had a marked influence on suppression of MCP-1 production (Jones et al., 1996; Peluso et al., 2010). Another prenylflavonoid extracted from the rhizomes of Helminthostachys zeylanica L. (Ophioglossaceae) turned to be the most effective inhibitor (IC50 value, 0.49 mM) in the FMLP/CB-induced elastase release assay among a few of the flavonoids, and the 3D-superimposed modeling of the chromanone core showed that the cyclization between ring B and ring C was important for the potency in inhibiting elastase release when compared with other prenylflavonoids from rhizomes of Helminthostachys zeylanica L. (Huang et al., 2009). Larvicidal activity From an ecological perspective, some prenylflavonoids may have evolved to defend against insects. Due to their
Anti-virus The prenylflavonoids had positive effects on anti-virus activity. ()-5,40 -Dihydroxy-7,8-[(300 -hydroxy-400 -one)-200 ,200 dimethylpyrano]-flavone from Poncirus trifoliata L. (Rutaceae) showed significant anti-HIV-1 activity with high therapeutic index (TI) of 143.65 (Feng et al., 2010). On the other hand, lonchocarpol A with two prenyl groups on both C-5 and C-6 showed a notable antimalarial activity (IC50 ¼ 1.6 mg/ml), but two other prenylflavonoids with a cycle on ring A showed no antimalarial activity (Khaomek et al., 2008). The anti-virus mechanism of prenylated flavonoids is still waiting to be elucidated. Anti-allergy Quan et al. (2008) analyzed anti-allergic activities of several flavonoids with the prenyl group or lavandulyl group, among which three prenylflavonoids with a lavandulyl group exhibited the suppressive effect on the degranulation of RBL-2H3 cells, a cultured mast cell line, which is widely used to predict possible anti-allergic activities of lead compounds. The IC50 values for these three compounds were 27.1 2.1 mM, 20.0 3.2 mM, and 16.5 1.1 mM, respectively, which were comparable to that of the clinically used anti-allergic drug azelastine (IC50 ¼ 20 mM).
Summary of the current situation on both in vivo and in vitro studies The previous investigations on bioactivities of prenylated flavonoids are mostly limited to in vitro studies. More animal and human studies need to be conducted to verify in vitro results. For example, an animal study was done to investigate the effect of prenylated flavonoids from Sophora Pavescens (SF) on the hepatic cytochrome P450 enzymes. The presence of prenylated Favonoids made SF extract to facilitate the elimination of a variety of xenobiotics including pollutants, carcinogens, and drugs by oxidative metabolism (Ueng et al., 2009). A first prospective, randomized, double-blind and placebo-controlled study has been done to investigate how the prenylated flavonoid, 8-PN, alleviated menopausal discomforts (Heyerick et al., 2006). Sixty-seven menopausal women were treated with 8-PN for over 12 weeks. The results showed that 8-PN significantly reduced the Kupperman index
DOI: 10.3109/13880209.2013.853809
(Kupperman et al., 1953), which reflected the extent of climacteric disorders, at both 6 weeks (p ¼ 0.023) and 12 weeks (p ¼ 0.086) posttreatment. Possessing many bioactivities, prenylated flavonoids have the potential to be developed as new drugs or supplements that will make contributions to human health. However, more persuasive and scientific evidence based on clinical studies are seriously needed (Anonymous, 2007; Evidence-Based Medicine Working Group, 1992), and the underlying action mechanisms and the structure–activity relationships of the prenylated flavonoids are still waiting to be well explored in further studies.
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Declaration of interest This work was sponsored by the Hong Kong Scholars Program (XJ2011022), China Postdoctoral Science Foundation funded project (2012M511115) and National Natural Science Foundation of China (No. 81202894). The authors have no potential conflicts of interest to declare.
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Mukne AP, Viswanathan V, Phadatare AG. (2011). Structure prerequisites for isoflavones as effective antibacterial agents. Pharmacog Rev 5:13–18. Niu HM, Zeng DQ, Long CL, et al. (2010). Clerodane diterpenoids and prenylated Favonoids from Dodonaea viscose. J Asian Nat Prod Res 12:7–14. Oh I, Yang WY, Chung SC, et al. (2011). In vitro sortase A inhibitory and antimicrobial activity of flavonoids isolated from the roots of Sophora flavescens. Arch Pharm Res 34:217–22. Oh WK, Kim BY, Oh H, et al. (2005). Phospholipase C gamma1 inhibitory activities of prenylated flavonoids isolated from Erythrina senegalensis. Planta Med 71:780–2. Omisore NO, Adewunmi CO, Iwalewa EO, et al. (2005). Antitrichomonal and antioxidant activities of Dorstenia barteri and Dorstenia convexa. Braz J Med Biol Res 38:1087–94. Oosterhuis WP, Bruns DE, Watine J, et al. (2004). Evidence-based guidelines in laboratory medicine: Principles and methods. Clin Chem 50:806–18. Paoletti T, Fallarini S, Gugliesi F, et al. (2009). Anti-inflammatory and vascularprotective properties of 8-prenylapigenin. Eur J Pharmacol 620:120–30. Park KH, Park YD, Han JM, et al. (2006). Anti-atherosclerotic and antiinflammatory activities of catecholic xanthones and flavonoids isolated from Cudrania tricuspidata. Bioorg Med Chem Lett 16: 5580–3. Pedro M, Ferreira MM, et al. (2005). Artelastin is a cytotoxic prenylated flavone that disturbs microtubules and interferes with DNA replication in MCF-7 human breast cancer cells. Life Sci 7:293–311. Peluso MR, Miranda CL, Hobbs DJ, et al. (2010). Xanthohumol and related prenylated flavonoids inhibit inflammatory cytokine production in LPS-activated THP-1 monocytes: Structure-activity relationships and in silico binding to myeloid differentiation protein-2 (MD-2). Planta Med 76:1536–43. Peng J, Hartley RM, Fest GA, Mooberry SL. (2012). Amyrisins A-C, O-prenylated flavonoids from Amyris madrensis. J Nat Prod 75: 494–6. Plazar J, Filipic M, Groothuis GM. (2008). Antigenotoxic effect of xanthohumol in rat liver slices. Toxicol in Vitro 22:318–27. Plazar J, Zegura B, Lah TT, Filipic M. (2007). Protective effects of xanthohumol against the genotoxicity of benzo(a)pyrene (BaP), 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and tert-butyl hydroperoxide (t-BOOH) in HepG2 human hepatoma cells. Mutat Res 63:1–8. Quan W, Lee HJ, Kim CY, et al. (2008). Anti-allergic prenylated flavonoids from the roots of Sophora flavescens. Planta Med 74: 168–70. Ruddock PS, Charland M, Ramirez S, et al. (2011). Antimicrobial activity of flavonoids from Piper lanceaefolium and other Colombian medicinal plants against antibiotic susceptible and resistant strains of Neisseria gonorrhoeae. Sex Transm Dis 38:82–8. Sasaki H, Kashiwada Y, Shibatav H, Takaishi Y. (2012). Prenylated flavonoids from the roots of Desmodium caudatum and evaluation of their antifungal activity. Planta Med 78:1851–6.
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Shen G, Huhman D, Lei Z, et al. (2012). Characterization of an isoflavonoid-specific prenyltransferase from Lupinus albus. Plant Physiol 159:70–80. Shin HJ, Kim HJ, Kwak JH, et al. (2002). A prenylated flavonol, sophoflavescenol: A potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett 12:2313–16. Simons R, Gruppen H, Bovee TF, et al. (2012). Prenylated isoflavonoids from plants as selective estrogen receptor modulators (phytoSERMs). Food Funct 3:810–27. Simpson B, Claudie D, Smith N, et al. (2010). Evaluation of the antiinflammatory properties of Dodonaea polyandra, a Kaanju traditional medicine. J Ethnopharmacol 132:340–3. Sohn HY, Son KH, Kwon CS, et al. (2004). Antimicrobial and cytotoxic activity of 18 prenylated flavonoids isolated from medicinal plants: Morus alba L., Morus mongolica Schneider, Broussnetia papyrifera (L.) Vent, Sophora flavescens Ait and Echinosophora koreensis Nakai. Phytomedicine 11:666–72. Stec E, Li SM. (2012). Mutagenesis and biochemical studies on AuaA confirmed the importance of the two conserved aspartate-rich motifs and suggested difference in the amino acids for substrate binding in membrane-bound prenyltransferases. Arch Microbiol 194:589–95. Stevens JF, Miranda CL, Frei B, Buhler DR. (2003). Inhibition of peroxynitrite-mediated LDL oxidation by prenylated flavonoids: The alpha, beta-unsaturated keto functionality of 20 -hydroxychalcones as a novel antioxidant pharmacophore. Chem Res Toxicol 16:1277–86. Sun D, Hurdle JG, Lee R, et al. (2012). Evaluation of flavonoid and resveratrol chemical libraries reveals abyssinone II as a promising antibacterial lead. Chem Med Chem 7:1541–5. Sutthivaiyakit S, Thongnak O, Lhinhatrakool T, et al. (2009). Cytotoxic and antimycobacterial prenylated flavonoids from the roots of Eriosema chinense. J Nat Prod 72:1092–6. Togola A, Hedding B, Theis A, et al. (2009). 15-Lipoxygenase inhibitory effects of prenylated flavonoids from Erythrina senegalensis. Planta Med 75:1168–70. Ueng YF, Chen CC, Tsai CC, Soucek P. (2009). Differential inductive profiles of hepatic cytochrome P450s by the extracts of Sophora flavescens in male and female C57BL/6JNarl mice. J Ethnopharmacol 126:437–46. Wang Y, Tan W, Li WZ, Li Y. (2001). A facile synthetic approach to prenylated flavanones: First total syntheses of ()-bonannione A and ()-sophoraflavanone A. J Nat Prod 64:196–9. Wu JY, Chung KT, Liu YW, Lu FJ, et al. (2008). Synthesis and biological evaluation of novel C(6) modified baicalein derivatives as antioxidative agents. J Agric Food Chem 56:2838–45. Yazaki K, Sasaki K, Tsurumaru Y. (2009). Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry 70:1739–45. Zakaria I, Ahmat N, Jaafar FM, Widyawaruyanti A. (2012). Flavonoids with antiplasmodial and cytotoxic activities of Macaranga triloba. Fitoterapia 83:968–72. Zhang Y, Li XL, Yao XS, Wong MS. (2008). Osteogenic activities of genistein derivatives were influenced by the presence of prenyl group at ring A. Arch Pharm Res 31:1534–9.
REVIEW
A systematic review on biological activities of prenylated flavonoids Xi Chen1,2, Emmanuel Mukwaya1, Man-Sau Wong3, and Yan Zhang1,3 School of Medical Instrument and Food Engineering, Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, People’s Republic of China, 2State Key Laboratory of Biocontrol, National Engineering Center of South China Sea for Marine Biotechnology, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, College of Life Sciences, Higher Education Mega Center, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China, and 3Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, People’s Republic of China Abstract
Keywords
Context: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant’s self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. Objective: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. Methods: PubMed and WEB OF KNOWLEDGEÕ were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure–activity relationship between prenylated flavonoids and their bioactivities. Results: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. Conclusion: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure–activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.
Bioactivity, flavonoids, herb, prenyl group
Introduction Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain (prenyl, geranyl) in the flavonoid skeleton (Wang et al., 2001). They are predominantly C-prenylated, whereas a few studies reported O-prenylation (Barron & Ibrahim, 1996). The prenyl chain generally refers to the 3,3-dimethylallyl substituent (3,3-DMA), a geranyl (E-3,7-dimethyl-2,6-octadienyl), a 1,1-dimethylallyl and/or a lavandulyl (5-methyl-2-isoprophenyl-hex-4-enyl) as well as variations of this structure based on oxidation and hydroxylation moiety as part of their flavonoid backbone structure (Mukne et al., 2011). The common 2,2-dimethylchromeno substituent is often termed a pyran ring. C-prenylation at positions 6 and/or 8, as well as 30 and/or 50 , appears to be generally preferred (Figure 1) (Ibrahim, 2005). Prenylated flavanones have important roles in the plant’s defensive strategy. Most of the prenylated isoflavonoids are considered to be the products of inducible metabolites (Ibrahim, 2005; Wang et al., 2001) and comes from the Correspondence: Yan Zhang, Ph.D., Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China. Tel: (86)21-65710369. Fax: (86)21-65710108. E-mail: [email protected]
History Received 20 March 2013 Revised 14 September 2013 Accepted 6 October 2013 Published online 20 November 2013
Leguminosae subfamily Papilionoideae (Botta et al., 2005; Yazaki et al., 2009). Recently the research on prenylated flavanones becomes a hot pot due to their promising and diverse bioactivities on multitarget tissues. In this review, we summarized the bioactivities of prenylated flavonoids, such as antibacterial activity, enzyme inhibition, osteogenic activity, antioxidant activity and so on. Simultaneously, the potential structure–activity relationship for this kind of flavonoid was analyzed.
Literature search and inclusion criteria
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1
We identified a systematic literature search with a limitation of being published from 1 January 2002 to 31 December 2012 Õ in the English language in PubMed . The search terms were ‘‘prenylated flavonoids,’’ ‘‘prenylation flavonoids,’’ ‘‘prenylated isoflavonoids,’’ ‘‘prenylflavonoids’’ and the related combinations of these keywords. In addition, WEB OF KNOWLEDGEÕ was used as an alternative for fully searching the relevant references. According to the articles extracted from these two databases, we found that most of the studies focused on in vitro studies, and only a few studies investigated on insects, tissues and animal models, with rarely any clinical studies. Articles with irrelevant research directions and low level of evidence (Eaves, 2011; Oosterhuis et al., 2004) were excluded, leaving 67 articles that are mainly
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One One One/Two Various Osteogenic activity Estrogenic activity Larvicidal activity Enzyme inhibitor and enhancer
C-6# C-8" C-8" Inactive C-8"
Prenyl Prenyl Prenyl Prenyl; Lavandulyl
Unclear Unclear Prenylated flavonoids have greater binding energies than those of the non-prenylated flavonoids Unclear Unclear Unclear Prenylation increases the lipophilic chain length to enhance the function of flavonoids skeleton Prenyl Prenyl; Lavandulyl Prenyl; Isoprenyl; farnesyl; geranyl Two One Four Anti-virus activity Anti-allergy Cytotoxicity
C-5/C-6" Various" C-3" C-8"
Unclear Various Various" Various Anti-oxidant activity
Number, Position, Type describe the characters of prenyl group. Mechanism shows how these factors affect the bioactivities of prenylated flavonoids.
Zhang et al. (2008); Ming et al. (2011) Kretzschmar et al. (2010); Milligan et al. (2002) Omisore et al. (2005); Niu et al. (2010) Kene´z et al. (2007); Habtemariam, (2012); Stec and Li (2012); Cho et al. (2011); Jang et al. (2008); Oh et al. (2005); Kim et al. (2003); Jung et al. (2010, 2012)
Peluso et al. (2010); Jones et al. (1996); Huang et al. (2009); Simpson et al. (2010) Kumazawa et al. (2007); Lee et al. (2006); Dufall et al. (2003); Park et al. (2006); Jung et al. (2008); Jayasinghe et al. (2008) Feng et al. (2010); Khaomek et al. (2008) Quan et al. (2008) Dat et al. (2010); Cassidy and Serzer (2010); Ma et al. (2011); Halabalaki et al. (2006); Wu et al. (2008) Various Various Anti-inflammatory activity
Various"
Prenyl; Lavandulyl; Isoprenyl C-8"
Emerging evidence has shown that prenylated flavonoids could protect plants against diseases by strongly inhibiting bacterial and fungal activities (Inui et al., 2012; Morel et al., 2012; Mukne et al., 2011; Ruddock et al., 2011; Sasaki et al., 2012; Shen et al., 2012; Sun et al., 2012; Sutthivaiyakit et al., 2009). There was some evidence suggesting that prenylation increased the lipophilicity of flavonoids, which resulted in an increased affinity to biological membranes and an improved interaction with target proteins (Hatano et al., 2000). Sasaki’s group (2012) found that prenylated C-methylflavonoids effectively inhibited Trichophyton sp. with a minimum inhibitory concentration (MIC) value of 1.95 mg/ ml, which was much lower than that (7.8 mg/ml) of flavonoids without a prenyl group. Sohn et al. (2004) obtained a similar result that five prenylflavonoids, purified from five different medicinal plants, showed strong antibacterial activity with MIC values of 5–30 mg/ml. It was suggested that the presence and position of the prenyl group played an important role for antibacterial activity. Prenyl group on the fused pyran ring system mostly governed this activity. On the contrary, there was no
Position
Antibacterial activity
Number
Biological activities of prenylated flavonoids
Type
discussed in this review (Table 1). Moreover, narrative summaries were used as a heterogeneity study (Hemingway & Brereton, 2009). The studies on potential relationships between the number, position, the type of prenyl group and the bioactivities of flavonoids are summarized in Table 2.
Various
19 7 12 3 2 25 3 7 3 19
Antibacterial activity
Antibacterial activity Anti-inflammatory activity Anti-oxidant activity Anti-virus activity Anti-allergic Cytotoxicity Osteogenic activity Estrogenic activity Larvicidal activity Enzyme inhibition or protection
Percentage (%)
Mechanism
Bioactivity
Prenylation increases the lipophilicity of flavonoids Unclear
Table 1. Summary on bioactivities of prenylated flavonoids.
Table 2. Summary on structure–bioactivity relationship of prenylated flavonoids.
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Figure 1. Chemical structure of prenylated flavonoids: R6, R8, R30 , R50 , one or more prenyl can be found in these positions as prenylated flavonoids: R20 , R40 , R3, R5, R7, can be –H, –OH or other functional groups.
Oh et al. (2011); Hatano et al. (2000)
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References
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Activities of prenylated flavonoids
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mandatory requirement for the presence of the prenyl group on aryl substitution (Madan et al., 2009). The results from Oh et al. (2011) indicated that the lavandulyl or isoprenyl moieties at C-8 contributed to the antibacterial activity of prenylflavonone derivatives. These studies revealed the importance of antibacterial activity of a prenyl group attached to the flavonoid molecule. Considering their strong antibacterial activity, prenylated flavonoids could be used to treat microbial infections.
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Enzyme inhibitor and enhancer The addition of the prenyl or lavandulyl group on flavonoids and isoflavonoids showed inhibitory or enhancing effects on a number of enzymes (Cho et al., 2011; Habtemariam, 2012; Jang et al., 2008; Kene´z et al., 2007; Kim et al., 2003; Oh et al., 2005; Stec & Li, 2012). This may be caused by the prenyl group, which could increase the lipophilic chain length, consequently enhancing the function of the flavonoids skeleton (Shin et al., 2002). Thus, the prenylation on flavonols and chalcones might make predominant contributions to the inhibition on b-site APP (amyloid protein precursor) cleaving enzyme 1 (BACE1). Furthermore, the inhibition of 8-lavandulylkaempferol on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 7.10 mM and 8.11 mM, respectively, indicated that the lavandulyl group might play a predominant role in both cholinesterase inhibitions, consistent with the recent findings that 3,40 -dihydroxy flavonols with a prenyl or lavandulyl group at the C-8 position and a hydroxyl or methoxy group at the C-5 position were important for aldose reductase (AR) inhibition (Jung et al., 2012). Additionally, Togola et al. (2009) suggested prenylflavonoids to be strong inhibitors on 15-lipoxygenase. Pterocarpan, isolated from the stem and root bark of Erythrina senegalensis DC. (Leguminosae), was identified to be the most effective inhibitor on 15-lipoxygenase. Its inhibitory rate, 61% at 32 mM, was even stronger than the positive control (quercetin) with IC50 at 30 mM (Jung et al., 2010). While at micromolar concentration, 3-hydroxykenusanone B, one of the prenylated flavonoids, could enhance the activities of alcohol-metabolizing enzymes, such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), suggesting the potential of prenylated flavonoids to prevent ‘‘hangovers’’ after alcohol intake. Currently, a combination of computational prediction and enzyme kinetics has begun to emerge as an effective screening technique for the potential on regulating enzyme activity (Jung et al., 2012). However, the underlying mechanisms for the regulation of prenylflavonoids on enzyme were not elucidated in almost all of the performed studies, and the levels of evidence (LOE) in these reported articles did not reach the highest standard as well. Therefore, more related mechanism studies with high LOE are needed to identify the molecular events involved in the modulations of prenylated flavonoids on certain enzymes. Cytotoxicity Prenylated flavonoid is one group of botanical compounds with potential cytotoxicity against tumor and cancer cells (Cho et al., 2012; Choi et al., 2009; Ko et al., 2005; Li et al.,
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2009; Paoletti et al., 2009; Pedro et al., 2005; Plazar et al., 2007, 2008; Zakaria et al., 2012). Two prenylflavonoids from Amyrisins showed cytotoxicity against PC-3 and DU 145 prostate cancer cells with IC50 values of 17.5 and 23 mM, respectively (Peng et al., 2012). It was also found that 30 geranyl-3-prenyl-20 ,40 ,50 ,70 -tetrahydroxyflavone, extracted from the M. alba leaves, showed strong cytotoxicity with an IC50 value of 0.64 mM against human cervical carcinoma HeLa cells by the MTT method (Dat et al., 2010). Furthermore, a molecular docking study on the cytotoxic activity of flavonoids with and without prenyl group from Lonchocarpus haberi M. Sousa (Leguminosae) with cancerrelevant chemotherapeutic targets was presented by Cassidy and Serzer (2010). Prenylated flavonoids generally showed greater binding energies than those of the non-prenylated flavonoids. It was concluded that the prenylated flavonoids from Lonchocarpus possibly owe the cytotoxic activity by suppressing the activity of some enzymes: aromatase (CYP 19), fatty acid synthase (FAS), xanthine oxidase (XO), cyclooxygenases (COX-1 and COX-2), lipoxygenase (LOX-3), ornithine decarboxylase (ODC), protein tyrosine kinase (PTK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), topoisomerase II (ATP-binding site), ATPbinding cassette (ABC) transporter and phospholipase A(2) (PLA) (Ma et al., 2011). Other studies showed that the prenyl-like groups, such as isoprenyl, geranyl and farnesyl groups, had influences on the cytotoxic activity of the parent compounds. Geranylation induced cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells (Cho et al., 2012). By studying the isoprenylated flavonoids extracted from Onobrychis ebenoides, the results suggested that the isoprenyl substituent at C-8 rendered cytotoxic and/or estrogenic in a cell-dependent manner (Halabalaki et al., 2006). The presence of prenyl, geranyl or farnesyl group at position 6 of the A ring of baicalein derivatives would affect their cytotoxic activities by modulating apoptosisrelated proteins such as Bax and Bcl-2. The significant down-regulation by baicalein derivatives on Bax expression was observed in the compound with farnesyl group by the possible explanation that the farnesyl group is more hydrophobic than the prenyl group and the geranyl group (Wu et al., 2008). Osteogenic activity Prenylated flavonoids played an optimistic role on promoting osteogenic differentiation and maturation of osteoblasts. Ming et al. (2011) reported an in vitro study which indicated that icariin, a prenylated flavonol glycoside with a prenyl group on C-8, had more potent osteogenic activity than the soy flavonoid genistein. While the prenyl group on C-6 could lead to the suppression of the maturation and proliferation of osteoblasts (Zhang et al., 2008), suggesting that the location of prenyl group at ring A affected the osteogenic activity of flavonoids, the prenylflavonoids with C-8 prenylation may represent a class of flavonoids with a higher osteogenic activity. However, the mechanism on how the position difference of prenyl group affects osteogenic activity is still unclear.
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Estrogenic activity
anti-inflammatory, antioxidant, and cytotoxic activities, it is supposed that the prenylflavonoids might be efficient on protecting plants from attacking insects. While several studies implied that the larvicidal activity may not mainly result from this kind of compound, Omisore et al. (2005) studied several compounds extracted from Dorstenia barteri var. (Moraceae) and D. convexa against Trichomonas gallinarum, and the order of the anti-trichomonal activity at 24 h turned to be quercetin (0.121 mg/ml)4quercitrin (0.244 mg/ml) bartericin B (0.244 mg/ml)4bartericin A (0.73 mg/ml)4stigmasterol (0.98 mg/ml)46,8-diprenyleridictyol ¼ isobavachalcone ¼ dorsmanin F (31.25 mg/ml). Similar results were observed in that the prenylflavonoids seemed to be inactive (LC50430 mg/ ml) of the larvicidal activity against the fourth-instar larvae of Aedes albopictus and Culex pipens quinquefasciatus (Niu et al., 2010).
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8-Prenylnaringenin (8-PN) showed comparable binding activity to both estrogen receptor isoforms (ERa and ERb) (Simons et al., 2012); interestingly, the estrogenic activity of 8-PN in vitro was greater than that of established phytoestrogens such as coumestrol, genistein, daidzein (Milligan et al., 2002) and its backbone compound naringenin (Barron & Ibrahim, 1996). Another study on structure–estrogenicity relationships in three functionally different estrogen receptor assays, including yeast-based assay, MVLN breast cancer cells and Ishikawa endometrial cancer cells, showed strong estrogenic activities of 8-PN in all assays used, while the parent compound naringenin displayed only very weak estrogenicity (Kretzschmar et al., 2010). Antioxidant activity The prenylated Favanones were reported to have better antioxidant activity than their non-prenylated counterparts. In the Stevens group’ study (2003), the prenylated flavonoids, extracted from the inflorescences of the female hop plant Humulus lupulus, could reduce the peroxynitrite-mediated oxidation of low-density lipoproteins (LDL) to low micromolar concentration. Further research was conducted to display that the prenylated flavonoids from Sophora flavescens Ait. (Fabaceae) possessed good anti-inflammatory activity as well as antioxidant activity by detecting 2,20 -azino-bis-3ethylbenzothiazoline-6-sulfonic acid (ABTS), 1,1-diphenyl-2picrylhydrazyl (DPPH), peroxynitrite (ONOO()) and total reactive oxygen species (ROS) (Jung et al., 2008). More emerging evidences also demonstrated that the prenylflavonoids had strong radical scavenging properties toward the DPPH radical (Dufall et al., 2003; Jayasinghe et al., 2008; Kumazawa et al., 2007; Lee et al., 2006; Park et al., 2006). Anti-inflammatory activity Prenylflavonoids extracted from crude leaf of D. polyandra could inhibit an acute inflammatory response in vivo model with TPA-induced mouse ear edema (Simpson et al., 2010). Lipopolysaccharide-induced cytokine production of monocyte chemo-attractant protein-1 (MCP-1) was inhibited by xanthohumol and isoxanthohumol with IC50 values of 14.4 mM and 12.6 mM, respectively, indicating that the position, number and length of the prenyl group had a marked influence on suppression of MCP-1 production (Jones et al., 1996; Peluso et al., 2010). Another prenylflavonoid extracted from the rhizomes of Helminthostachys zeylanica L. (Ophioglossaceae) turned to be the most effective inhibitor (IC50 value, 0.49 mM) in the FMLP/CB-induced elastase release assay among a few of the flavonoids, and the 3D-superimposed modeling of the chromanone core showed that the cyclization between ring B and ring C was important for the potency in inhibiting elastase release when compared with other prenylflavonoids from rhizomes of Helminthostachys zeylanica L. (Huang et al., 2009). Larvicidal activity From an ecological perspective, some prenylflavonoids may have evolved to defend against insects. Due to their
Anti-virus The prenylflavonoids had positive effects on anti-virus activity. ()-5,40 -Dihydroxy-7,8-[(300 -hydroxy-400 -one)-200 ,200 dimethylpyrano]-flavone from Poncirus trifoliata L. (Rutaceae) showed significant anti-HIV-1 activity with high therapeutic index (TI) of 143.65 (Feng et al., 2010). On the other hand, lonchocarpol A with two prenyl groups on both C-5 and C-6 showed a notable antimalarial activity (IC50 ¼ 1.6 mg/ml), but two other prenylflavonoids with a cycle on ring A showed no antimalarial activity (Khaomek et al., 2008). The anti-virus mechanism of prenylated flavonoids is still waiting to be elucidated. Anti-allergy Quan et al. (2008) analyzed anti-allergic activities of several flavonoids with the prenyl group or lavandulyl group, among which three prenylflavonoids with a lavandulyl group exhibited the suppressive effect on the degranulation of RBL-2H3 cells, a cultured mast cell line, which is widely used to predict possible anti-allergic activities of lead compounds. The IC50 values for these three compounds were 27.1 2.1 mM, 20.0 3.2 mM, and 16.5 1.1 mM, respectively, which were comparable to that of the clinically used anti-allergic drug azelastine (IC50 ¼ 20 mM).
Summary of the current situation on both in vivo and in vitro studies The previous investigations on bioactivities of prenylated flavonoids are mostly limited to in vitro studies. More animal and human studies need to be conducted to verify in vitro results. For example, an animal study was done to investigate the effect of prenylated flavonoids from Sophora Pavescens (SF) on the hepatic cytochrome P450 enzymes. The presence of prenylated Favonoids made SF extract to facilitate the elimination of a variety of xenobiotics including pollutants, carcinogens, and drugs by oxidative metabolism (Ueng et al., 2009). A first prospective, randomized, double-blind and placebo-controlled study has been done to investigate how the prenylated flavonoid, 8-PN, alleviated menopausal discomforts (Heyerick et al., 2006). Sixty-seven menopausal women were treated with 8-PN for over 12 weeks. The results showed that 8-PN significantly reduced the Kupperman index
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(Kupperman et al., 1953), which reflected the extent of climacteric disorders, at both 6 weeks (p ¼ 0.023) and 12 weeks (p ¼ 0.086) posttreatment. Possessing many bioactivities, prenylated flavonoids have the potential to be developed as new drugs or supplements that will make contributions to human health. However, more persuasive and scientific evidence based on clinical studies are seriously needed (Anonymous, 2007; Evidence-Based Medicine Working Group, 1992), and the underlying action mechanisms and the structure–activity relationships of the prenylated flavonoids are still waiting to be well explored in further studies.
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Declaration of interest This work was sponsored by the Hong Kong Scholars Program (XJ2011022), China Postdoctoral Science Foundation funded project (2012M511115) and National Natural Science Foundation of China (No. 81202894). The authors have no potential conflicts of interest to declare.
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