Chemical constituents of Callicarpa nudiflora and their anti-platelet aggregation activity

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Zhiqiang Zhou a,b, Xiaoyi Wei c, Huizheng Fu b, Yuehua Luo b,⁎ a Pharmaceutical Department of Nanchang University, Nanchang 330006, PR China b Jiangxi Provincial Institute for Drug and Food Control, Nanchang 330029, PR China c Key Labotatory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, PR China a r t i c l e i n f o a b s t r a c t Article history: Received 30 January 2013 Accepted in revised form 30 April 2013 Available online 10 May 2013 Two new triterpenoids, 2α,3α,19α,23-tetrahydroxyurs-12,20(30)-dien-28-oic acid (1) and 2α,3α,19α-trihydroxyurs-12-en-28-oic acid-28-O-β-D-xylopyranosyl (1 → 2)-β-D-glucopyranoside (2), and a new acylated flavone glycoside, luteolin 3′-O-(6″-E-caffeoyl)-β-D-glucopyranoside (3), together with three known compounds (4–6), were isolated from the leaves of Callicarpa nudiflora Hook. Their structures were elucidated on the basis of spectroscopic data and chemical methods. Anti-platelet aggregation activities of these compounds were evaluated in vitro. Compounds 1 and 2 showed inhibitory effects on ADP-induced platelet aggregation with EC50 values of 9.48 μM and 25.31 μM, respectively. © 2013 Elsevier B.V. All rights reserved. Keywords: Callicarpa nudiflora Hook Flavone glycoside Triterpenoids Anti-platelet aggregation 1. Introduction Callicarpa nudiflora Hook, belonging to the family Verbenaceae, is distributed widely in Guangdong, Guangxi, and Hainan Provinces of mainland China. It is commonly used as a folk Chinese medicine for eliminating stasis to subdue swelling and hemostasis [1]. Flavonoids, triterpenoids and phenylpropanoid glycosides from the leaves were previously reported [2,3]. According to traditional Chinese medicine theory, eliminating stasis to subdue swelling is similar to the antithrombotic effect, by reducing the surfactant of platelet, inhibiting platelet aggregation, regulating the blood rheology. In order to elucidate the function of C. nudiflora, we investigated the plant. In our preliminary screening, the EtOAc part of the 80% EtOH extract of the leaves of C. nudiflora showed significant anti-platelet aggregation activity. One of our efforts to discover biologically significant anti-platelet aggregation property from plant resources has led to the isolation of three new compounds, 2α,3α,19α,23-tetrahydroxyurs-12,20(30)-dien- 28-oic acid (1), 2α,3α,19α-trihydroxyurs-12-en-28-oic acid- 28-O-β-D-xylopyranosyl (1 → 2)-β-D-glucopyranoside (2), and luteolin 3′-O-(6″-E-caffeoyl)-β-D-glucopyranoside (3), and three known compounds, myrianthic acid (4), kajiichigoside F1 (5), and luteolin 4′-O-(6″-E-caffeoyl)-β-Dglucopyranoside (6) from the leaves of C. nudiflora. Reported herein are the isolation, structure elucidation and biological activity of these compounds. 2. Experimental 2.1. General experimental procedures Optical rotations were measured on a Perkin-Elmer 341 polarimeter. The UV spectra were recorded in MeOH on a Perkin-Elmer Lambda 25 UV–vis spectrophotometer. The 1H (400 MHz), 13C (100 MHz), and 2D NMR spectra were recorded on a Bruker DRX-400 instrument using TMS as an internal reference. ESIMS data were collected on a MDS SCIEX API 2000 LC/MS/MS instrument. HRESIMS data were obtained on a Bruker Bio TOF IIIQ mass spectrometer. Preparative HPLC was conducted with a Shimadzu LC-6A instrument with a RID-10A Fitoterapia 88 (2013) 91–95 ⁎ Corresponding author. Tel.: +86 791 88158689. E-mail address: emailluo@sohu.com (Y. Luo). 0367-326X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.fitote.2013.05.007 Contents lists available at SciVerse ScienceDirect Fitoterapia journal homepage: www.elsevier.com/locate/fitote refractive index detector using an XTerra prep MS C18 column (10 μm, 300 × 19 mm). Column chromatography was performed with silica gel 60 (100–200 mesh, Qingdao Marine Chemical Ltd., Qingdao, China) and Develosil ODS (75 μm, Nomura Chemical Co. Ltd., Japan). 2.2. Plant material The leaves of C. nudiflora were collected from Wuzhishan, Hainan, China, in Aug. 2011 and identified by Prof. Guiping Yuan at Jiangxi Provincial Institute for Drug and Food Control, China. A voucher specimen (No. 20110817) has been deposited in the Herbarium of Jiangxi Provincial Institute for Drug and Food Control. 2.3. Extraction and isolation The powdered dried leaves of C. nudiflora (9.6 kg) were extracted three times with 80% EtOH under reflux (2 h each). The extracting solution was evaporated under reduced pressure to yield a dark brown residue (1.8 kg). The residue was suspended in water (15 L) and then successively partitioned with petroleum ether (3 × 15 L), EtOAc (3 × 15 L), and n-BuOH (3 × 15 L). After removing the solvent, the EtOAc-soluble portion (220 g) was fractionated via silica gel column chromatography (CC), eluting with CHCl3−MeOH (100:0−60:40, v/v) to give sixteen fractions (E1−E16). Fraction E9 (21.5 g) was subjected to silica gel CC and eluted with CHCl3−MeOH (95:5− 75:25, v/v) to afford nine fractions (E9-1−E9-9). Fraction E9-5 (6 g) was separated by ODS CC (30−100%, MeOH−H2O) to give ten subfractions. Subfraction 7 (400 mg) was further separated by preparative HPLC using 65% MeOH as mobile phase to yield 1 (5 mg) and 4 (10 mg). Fraction E9-7 (3 g) was separated by ODS CC (30–100%, MeOH–H2O) to afford six subfractions. Subfraction 4 (700 mg) was further separated by preparative HPLC using 60% MeOH to afford 5 (41 mg). Fraction E10 (5.0 g) was separated by ODS CC using MeOH−H2O (30:70–100:0) to give seven fractions (E10-1−E10-7). Fractions E10-3 and E10-5 were separated by Sephadex LH-20 CC using MeOH to yield 3 (12 mg) and 6 (26 mg), respectively. Fraction E14 (2.34 g) was separated by ODS CC using MeOH−H2O (30:70–100:0) to give four fractions (E14-1−E14-4). Fraction E14-4 (720 mg) was further separated by preparative HPLC using 59% MeOH to afford 2 (13 mg). 2α,3α,19α,23-Tetrahydroxyurs-12,20(30)-dien-28-oic acid (1): white amorphous powder; [α]20D +34.0 (c 0.25, MeOH); UV (MeOH) λmax (logε): 203 (3.89) nm; 1H NMR (400 MHz, C5D5N) and 13C NMR (100 MHz, C5D5N) see Table 1; positive ESIMS m/z: 525 [M + Na]+; negative ESIMS m/z: 501 [M − H]−; HRESIMS m/z 503.3371 [M + H]+ (calcd for C30H47O6, 503.3373). 2α,3α,19α-Trihydroxyurs-12-en-28-oic acid 28-O-β-Dxylopyranosyl (1 → 2)-β-D-glucopyranoside (2): white needle; [α]20D +1.2 (c 0.33, MeOH); UV (MeOH) λmax (logε): 211 (3.69) nm; 1H NMR (400 MHz, CD3OD) and 13C NMR (100 MHz, CD3OD) see Table 1; negative ESIMS m/z: 781 [M − H]−; HRESIMS m/z 781.4371 [M − H]− (calcd for C41H65O14, 781.4374). Luteolin 3′-O-(6″-E-caffeoyl)-β-D-glucopyranoside (3): yellow amorphous powder; [α]20D − 110 (c 0.30, MeOH); UV (MeOH) λmax (logε): 213 (3.99), 241 (3.78), 271 (3.70), 331 (3.90) nm; 1H NMR (400 MHz, DMSO-d6) δ: 12.91 (1H, s, 5-OH), 7.68 (1H, d, J = 1.8 Hz, H-2′), 7.64 (1H, dd, J = 8.5, 1.8 Hz, H-6′), 7.33 (1H, d, J = 15.8 Hz, H-7″′), 6.98 (1H, d, J = 8.5 Hz, H-5′), 6.83 (1H, s, H-3), 6.81 (1H, d, J = 8.1 Hz, H-5″′), 6.58 (1H, d, J = 1.7 Hz, H-2″′), 6.54 (1H, dd, J = 8.1, Table 1 1H and 13C NMR data of compound 1 and 2 at 400/100 MHz, respectively (δ in ppm, J in Hz). 1 2 Position δH δC Position δH δC 1 1.83 (1H, m) 42.8 1 1.30 (1H, m) 42.5 1.94 (1H, m) 1.55 (1H, m) 2 4.27 (1H, m) 66.3 2 3.93 (1H, ddd, 11.3, 6.0, 2.9 Hz) 67.2 3 4.15 (1H, d, 1.9 Hz) 78.9 3 3.32 (1H, d, 2.9 Hz) 80.1 4 42.0 4 39.5 5 2.09 (1H, m) 43.7 5 1.23 (1H, m) 49.3 6 1.56 (1H, m) 18.5 6 1.37 (1H, m) 19.3 1.58 (1H, m) 1.47 (1H, m) 7 1.39 (1H, m) 33.4 7 1.35 (1H, m) 34.1 1.80 (1H, m) 1.54 (1H, m) 8 40.4 8 41.5 9 2.18 (1H, m) 47.8 9 1.82 (1H, m) 48.3 10 38.5 10 39.4 11 2.04 (1H, m) 24.1 11 1.97 (1H, m) 24.7 2.16 (1H, m) 2.00 (1H, m) 12 5.59 (1H, br s) 128.2 12 5.29 (1H, br s) 129.5 13 139.7 13 139.8 14 42.3 14 42.7 15 1.28 (1H, m) 29.2 15 0.90 (1H, m) 30.0 2.28 (1H, m) 1.85 (1H, m) 16 2.13 (1H, m) 26.8 16 1.62 (1H, m) 26.1 3.20 (1H, m) 2.54 (1H, m) 17 48.4 17 48.5 18 3.21 (1H, s) 55.4 18 2.50 (1H, s) 54.9 19 73.0 19 73.6 20 156.7 20 1.31 (1H, m) 43.0 21 2.22 (1H, m) 29.0 21 1.68 (1H, m) 27.3 3.12 (1H, m) 1.75 (1H, m) 22 2.09 (1H, m) 39.5 22 1.60 (1H, m) 38.3 2.29 (1H, m) 1.72 (1H, m) 23 3.74 (1H, d, 10.8 Hz) 71.3 23 0.98 (3H, s) 29.3 3.91 (1H, d, 10.8 Hz) 24 0.86 (3H, s) 22.5 24 0.86 (3H, s) 17.8 25 0.98 (3H, s) 17.0 25 1.00 (3H, s) 17.1 26 0.74 (3H, s) 17.6 26 1.09 (3H, s) 17.5 27 1.33 (3H, s) 24.8 27 1.68 (3H, s) 24.1 28 178.7 28 180.2 29 1.19 (3H, s) 27.1 29 1.61 (3H, s) 27.5 30 0.92 (3H, d, 6.7 Hz) 16.6 30 4.78 (1H, s) 105.3 Sugar (C-28) Glc 4.97 (1H, s) 1 5.37 (1H, d, 7.7 Hz) 94.0 2 3.57 (1H, m) 80.3 3 3.29 (1H, m) 78.0 4 3.41 (1H, m) 71.2 5 3.30 (1H, m) 78.5 6 3.65 (1H, dd, 12.0, 4.7 Hz) 62.4 3.77 (1H, m) Xyl (1 → 2) Glc 1 4.59 (1H, d, 7.8 Hz) 105.5 2 3.18 (1H, m) 75.8 3 3.60 (1H, m) 78.6 4 3.38 (1H, m) 70.8 5 3.13 (1H, m) 67.1 3.80 (1H, m) Compound 1 was measured in C5D5N. Compound 2 was measured in CD3OD. 92 Z. Zhou et al. / Fitoterapia 88 (2013) 91–95 1.7 Hz, H-6″′), 6.50 (1H, d, J = 2.0 Hz, H-8), 6.18 (1H, d, J = 2.0 Hz, H-6), 6.07 (1H, d, J = 15.8 Hz, H-8″′), 5.14 (1H, d, J = 7.2 Hz, H-1″), 4.48 (1H, dd, J = 12.0, 1.8 Hz, H-6″a), 4.21 (1H, dd, J = 12.0, 7.6 Hz, H-6″b), 3.95 (1H, m, H-5″), 3.40 (1H, m, H-3″), 3.38 (1H, m, H-2″), 3.25 (1H, m, H-4″); 13C NMR (100 MHz, DMSO-d6) δ: 163.1 (C-2), 103.1 (C-3), 181.7 (C-4), 161.4 (C-5), 98.9 (C-6), 164.1 (C-7), 94.0 (C-8), 157.2 (C-9), 103.8 (C-10), 121.6 (C-1′), 113.2 (C-2′), 145.3 (C-3′), 150.5 (C-4′), 116.4 (C-5′), 121.5 (C-6′), 100.3 (C-1″), 73.0 (C-2″), 75.7 (C-3″), 70.3 (C-4″), 73.8 (C-5″), 63.8 (C-6″), 125.1 (C-1″′), 115.6 (C-2″′), 145.3 (C-3″′), 148.2 (C-4″′), 115.9 (C-5″′), 119.5 (C-6″′), 145.3 (C-7″′), 113.2 (C-8″′), 166.5 (C-9″′); positive ESIMS m/z: 611 [M + H]+; negative ESIMS m/z: 609 [M − H]−; HRESIMS m/z 609.1241 [M − H]− (calcd for C30H25O14, 609.1244). 2.4. Determination of absolute configurations of the sugar moieties in 2 and 3 Based on the reported procedure [4], each (2 mg) of compounds 2 and 3 was dissolved in 2 M HCl (dioxane–H2O, 1:1 v/v) and refluxed for 10 h. After removal of the HCl by evaporation and extraction with EtOAc, the H2O extract was again evaporated and dried in vacuo to furnish a monosaccharide residue. The residue was dissolved in pyridine (1 ml) to which 2 mg L-cysteine methyl ester hydrochloride was added. The mixture was kept at 60 °C for 2 h, evaporated under an N2 stream, and dried in vacuo, then trimethylsilylated with N-trimethylsilylimidazole (0.2 ml) for 2 h. The mixture was partitioned between n-hexane and H2O (2 ml each), and the n-hexane extract was analyzed by GC. In the acid hydrolysate of 2 and 3, D-glucose and D-xylose were verified by comparison with retention times of their derivatives and those of corresponding control samples prepared in the same way. 2.5. Anti-platelet aggregation assay The in vitro activity studies on anti-platelet aggregation of 6 compounds have been done by using Born test [5,6]. Arterial blood gathering from the rat femoral artery was collected into tubes which was containing 3.8% sodium citrate (1:9, v/v). Platelet aggregation was assessed in platelet-rich plasma (PRP), obtained by centrifugation of citrated whole blood at room temperature for 10 min (500–800 rpm). The aggregation rate was measured by platelet aggregation analyzer after stimulation with ADP (3 μM) using platelet-poor plasma (PPP) to set zero. The PPP was obtained by centrifugation of PRP at room temperature for 15 min (3000 rpm). The solution of the compounds dissolved in C2H5OH (10 μl) was added into PRP (250 μl), and the same volume of C2H5OH with no test compound was added as a reference sample (according to the pre-experiment, 10 μl of C2H5OH appears no significant effect on the platelet aggregation). After 2 min incubating, we assessed the platelet aggregation activities and calculated the percentage inhibition of platelet aggregation using the corresponding ADP. 3. Results and discussion The EtOH extract of the leaves of C. nudiflora Hook was fractionated with petroleum ether, EtOAc and n-BuOH. Separation of the EtOAc-soluble extract by a combination of silica gel, ODS column chromatography and preparative HPLC afforded three new compounds (1–3) (Fig. 1) together with three known compounds, myrianthic acid (4) [7], kajiichigoside F1 (5) [8], and luteolin 4′-O-(6″-E-caffeoyl)-β-Dglucopyranoside (6) [9]. The structures of the known compounds were determined by interpretation of their spectroscopic data as well as by comparison with reported data. Compound 1 was obtained as a white amorphous powder. The HRESIMS of 1 showed a quasi-molecular ion peak at m/z 503.3371 [M + H]+, indicating a molecular formula of C30H46O6 (calcd for C30H47O6, 503.3373). The 1H NMR spectrum of 1 in C5D5N showed five methyl singlets (δH 0.86, 1.00, 1.09, 1.61, 1.68). Additional proton resonances observed included those ascribed to an olefinic proton at δH 5.59 (1H, br s), two exocyclic methylene protons at δH 4.78 (1H, br s) and 4.97 (1H, br s), two oxymethine protons at δH 4.15 (1H, d, J = 1.9 Hz) and 4.27 (1H, m), two oxymethylene protons at δH 3.74 and 3.91 (1H each, d, J = 10.8 Hz) (Table 1). The 13C NMR spectrum of 1 displayed 30 carbon signals, including those for a terminal olefinic methylene carbon δC 105.3, an olefinic methine carbon at δC 128.2, and two olefinic quaternary carbons at δC 139.7 and 156.7. These data suggested that 1 is likely to be a pentacyclic triterpene [10] with four hydroxyl groups, a trisubstituted double bond, and a terminal double bond. The two oxymethylene proton signals at δH 3.74 and 3.91, which correlated with the carbon resonance at δC 71.3 in the HSQC spectrum, showed HMBC correlations with C-3, C-4, C-5 and C-24, justifying its assignment to C-23. The assignment of hydroxyl groups at C-2 and C-3 was confirmed by the HMBC correlations from H-2 to C-4 and C-10 and from H-1, H-2, H-23 and H-24 to C-3. Comparison of the NMR spectroscopic data of 1 (Table 1) with those of myrianthic acid (4), a known compound [7] also obtained in the present study, demonstrated that two compounds were almost identical, except for a terminal double bond was located at C-20(30) in 1. The presence of a terminal double bond between C-20 and C-30 was confirmed by the HMBC spectrum, in which correlations (Fig. 2) were observed from H2-30 to C-19, C-20 and C-21. The α-orientation of 2-OH, 3-OH, and 19-OH in 1 was deduced by analysis of the NOESY spectrum which showed NOE correlations between the following proton pairs: H-2/ H-24, H-3/H-25, and H-29/H-18. Therefore, the structure of 1 was elucidated as 2α,3α,19α,23-tetrahydroxyurs-12,20(30)- dien-28-oic acid. Compound 2 was obtained as a white needle. Its molecular formula, C41H66O14, was determined from HRESIMS (m/z 781.4371 [M − H]− calcd for 781.4374) and supported by the NMR spectroscopic data. Comparison of the NMR data of 2 (Table 1) and 1 showed that the two compounds had the same triterpenoid core. The difference is that the hydroxymethyl (C-23) and the terminal double bond (C-30) in 1 are each replaced by methyl in 2. The 1H NMR spectrum of 2 displayed two anomeric proton signals at δH 4.59 (1H, d, J = 7.8 Hz) and δH 5.37 (1H, d, J = 7.7 Hz). These spectroscopic data suggested that 2 is a diglycoside of a tri-hydroxylated urs-12-en-28-oic acid. Acid hydrolysis of 2 with 2 M HCl afforded two monosaccharides, which were identified to be D-glucose and D-xylose by GC analysis of their trimethylsilyl L-cysteine derivatives [4]. In the HMBC spectrum, the presence of correlations from Glc-H-1 (δH 5.37) to C-28 (δC 178.7) and from Xyl-H-1 (δH 4.59) to Glc-C-2 (δC 80.3) confirmed that the glucose unit is Z. Zhou et al. / Fitoterapia 88 (2013) 91–95 93 located at C-28 of the aglycone and the xylose unit is attached to C-2 of the glucose unit. In the NOESY spectrum, NOE correlations were observed between the following proton pairs: H-2/H-24, H-3/H-25, H-29/H-18, and H-29/H-20, indicating that hydroxyl groups at C-2, C-3, and C-19 were all oriented to α position. Thus, compound 2 was determined as O OH OH HO HO OH 1 2 O OH O O HO HO HO O O HO HO OH HO HO O O HO HO OH O HO HO O O O OH OH HO 3 1 3 2 4 23 5 25 26 27 15 13 17 28 29 30 19 21 7 9 11 3 10 9 7 5 3' 1' 4' 1'' 6'' 8''' 9''' 7''' 3''' 1''' 4''' Fig. 1. Chemical structures of compounds 1–3. O OH OH HO HO OH 1 2 O OH O O HO HO HO O O HO HO OH HO HO O O HO HO OH O HO HO O O O OH OH HO 3 Fig. 2. Key HMBC (H → C) correlations of compounds 1–3. 94 Z. Zhou et al. / Fitoterapia 88 (2013) 91–95 2α,3α,19α-trihydroxyurs-12-en-28-oic acid-28-O-β-D-xylopyranosyl (1 → 2)-β-D-glucopyranoside. Compound 3 was obtained as a yellow amorphous powder. Its molecular formula was determined to be C30H26O14 from the HRESIMS ion at m/z 609.1241 [M − H]−. The 1H NMR spectrum of 3 in DMSO-d6 showed two sets of ABX spin systems at δH 7.68 (1H, d, J = 1.8 Hz), 7.64 (1H, dd, J = 8.5, 1.8 Hz), and 6.98 (1H, d, J = 8.5 Hz) and at δH 6.81 (1H, d, J = 8.1 Hz), 6.58 (1H, d, J = 1.7 Hz), 6.54 (1H, dd, J = 8.1, 1.7 Hz), respectively. It also showed that two meta-coupled aromatic protons at δH 6.18 (1H, d, J = 2.0 Hz) and 6.50 (1H, d, J = 2.0 Hz), a pair of doublets due to a trans-disubstituted double bond at δH 6.07 (1H, d, J = 15.8 Hz) and 7.33 (1H, d, J = 15.8 Hz), and a doublet due to an anomeric proton at δH 5.14 (1H, d, J = 7.2 Hz), together with signals attributed to oxymethylenes and oxymethines between δH 3.25 and 4.48, indicating the presence of a β-glycosyl group which was determined to be in D-form by acid hydrolysis followed by GC analysis of the monosaccharide trimethylsilyl L-cysteine derivative [4]. The 13C NMR spectrum of 3 showed carbon signals corresponding to the above structure units and an ester carbonyl at δC 166.5. These data indicated that 3 is a luteolin β-D-glucoside possessing a caffeoyl moiety. Comparison of the NMR data of 3 with those of luteolin 4′-O-(6″-E-caffeoyl)- β-D-glucopyranoside [9] demonstrated that two compounds were almost identical, except for the different glycosidic site. A series of HMBC correlations from H-1″ to C-3′ and from H-6″ to C-9″′ indicated that C-3′ and C-9″′ are attached to the glucose C-1″ and C-6″, respectively. Therefore, compound 3 was identified as luteolin 3′-O-(6″-E-caffeoyl)-β-D-glucopyranoside. Compounds 1–6 were evaluated for their in vitro activities on ADP-induced platelet aggregation by using Born method. Compounds 1 and 2 exhibited significant anti-platelet aggregation activities with EC50 values of 9.48 μM and 25.31 μM, respectively. Compounds 3–6 had no effects on anti-platelet aggregation. In hemolysis test, no hemolytic effect was observed in compounds 1 and 2. Compound 2 showed weaker anti-platelet aggregation activity than compound 1, suggesting that introduction sugar units may decrease the inhibitory activity, which may attribute to the increased hydrophilicity of the triterpenoid molecule. It was reported [11–13] that chiisanogenin, chiisanoside, ursolic acid, oleanolic acid isolated from Acanthopanax sessiliflorus had significant inhibitory effect on rat platelet aggregation in vitro. The result above demonstrated that triterpenoids may be the active ingredients of anti-platelet aggregation. In addition, phenylpropanoid glycosides were previously reported as the main active constituent of hemostasis [14]. Therefore, we think that C. nudiflora plays a two-way regulatory role in hemostasis and removing blood stasis. It also shows that the pharmacological test results are basically consistent with the traditional effect. Acknowledgements We thank Prof. Ruiqiang Chen at Guangzhou Institute of Chemistry, Chinese Academy of Sciences for NMR measurements. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.fitote.2013.05.007. References [1] Guangdong Institute of Botany. Flora hainanica. Beijing: Science Press; 197710. [2] Gao FP, Wang H, Ye WC, Zhao SX. J China Pharm Univ 2010;41:120. [3] Wang ZN, Han Z, Cui HB, Dai HF. J Trop Subtrop Bot 2007;15:359. [4] Kinjo J, Araki K, Fukui K, Higuchi H, Ikeda T, Nohara T, et al. Chem Pharm Bull 1992;40:3269. [5] Dong ED. Acta Pharmacol Sin 1990;6:375. [6] Born GVR. Nature 1962;194:927. [7] Jing LJ, Yong YL, Jung EH. Arch Pharm Res 2004;27:376. [8] Takashi S, Takashi T, Osamu T, Naohiro N. Phytochemistry 1984;23: 2829. [9] Xi ZX, Chen WS, Wu ZJ, Wang Y. Food Chem 2012;130:165. [10] Zhang BB, Han XL, Jiang Q, Liao ZX, Liu C, Qu YB. Fitoterapia 2012;83: 1242. [11] Yang CJ, An Q, Xiong ZL, Song Y, Yu K, Li FM. Planta Med 2009;75:656. [12] Liu YL, Wang HS. J Shenyang Pharm Univ 1993;4:275. [13] Jing LJ, Yong YL, Jung EH. Planta Med 2004;70:564. [14] Dan Y, Qian ZZ, Liu YZ, Zhou GP, Peng Y, Xiao PG. Chin Herb Med 2010;2:272. Z. Zhou et al. / Fitoterapia 88 (2013) 91–95 95

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