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Molecules 2013, 18(3), 2563-2570; doi:10.3390/molecules18032563

Article
A New Hydroxychavicol Dimer from the Roots of Piper betle
Chwan-Fwu Lin 1,2, Tsong-Long Hwang 3,4, Chun-Chien Chien 5, Huei-Yu Tu 6 and Horng-Liang Lay 6,*
1
Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; E-Mail: cflin@gw.cgust.edu.tw
2
Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
3
Cell Pharmacology Laboratory, Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; E-Mail: htl@mail.cgu.edu.tw
4
Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
5
Department of Dentistry, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; E-Mail: meridian_chien@hotmail.com
6
Department of Plant Industry, National Pingtung University of Science and Technolog, Pingtung 912, Taiwan; E-Mail: layhl@mail.npust.edu.tw
*
Author to whom correspondence should be addressed; E-Mail: layhl@mail.npust.edu.tw; Tel.: +886-8-774-0365; Fax: +886-8-774-0415.
Received: 28 November 2012; in revised form: 8 February 2013 / Accepted: 21 February 2013 /
Published: 26 February 2013

Abstract

: A new hydroxychavicol dimer, 2-(γ'-hydroxychavicol)-hydroxychavicol (1), was isolated from the roots of Piper betle Linn. along with five known compounds, hydroxychavicol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6). The structures of these isolated compounds were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils.
Keywords:
Piper betle; 2-(γ'-hydroxychavicol)-hydroxychavicol; hydroxychavciol; superoxide anion; elastase; neutrophils

1. Introduction

Piper betle Linn. (Piperaceae) has been extensively used in India, China, Taiwan, Thailand and many other countries [1]. The leaves are chewed with betel nut, to improve the taste and to prevent halitosis [2,3]. Traditionally, the roots has been used for the treatment of wind-cold cough, bronchial asthma, rheumatism, stomachalgia, edema of pregnancy, and as a contraceptive [4,5]. In previous phytochemical studies, several compounds, including β-sitosteryl palmitate, 3β-acetate ursolic acid, ursolic acid, 4-allylresorcinol, stigmast-4-en-3,6-dione and aristololactam A-II, have been isolated from the roots of P. betle [6,7,8]. Recently, we found that the ethanolic extract of the roots of this plant exhibited anti-inflammatory effects. Chromatography of the ethanolic extract led to the isolation of a new phenolic compound, 2-(γ'-hydroxychavicol)-hydroxychavicol (1), together with hydroxychavciol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6) [9,10,11,12,13] (Figure 1).

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Figure 1. The chemical structures of compounds 16.

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Figure 1. The chemical structures of compounds 16.
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Neutrophils play a pivotal role in the defense of the human body against infections. However, activated human neutrophils are known to cause tissue damage and to play a critical role in a variety of acute and chronic inflammatory diseases [14,15]. For example, high concentrations of reactive oxygen species and elastase produced by activated neutrophils in the sputum of patients with airway mucus hypersecretion has been implicated in the pathogenesis of many pulmonary diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis and acute respiratory distress syndrome [16,17,18,19]. In a search for suitable new anti-neutrophilic inflammatory agents from natural sources, the inhibition of O2•− production and elastase release in human neutrophil by compounds 16 were assayed. This paper describes the isolation, the determination of the structure of the new compound and the anti-inflammatory activity of the isolated compounds.

2. Results and Discussion

Compound 1 was obtained as a brown solid with a melting point of 73–75 °C. The EIMS gave a molecular ion at m/z 298 and the HREIMS spectrum gave 298.1216 (Calcd 298.1205), which corresponds to a molecular formula of C18H18O4. In the 1H-NMR spectrum of 1, two groups of aromatic proton signals could be attributed to a set of ABX-type aromatic protons at δH 6.90 (1H, d, J = 2.4 Hz, H-2'), 6.74 (1H, d, J = 8.4 Hz, H-5'), 6.70 (1H, dd, J = 2.4, 8.4 Hz, H-6') and a 1,2,4,5-tetrasubstituted aromatic protons at δH 6.68 (1H, s, H-3) and 6.65 (1H, s, H-6), respectively. In addition, the signals at δH 3.27 (2H, dd, J = 1.2, 6.6 Hz, H-α), 5.92 (1H, m, H-β), 4.99 (1H, m, H-γ) and 4.96 (1H, dd, J = 2.4, 4.2 Hz, H-γ) were assigned to an allyl substituent, and another set of resonances at δH 6.24 (1H, bd, J = 15.6 Hz, H-α'), 6.09 (1H, td, J = 6.6, 15.6 Hz, H-β') and 3.34 (2H, dd, J = 1.2, 6.6 Hz, H-γ') were assigned to a propeneyl moiety, based on their 1H-1H COSY correlations.

In the HMBC spectrum of 1 (Table 1 and Figure 2), the methylene proton signal at δH 3.34 (H-γ') showed correlations with carbon signals at δC 117.33 (C-3) and 129.79 (C-1), which also correlated to the olefinic methane proton signal at δH 5.92 (H-β) clearly suggested that the allyl group and C-γ' were connected to C-2 and C-1 of the tetrasubstrate benzene ring, respectively. Forthemore, the olefinic methane proton signal at δH 6.09 (H-β') displayed correlations with two aromatic quaternary carbon signals at δC 130.46 (C-2) and 130.98 (C-1'), and the signals at δH 6.24 (H-α') correlated with the signals of C-2' and C-6', indicated that C-α' was located at C-1'. The coupling constant (Jα'-β' = 15.6 Hz) indicated a trans configuration between H-α and H-β. From the above data, the structure of 1 was identified as 2-(γ'-isohydroxychavicol)hydroxychavicol.

Table 1. 1H-(600 MHz) and 13C-NMR (150 MHz) data of compound 1 (in acetone-d6, δ inppm, J in Hz).

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Table 1. 1H-(600 MHz) and 13C-NMR (150 MHz) data of compound 1 (in acetone-d6, δ inppm, J in Hz).
No.δCδHKey HMBC (H to C)
1129.79
2130.46
3117.336.68 (1H, s)C-1, C-γ'
4144.06
5144.06
6117.466.65 (1H, s)C-2, C-5, C-α
α37.053.27 (2H, dd, J = 1.2, 6.6 Hz)C-2, C-6, C-γ
β138.855.92 (1H, m)C-1
γ115.234.96 (1H, dd, J = 2.4, 4.2 Hz)C-α, C-β
4.99 (1H, m)
1'130.98
2'113.356.90 (1H, d, J = 2.4 Hz)C-α', C-6', C-4'
3'145.87
4'145.29
5'116.006.74 (1H, d, J = 8.4 Hz)C-1', C-3'
6'119.056.70 (1H, dd, J = 2.4, 8.4 Hz)C-2', C-4', C-α'
α'131.056.24 (1H, bd, J = 15.6 Hz)C-2', C-6', C-γ'
β'127.356.09 (1H, td, J =6.6, 15.6 Hz)C-2, C-1'
γ'35.983.34 (2H, dd, J = 1.2, 6.6 Hz)C-1, C-3, C-α'
Molecules 18 02563 g002 200
Figure 2. Key HMBC (arrow) and 1H-1H COSY (bold line) correlations of 1.

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Figure 2. Key HMBC (arrow) and 1H-1H COSY (bold line) correlations of 1.
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The in vitro anti-inflammatory effects of compounds 16 were tested (Table 2). Compound 2 (hydroxychavicol monomer) showed significant inhibitory effects in superoxide anion generation and elastase release (IC50 0.27 and 5.78 μM; Table 2 and Figure 3).

Table 2. Effects of compounds on superoxide anion generation and elastase release by human neutrophils in response to FMLP/CB.

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Table 2. Effects of compounds on superoxide anion generation and elastase release by human neutrophils in response to FMLP/CB.
CompoundSuperoxide anionElastase release
IC50 (μM)Inh % aIC50 (μM)Inh % a
18.59 ± 2.3094.85 ± 6.14 ***13.14 ± 7.0560.24 ± 3.82 ***
20.27 ± 0.09107.12 ± 1.36 ***5.78 ± 1.5694.42 ± 6.49 ***
3>304.15 ± 2.07>3019.36 ± 4.27 *
4>3028.96 ± 4.05 **>3013.65 ± 3.67 *
5>3041.06 ± 1.71 ***>3048.92 ± 5.32 ***
6>3043.63 ± 1.05 ***19.19 ± 3.9158.43 ± 2.31 ***
Sorafenib b3.01 ± 0.25 2.25 ± 0.36

a Percentage of inhibition (Inh %) at 30 μM concentration. Results are presented as the mean ± S.E.M. (n = 3). * p < 0.05; ** p < 0.01; *** p < 0.001 compared with the control value. b Sorafenib, a tyrosine kinase inhibitor, was used as a positive control.

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Figure 3. Concentration-dependent effects of compound 1 on O2•− production and elastase release in human neutrophils. Human neutrophils were preincubated with DMSO (control) or compound 1 for 5 min before activation by FMLP/CB. (A) O2•− production and (B) Elastase release was induced by FMLP/CB. All data are expressed as the mean ± S.E.M. (n = 3). * p < 0.025; ** p < 0.01; *** p < 0.001 compared to the control.

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Figure 3. Concentration-dependent effects of compound 1 on O2•− production and elastase release in human neutrophils. Human neutrophils were preincubated with DMSO (control) or compound 1 for 5 min before activation by FMLP/CB. (A) O2•− production and (B) Elastase release was induced by FMLP/CB. All data are expressed as the mean ± S.E.M. (n = 3). * p < 0.025; ** p < 0.01; *** p < 0.001 compared to the control.
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Compound 1 (a dimer of hydroxychavicol) also showed moderate effects in both assays (IC50 8.59 and 13.14 μM; Table 2 and Figure 4). These findings suggest that compounds 1 and 2 merit further investigation as potential anti-inflammatory compounds.

Molecules 18 02563 g004 200
Figure 4. Concentration-dependent effects of compound 2 on O2•− production and elastase release in human neutrophils. Human neutrophils were preincubated with DMSO (control) or compound 2 for 5 min before activation by FMLP/CB. (A) O2•− production and (B) Elastase release was induced by FMLP/CB. All data are expressed as the mean ± S.E.M. (n = 3). * p < 0.025; ** p < 0.01; *** p < 0.001 compared to the control.

Click here to enlarge figure

Figure 4. Concentration-dependent effects of compound 2 on O2•− production and elastase release in human neutrophils. Human neutrophils were preincubated with DMSO (control) or compound 2 for 5 min before activation by FMLP/CB. (A) O2•− production and (B) Elastase release was induced by FMLP/CB. All data are expressed as the mean ± S.E.M. (n = 3). * p < 0.025; ** p < 0.01; *** p < 0.001 compared to the control.
Molecules 18 02563 g004 1024

3. Experimental

3.1. General

Melting points were determined using a Yanaco MP-I3 micro melting point apparatus and the thermometer was used without correction. Mass spectra were recorded using a Finnigan MAT GCQ spectrometer (EIMS). 1H, 13C, and 2D-NMR spectra were measured with a Varian VNMRS 600 MHz spectrometer.

3.2. Plant Material

The roots of P. betle Linn. were collected from Taitung County, Taiwan, in April 2011, and was identified by a taxonomist, Mr. Jun-Chih Ou. A voucher specimen (No.20110401) was deposited in the Department of Plant Industry, National Pingtung University of Science and Technology.

3.3. Extraction and Isolation

The air-dried roots of P. betle (13.6 kg) were extracted with ethanol (50 L × 2) at 50 °C for 24 h. After evaporation of the solvent in vacuo, the residue was partitioned between water and EtOAc to give water-soluble and EtOAc-soluble portions. The chromatography of the EtOAc soluble portion was performed using a silica gel column (70–230 mesh, 10 × 40 cm) and elution with gradient solvent of n-hexane−EtOAc (20:1 to 0:1) and then EtOAc−MeOH (20:1 to 1:1) to yield 16 fractions (Fr. 1 to Fr. 16). Material Fr. 7, n-hexane−EtOAc = 5:1 eluate, was separated over a silica gel column and eluted with n-hexane−EtOAc (10:1 to 1:1) and Sephadex LH-20 column with MeOH to yield hydroxychavicol (2, 200.3 mg). Material Fr.10, n-hexane−EtOAc = 2:1 eluate, was separated using Sephadex LH-20 column with MeOH to yield five subfractions (Fr. 10-1 to Fr. 10-5), of which Fr. 10-3 was repeatedly chromatographed on Sephadex LH-20 column with MeOH, silica gel column eluted with n-hexane−EtOAc (3:1–0:1) and preparative TLC (n-hexane−EtOAc = 5:4) to yield aristololactam B II (4, 2.4 mg), 2-(γ'-hydroxychavicol)-hydroxychavicol (1) and aristololactam A II (3, 2.1 mg). Fr. 11, n-hexane−EtOAc = 1:1 eluate, was re-separated on a silica gel column eluting with n-hexane−EtOAc (10:1–0:1) to yield piperolactam A (5, 3.5 mg) and cepharadione A (6, 4.5 mg).

2-(γ'-Hydroxychavicol)-hydroxychavicol (1). Brown solid, melting point 73–75 °C. 1H-NMR, 13C-NMR and HMBC: see Table 1. EIMS m/z (rel. int.) 298 [M]+ (6), 284 (59), 256 (23), 241 (19), 213 (39), 199 (32), 185 (100), 171 (66), 163 (28), 157 (47). HREIMS: 298.1216 (Calcd 298.1205 for C18H18O4).

Hydroxychavicol (2). Brown solid, melting point of 35–36 °C. 1H-NMR (600 MHz, acetone-d6): δ 3.21 (2H, d, J = 6.6 Hz, H-α), 5.04–4.95 (2H, m, H-γ), 5.93–5.87 (1H, m, H-β), 6.50 (1H, dd, J = 8.4, 1.8 Hz, H-6), 6.67 (1H, d, J = 1.8 Hz, H-2), 6.73 (1H, d, J = 8.4 Hz, H-5), 13C-NMR (150 MHz, acetone-d6) δ 40.1 (C-α), 115.2 (C-γ), 115.9 (C-5), 116.4 (C-2), 120.5 (C-6), 132.4 (C-1), 139.1 (C-β), 144.1 (C-4), 145.7 (C-3). EIMS m/z (rel. int.) 150 [M]+ (72), 131 (63), 123 (61), 103 (82), 77 (72), 51 (100).

Aristololactam A II (3). Yellow powder, melting point 270–271 °C. 1H-NMR (600 MHz, acetone-d6) δ 3.91 (3H, s, 4-OMe), 6.97 (1H, s, H-9), 7.44 (2H, m, H-6 and H-7), 7.51 (1H, s, H-2), 7.82 (1H, m, H-8), 9.00 (1H, m, H-5), 10.67 (1H, br s, NH). EIMS m/z (rel. int.) 265 [M]+ (68), 250 (63), 222 (60), 166 (100).

Aristololactam B II (4). Yellow powder, melting point 260–262 °C. 1H-NMR (600 MHz, DMSO-d6) δ 4.03 (3H, s, 4-OMe), 4.12 (3H, s, 3-OMe), 7.13 (1H, s, H-9), 7.56 (2H, m, H-6 and H-7), 7.85 (1H, s, H-2), 7.94 (1H, m, H-8), 9.11 (1H, m, H-5), 10.83 (1H, br s, NH). 13C-NMR (150 MHz, DMSO-d6) δ 56.9 (3-OMe), 59.9 (4-OMe), 104.7 (C-9), 109.9 (C-2), 120.0 (C-4a), 121.6 (C-1), 123.4 (C-10a), 125.5 (C-6), 126.0 (C-4b), 126.9 (C-5), 127.5 (C-7), 129.1 (C-8), 134.9 (C-8a), 135.2 (C-10), 150.5 (C-4), 154.3 (C-3), 168.5 (C=O). EIMS m/z (rel. int.) 279 [M]+ (100), 264 (24), 236 (34), 221 (23), 209 (21), 193 (35), 181 (35), 165 (49), 164 (56).

Piperolactam A (5). Yellow powder, melting point >300 °C. 1H-NMR (600 MHz, CD3OD) δ 4.09 (3H, s, 3-OMe), 6.58 (3H, s, 3-OMe), 7.15 (1H, s, H-9), 7.53 (2H, m, H-6 and H-7), 7.77 (1H, s, H-2), 7.85 (1H, m, H-8), 9.32 (1H, m,H-5). 13C-NMR (150 MHz, CD3OD) δ 57.7 (3-OMe), 107.2 (C-9), 108.9 (C-2), 116.0 (C-4a), 116.9 (C-1), 126.2 (C-10a), 126.4 (C-6), 127.7 (C-7), 128.8 (C-4b), 129.2 (C-5), 129.8 (C-8), 135.7 (C-8a), 135.9 (C-10), 149.7.5 (C-3), 151.6 (C-4), 172.3 (C=O). EIMS m/z (rel. int.) 265 [M]+ (81), 250 (52), 222 (46), 166 (100), 139 (68).

Cepharadione A (6). Orange powder, melting point >300 °C. 1H-NMR (600 MHz, DMSO) δ 3.74 (3H, s, NMe), 6.58 (2H, s, OCH2O), 7.72 (2H, m, H-6 and H-7), 7.92 (1H, s, H-9), 7.99 (1H, s, H-2), 8.11 (1H, m, H-8), 8.84 (1H, m,H-5). 13C-NMR (150 MHz, DMSO) δ 30.2 (NMe), 103.6 (OCH2O), 107.7 (C-2), 113.9 (C-4a), 114.3 (C-9), 120.4 (C-10a), 122.6 (C-1), 124.5 (C-4b), 125.9 (C-5), 127.3 (C-6), 128.2 (C-7), 128.8 (C-8), 131.6 (C-8a), 132.2 (C-10), 147.6 (C-3), 151.1 (C-4), 155.8 (11-C=O), 174.2 (12-C=O). ESIMS m/z (rel. int.) 328 [M+Na]+ (100), 320 (54), 306 [M+H]+ (44), 301 (15), 277 (13).

3.4. Anti-Inflammatory Activity

Compounds 16 were evaluated for their anti-inflammatory activity based on their inhibition of against superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. The measurements were assayed using the method described previously [19,20,21].

4. Conclusions

In summary, compound 1 is a new hydroxychavicol dimer and compounds 2 and 46 were isolated from the roots of P. betle for the first time. Hydroxychavicol monomer 2 was found to significantly inhibit superoxide anion and elastase released by human neutrophils, in response to fMLP/CB. The new compound 1 also proved to be moderately active in both anti-inflammatory assays.

Supplementary Materials

Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/3/2563/s1.

Acknowledgments

This work was supported by grants from the Chang Gung Memorial Hospital (CMRPF3A0011-12) and Chang Gung University (EMRPD1A0881) in Taiwan. The authors are grateful to Jun-Chih Ou for his identification of the studied plant.

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  • Sample Availability: Samples of the compounds 26 are available from the authors.
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