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Marine Drugs 2011, 9(9), 1477-1486; doi:10.3390/md9091477

Frajunolides L–O, Four New 8-Hydroxybriarane Diterpenoids from the Gorgonian Junceella fragilis
Chia-Ching Liaw 1,2, Yao-Haur Kuo 3, Yun-Sheng Lin 2, Tsong-Long Hwang 4 and Ya-Ching Shen 1,*
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; E-Mail:
Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; E-Mail:
National Research Institute of Chinese Medicine, Taipei 112, Taiwan; E-Mail:
Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan; E-Mail:
Author to whom correspondence should be addressed; E-Mail:; Tel.: +886-2-23123456 (ext. 62226); Fax: +886-2-2391-9098.
Received: 8 July 2011; in revised form: 23 August 2011 / Accepted: 25 August 2011 /
Published: 2 September 2011


: Four new 8-hydroxybriarane diterpenoids, frajunolides L–O (14), were isolated from the Taiwanese gorgonian Junceella fragilis. The structures of compounds 14 were elucidated based on spectroscopic analysis, especially 2D NMR (1H-1H COSY, HSQC, HMBC and NOESY) and HRMS. Compounds 1 and 4 showed weak anti-inflammatory activity as tested by superoxide anion generation and elastase release by human neutrophil in response to fMLP/CB. Compound 3 showed selective inhibition on elastase release in vitro.
Junceella fragilis; 8-hydroxybriarane; frajunolides; anti-inflammatory activities

1. Introduction

A number of secondary metabolites with potential pharmacological activities such as cytotoxic, antiviral, anti-inflammatory, and insecticidal effects were discovered from marine organisms [1]. Marine diterpenoids of the class briarane have been investigated with great interest owing to their novel structures and interesting bioactivities [25]. The gorgonian of the genus Junceella grown in the tropical and subtropical waters of Indo-West Pacific regions are well known as a source of highly oxidized briarane-type diterpenoids with a γ-lactone moiety [69]. In continuation of our study on the chemistry and biological activities of briarane diterpenoids [1016], we investigated the Taiwanese gorgonian J. fragilis. A chemical investigation of the acetone extract has yielded four new 8-hydroxybriarane diterpenoids, designated as frajunolides L–O (14). In this paper, we report the isolation, structural elucidation, and anti-inflammatory activity as tested by superoxide anion generation and elastase release by human neutrophil in response to fMLP/CB, of these compounds.

2. Results and Discussion

Compound 1 was deduced to have the molecular formula C28H38O11 with ten degrees of unsaturation from high-resolution ESI mass spectrometry. The IR absorptions were observed at 3439, 1768 and 1735 cm−1 suggesting the presence of hydroxyl, γ-lactone and ester groups, respectively. The 1H-, 13C-NMR and DEPT spectroscopic data (Table 1) revealed that compound 1 possessed four acetyl groups (δH 1.94, 1.98, 2.13, and 2.21), two tertiary methyl protons (δH 1.15, Me-15; δH 2.03, Me-16), a doublet methyl (δH 1.15, d, J = 6.9 Hz, Me-19), five oxygenated methine protons (δH 4.94, t, J = 3.3 Hz, H-2; δH 5.28, d, J = 9.6 Hz, H-7; δH 5.62, d, J = 5.1 Hz, H-9; δH 5.32, m, H-12; 4.77, br s, H-14), a trisubstituted olefinic group (δH 5.58, d, J = 9.6 Hz, H-6; δC 120.0, C-6; δC 145.2, C-5), an oxygenated quaternary carbon (δC 82.6, C-8), an exocyclic double bond (δH 5.34, 5.30, H2-20; δC 118.3, C-20; 146.3, C-11), two methine carbons (δC 40.6, C-10; δC 43.2, C-17), three methylene carbons (δC 30.8, C-3; δC 29.0, C-4; δC 33.5, C-13), along with a γ-lactone carbonyl carbon (δC 175.9, C-18). The proton and carbon assignments of 1 were completely established by using 1D- and 2D NMR experiments, including 1H-1H COSY, HSQC, and HMBC (Figure 1). The 1H-1H COSY spectrum exhibited four sets of correlations (H-2/H-3/H-4, H-6/H-7, H-9/H-10, and H-12/H-13/H-14). The HMBC correlations of Me-15 (δH 1.15, s)/C-1 (δC 47.0), C-2 (δC 74.2), C-10 (δC 40.6), C-14 (δC 73.6); Me-16 (δH 2.03, s)/C-4 (δC 29.0), C-5 (δC 145.2), C-6 (δC 120.0); Me-19 (δH 1.15, d, J = 6.9 Hz)/C-8 (δC 82.6), C-18 (δC 175.9); H-9 (δH 5.62, d, J = 5.1 Hz)/C-8, C-7 (δC 78.0); H-10 (δH 3.57, d, J = 5.1 Hz)/C-1, C-2, C-11 (δC 146.3), C-12 (δC 71.5); H2-20 (δH 5.34, s; 5.30, s)/C-11, C-12; H-13 (δH 1.95, m; 2.20, m)/C-14, C-1 established the connectivities from C-1 to C-20 unambiguously, and revealed that compound 1 belongs to 8-hydroxybriarane diterpenoids with a γ-lactone ring [11]. The four acetate groups of 1 were assigned at C-2, C-9, C-12, and C-14 positions by the HMBC correlations between the acetate carbonyl carbons (δC 170.4 × 2, 170.3, and 168.9) and four oxygenated methine protons (δH 4.94, H-2; δH 5.62, H-9; δH 5.32, H-12; 4.77, H-14). Thus the planar structure of 1 was completely established.

Our results showed that the planar structure of compound 1 is the same as frajunolide A, but differing in the 1H- and 13C NMR data of the methylenecyclohexane ring, especially at C-12 and C-20 positions [10]. The 13C NMR chemical shift of C-12 (δC 71.5) was shifted downfield in comparison with frajunolide A (δC 67.3), suggesting that the relative stereochemistry of H-12 was α-orientation [11]. The relative configuration of 1 was determined by NOESY correlations (Figure 1) and MM2 minimized energy calculated molecular modeling, and comparison with other naturally occurring briarane diterpenoids [25]. Briarane-type diterpenoids were reported to have the Me-15 in the β-orientation and H-10 in the α-orientation. In the NOESY of 1, H-10 showed correlations with H-2, H-9, H-12, suggesting that these protons are located on the α-face. In addition, the correlation between H-9 and Me-19 indicated that Me-19 is α-oriented too. However, correlation of H-17/H-7 suggested that H-7 and H-17 are on the β-face. Moreover, NOESY correlation of H-14/Me-15 suggested that 14-acetoxy group is located on the α-face. The Z-configuration at C-5 was elucidated by the observation of NOESY correlation between H-6 and Me-16. On the basis of the above interpretation, the structure of compound 1 was elucidated. The name frajunolide L was given.

Compound 2 had the molecular formula C28H38O11, the same as that of 1, as determined by HRESIMS, suggesting that the structure of 2 was similar to 1. The IR spectrum of 2 also displayed strong absorptions at 3429, 1776 and 1735 cm−1 indicating that compound 2 contained hydroxyl and carbonyl groups of five-membered γ-lactone ring and ester groups. Both 1H- and 13C NMR spectroscopic data (Table 1) of 2 were found to be similar to those of 1. These signals include four acetyl group (δH 1.92, 2.01, 2.07, and 2.16), two tertiary methyl protons (δH 0.99, Me-15; δH 1.99, Me-16), a methyl doublet (δH 1.17, d, J = 6.8 Hz, Me-19), and a methine quartet (δH 1.15, q, J = 7.2 Hz). However, 1D- and 2D-spectroscopic data of 2 revealed that the exocyclic double bond (C-11/C-20) in 1 shifted to C-12 (δC 127.6)/C-11 (δC 134.2) and an acetate group was found to locate at C-20 (δC 68.7). The gross structure of 2 was further deduced from the 1H-1H COSY, HMQC, HMBC correlations (Figure 2). The relative configuration of 2 was determined by NOESY correlations (Figure 2) and application of MM2 molecular modeling together with comparing the NMR spectra of 2 with those of 1. The NOESY correlations of H-10/H-2, H-9, and H-9/Me-19 suggested that the configurations of H-2, H-9, H-10, and Me-19 were in α-orientation while correlations of H-7/H-6, H-17, and H-14/Me-15 agreed with β-disposition of H-7, H-14, Me-15 and H-17.

The HRESI mass spectrum of 3 gave a quasi-molecular ion peak at m/z 589.2266 [M + Na]+, indicative of a molecular formula C28H38ClO12 (calc. for m/z 589.2261), consistent with 10 degrees of unsaturation. The presence of a chloride was evident from the fragment [M + Na]+ at m/z 589 and the isotope fragment [M + Na + 2]+ at m/z 591 in ESIMS, with the typical ratio of relative intensity (3:1) in the mass spectrum. In the infrared spectrum, strong absorption bands were found at 3436, 1735 and 1780 cm−1 characteristic for hydroxyl, ester carbonyl (acetyl) and five-membered γ-lactone ring, suggesting a briarane-type diterpenoid similar to compounds 1 and 2. It was found that the 1H- and 13C NMR spectra of 3 in CDCl3 showed mostly broad peaks and in some cases, certain peaks were not observed. In order to mark more optimum signals of the NMR spectra, compound 3 was dissolved in pyridine-d5. The 1H- and 13C NMR data (Table 1) of 3 revealed the presence of four acetate groups (δH 1.99, 2.11, and 2.30 × 2; δC 172.5, 171.1 × 2, 170.3, 22.2, 21.9, 21.8, and 21.5), an exocyclic double bond (δH 5.83, 5.42, H2-16; δC 144.0, C-5; 125.5, C-16) and a γ-lactone carbonyl carbon (δC 176.4, C-19). Judging from the molecular formula and NMR data of 3, six degrees of unsaturation were counted for, indicating that compound 3 contained a tetracyclic system including an exocyclic epoxide (δH 2.84, d, J = 4.0 Hz; 2.59, br s, H2-20; δC 58.2, C-11; 52.6, C-20). The HMBC correlations (Figure 3) between H-2 (δH 6.68, d, J = 8.5 Hz), H-4 (δH 5.90, d, J = 10.5 Hz), H-9 (δH 6.30, s), and H-14 (δH 5.25, s) with one of ester carbonyl carbons, respectively, revealed that four acetyl groups were connected to the C-2, C-4, C-9, and C-14 positions. By interpretation of the NMR spectroscopic data, the planar structure of compound 3 was elucidated. The relative configuration of 3 was determined by NOESY (Figure 3) and detailed comparison with known compounds [10]. The chemical shift of C-11 (δC 58.2) and C-20 (δC 52.6), and the NOESY correlations between H2-20 and Me-15 agreed with β-face of H2-20, 11R-configuration regarding the exocyclic epoxide, and chair conformation of the cyclohexane ring. Furthermore, NOESY correlations of H-10/H-2, H-4/H-2 and H-10/H-9 suggested that H-2, H-4 and H-9 were located on the same face and could be assigned as α.

Compound 4 showed a pair of quasi-molecular ion peaks at m/z 607 and 609 [M + H]+ with a ratio of 3:1 in the ESIMS, indicating the presence of a chlorine atom. Moreover, a molecular formula C28H37ClO11 was established by HRESIMS and confirmed by 1H- and 13C NMR spectroscopic analysis (Table 1). The IR absorption bands at 3467, 1780 and 1739 cm−1 indicated that 4 contained hydroxyl, γ-lactone, and ester carbonyl functionalities similar to 13. Detailed inspection of 1H- and 13C NMR spectroscopic data revealed the presence of the key structural feature of a 8-hydroxybriarane diterpenoid with two exocyclic double bonds. The locations of the two exocyclic double bonds were confirmed by the HMBC experiment (Figure 4), which showed correlations of H2-16 (δH 4.92, s; 5.49, s)/C-4 (δC 33.4), C-5 (δC 144.9), and C-6 (δC 56.2), and H2-20 (δH 4.92, s; 5.19, s)/C-10 (δC 44.6), C-11 (δC 147.0), and C-12 (δC 38.6), respectively. In addition, the oxygenated methine proton H-2 (δH 6.62, d, J = 8.0 Hz), H-9 (δH 6.28,), H-13 (δH 5.72, ddd, J = 12.0, 5.2, 3.2 Hz), and H-14 (δH 5.66, s) showed HMBC correlations with the acetate carbonyl carbons (δC 171.8, 170.9, 170.8, 170.3). Furthermore, detailed analysis of 2D NMR spectroscopic data (1H-1H COSY and HMBC) established the planar structure of 4. The configuration of compound 4 was determined on the basis of NOESY correlations (Figure 4). The NOESY correlations of Me-15 (δH 1.27, s)/H-14 and H-13/H-14 implied that H-13 and H-14 are on the β-face while correlations of H-2/H-10, H-10/H-9, H-9/Me-19, H-17/H-7 and H-6/H-7 confirmed that the configuration of these protons are identical to those of compound 3.

General pharmacological study of the anti-inflammatory activities of compounds 14 were evaluated by measuring superoxide anion generation and elastase release by human neutrophils in response to fMet-Leu-Phe (fMLP)/Cytochalasin B (CB) [17]. The results are illustrated in Table 2. Compounds 1 and 4 showed mild inhibitory effects on both superoxide anion generation and elastase release at 10 μg/mL. It is notable that compound 3 exhibited selective but modest inhibition of elastase release in vitro.

3. Experimental Section

3.1. General Experimental Procedures

Optical rotations were recorded on a JASCO DIP-1000 polarimeter. IR spectra were measured on a Hitachi T-2001 spectrophotometer. The 1H-13C NMR, COSY, HMQC, HMBC, and NOESY spectra were recorded on a Bruker AV-400 or a AV-500 spectrometer, using TMS as internal standard. The chemical shifts are given in δ (ppm) and coupling constants (J) in Hz. HRESIMS were run on a JEOL JMS-HX 110 mass spectrometer. Silica gel 60 (Merck) was utilized for column chromatography, and precoated silica gel plates (Merck, Kieselgel 60 F-254, 1 mm) were used in preparative TLC. Sephadex LH-20 (Amersham Pharmacia Biotech AB, Sweden) was used for separation and purification of compounds. LiChrospher Si 60 (5 μm, 250-10, Merck) and LiChrospher 100 RP-18e (5 μm, 250-10, Merck) were used in NP-HPLC and RP-HPLC (Hitachi), respectively.

3.2. Animal Material

The gorgonian Junceella fragilis Ridley (Ellisellidae) was collected in Tai-Tong County, Taiwan, by scuba diving at a depth of 15 meters, in February 2006. The fresh gorgonian was immediately frozen after collection and kept at −20 °C until processing. A voucher specimen (WSG-5) was deposited in the School of Pharmacy, College of Medicine, National Taiwan University, Taipei.

3.3. Extraction and Isolation

The gorgonian J. fragilis (wet, 2.5 kg) was minced and extracted with acetone (3 × 5 L) at room temperature and the acetone extract was concentrated under vacuum. The crude extract (20 g) was partitioned between EtOAc and H2O (1:1). The EtOAc-soluble portion (15 g) was subjected to column chromatography using silica gel and eluted with a gradient of n-hexane/EtOAc (10:1 to 0:1) to obtain thirteen fractions (Fr.1~13). Fraction 6 (202 mg) was subjected to RP-HPLC using MeOH/H2O (60:40) to give 1 (3.9 mg) and 2 (1.8 mg). Fraction 9 (874 mg) was separated on silica gel column and eluted with gradient n-hexane/EtOAc to give seven fractions (Fr. 9-1~6). Fr. 9-4 (157 mg) was purified by RP-HPLC, using solvent mixture of MeOH and H2O (65:35) to yield 4 (8.2 mg). Fr. 9-6 (211 mg) was separated on RP-HPLC using MeOH/H2O (60:40) to furnish 3 (4.5 mg).

Frajunolide L (1): colorless amorphous gum; [α]24 D +6.0 (c 0.2, CH2Cl2); IR νmax 3439, 2922, 2749, 1768, 1735, 1370, 1248, 1221, 1040 cm−1; 1H NMR data (400 MHz, CDCl3), see Table 1; 13C NMR data (100 MHz, CDCl3), see Table 2; ESIMS m/z 573 [M + Na]+; HRESIMS m/z 573.2313 [M + Na]+ (calcd for C28H38O11Na, 573.2312).

Frajunolide M (2): colorless amorphous powder; [α]24 D +8.0 (c 0.2, CH2Cl2); IR νmax 3447, 2923, 2853, 1773, 1735, 1645, 1375, 1240, 1223, 1041 cm−1; 1H NMR data (400 MHz, CDCl3), see Table 1; 13C NMR data (100 MHz, CDCl3), see Table 2; ESIMS m/z 573 [M + Na]+; HRESIMS m/z 573.2315 [M + Na]+ (calcd for C28H38O11Na, 573.2312).

Frajunolide N (3): colorless amorphous powder; [α]24 D +18.0 (c 0.1, CH2Cl2); IR νmax 3436, 2933, 1780, 1735, 1376, 1255, 1235, 1212, 1044, 1017 cm−1; 1H NMR data (400 MHz, pyridine-d5), see Table 1; 13C NMR data (100 MHz, pyridine-d5), see Table 2; ESIMS m/z 589 [M + Na]+, 591 [M + Na + 2]+; HRESIMS m/z 589.2266 [M + Na]+ (calcd for C28H38ClO12Na, 589.2261).

Frajunolide O (4): colorless amorphous gum; [α]24 D +6.7 (c 0.7, CH2Cl2); IR νmax 3467, 2927, 1780, 1739, 1368, 1250, 1223, 1041 cm−1; 1H NMR data (400 MHz, pyridine-d5), see Table 1; 13C NMR data (100 MHz, pyridine-d5), see Table 2; ESIMS m/z 607 [M]+; HRESIMS m/z 607.1925 [M + Na]+ (calcd for C28H37ClO11Na, 607.1922), 609.1892 [M + Na + 2]+.

3.4. Human Neutrophils Superoxide Generation and Elastase Release

Human neutrophils were obtained by means of dextran sedimentation and Ficoll centrifugation. The assay of O2 •− generation was based on the SOD-inhibitable reduction of ferricytochrome c. Degranulation of azurophilic granules was determined by elastase release as described previously [16]. The elastase release experiments were performed using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as the elastase substrate. The fMet-Leu-Phe (fMLP), activated by Cytochalasin B (CB), was used as a stimulant. Genistein was used as a standard compound.

4. Conclusion

Chemical investigation of the Taiwanese gorgonian Junceella fragilis has resulted in the isolation of four new briarane diterpenoids, frajunolides L–O (14). Among them, compounds 1, 3 and 4 exhibited mild or selective anti-inflammatory activity.

Supplementary Data

Supplementary data associated with this article can be found in the online version.

Supporting Information



The authors thank the National Science Council, Taiwan, for financial support (NSC 98-2113-M- 002-002-MY2).

  • Samples Availability: Not available.


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Marinedrugs 09 01477f1 1024
Figure 1. 1H-1H COSY and HMBC correlations of 1; NOESY correlations and computer-generated perspective model of 1 using MM2 force field calculation.

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Figure 1. 1H-1H COSY and HMBC correlations of 1; NOESY correlations and computer-generated perspective model of 1 using MM2 force field calculation.
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Figure 2. 1H-1H COSY and HMBC correlations of 2; NOESY correlations and computer-generated perspective model of 2 using MM2 force field calculation.

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Figure 2. 1H-1H COSY and HMBC correlations of 2; NOESY correlations and computer-generated perspective model of 2 using MM2 force field calculation.
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Figure 3. 1H-1H COSY, HMBC, and NOESY correlations of 3.

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Figure 3. 1H-1H COSY, HMBC, and NOESY correlations of 3.
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Figure 4. 1H-1H COSY, HMBC, and NOESY correlations of 4.

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Figure 4. 1H-1H COSY, HMBC, and NOESY correlations of 4.
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Chart 1. Structures of Frajunolides L–O (14).

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Chart 1. Structures of Frajunolides L–O (14).
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Table Table 1. NMR spectroscopic data for compounds 14.

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Table 1. NMR spectroscopic data for compounds 14.
1 b2 b3 c4 c

PositionδH (J in Hz) aδH, mult. dδH (J in Hz)δH, mult.δH (J in Hz)δH, mult.δH (J in Hz)δH, mult.
147.0, C45.7, C48.9, C48.3, C
24.94, t (3.3)74.2, CH5.01, m75.0, CH6.68, d (8.5)73.2, CH6.62, d (8.0)74.8, CH
32.16, m30.8, CH22.54, m33.3, CH23.58, dd (16.0, 10.5)37.3, CH22.88, m29.3, CH2
1.72, m1.61, m2.03, dd (16.0, 8.5)1.70, m
42.58, m29.0, CH21.95, m29.7, CH25.90, d (10.5)77.6, CH2.52, m33.4, CH2
2.08, m
5145.2, C146.1, C144.0, C144.9, C
65.58, d (9.6)120.0, CH5.41, d (9.2)117.7, CH5.42, d (3.5)54.2, CH5.21, d (3.2)56.2, CH
75.28, d (9.6)78.0, CH5.32, d (9.2)79.1, CH4.94, d (3.5)85.3, CH4.92, m84.9, CH
882.6, C82.5, C82.7, C82.1, C
95.62, d (5.1)72.6, CH5.74, s71.4, CH6.30, s72.6, CH6.28, s79.3, CH
103.57, d (5.1)40.6, CH3.07, s39.9, CH3.62, s42.4, CH3.82, s44.6, CH
11146.3, C134.2, C58.2, C147.0, C
125.32, m71.5, CH5.85 br, s127.6, CH2.27, m31.6, CH22.63, t (12.4)38.6, CH2
1.28, m2.49, m
132.20, m33.5, CH22.28, m28.1, CH21.94, m25.5, CH25.27, ddd (3.2, 5.2, 12.0)70.1, CH
1.95, m2.11, m
144.77 br, s73.6, CH4.75 br, s73.7, CH5.25, s75.2, CH5.66, s73.8, CH
151.15, s15.4, CH30.99, s16.2, CH31.31, s15.2, CH31.27, s14.4, CH3
162.03, s27.0, CH31.99, s29.0, CH35.83, s125.5, CH24.92, s118.3, CH2
5.42, s5.49, s
172.54, q (6.9)43.2, CH2.45, q (7.2)44.7, CH3.44, q (7.0)51.8, CH3.41, q (7.6)51.4, CH
18175.9, C174.7, C176.4, C175.8, C
191.15, d (6.9)6.7, CH31.17, d (6.8)8.7, CH31.41, d (7.0)7.3, CH31.26, d (7.6)6.7, CH3
205.34, s118.3, CH24.67, d (12.0)68.7, CH22.84, d (4.0)52.6, CH24.92, s113.1, C
5.30, s5.02, d (12.0)2.59 br, s5.19, s
OAc2.21, s170.4, C2.16, s169.9, C2.30, s172.5, C2.28, s171.8, C
2.13, s170.4, C2.07, s169.7, C2.30, s171.1, C2.09, s170.9, C
1.98, s170.3, C2.01, s169.3, C2.11, s171.1, C2.07, s170.8, C
1.94, s168.9, C1.92, s168.4, C1.99, s170.3, C1.99, s170.3, C
21.7, CH323.1, CH322.2, CH321.9, CH3
21.2, CH322.9, CH321.9, CH321.1, CH3
21.2, CH322.8, CH321.8, CH321.0, CH3
21.1, CH322.7, CH321.5, CH320.9, CH3
8-OH8.05 br, s

aData were recorded at 400 and/or 500 MHz in CDCl3;bIn CDCl3;cIn pyridine-d5;dData recorded at 100 and/or 125 MHz and were assigned by DEPT, COSY, HSQC, and HMBC experiments.

Table Table 2. Effects of compounds on superoxide anion generation and elastase release by human neutrophils in response to fMet-Leu-Phe (fMLP)/Cytochalasin B (CB).

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Table 2. Effects of compounds on superoxide anion generation and elastase release by human neutrophils in response to fMet-Leu-Phe (fMLP)/Cytochalasin B (CB).
CompoundsSuperoxide anion Inh % aElastase release Inh % a
118.7 ± 2.6 **16.2 ± 0.7 ***
22.0 ± 2.313.3 ± 3.1 *
30.6 ± 1.522.3 ± 7.7
48.3 ± 3.617.2 ± 6.7 *
Genistein65.0 ± 5.751.6 ± 5.9

aPercentage of inhibition Inh % at 10 μg/mL concentration. Results are presented as mean ± S.E.M. (n = 3).*P < 0.05,**P < 0.01,***P < 0.001 compared with the control value.

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