New seco-dibenzocyclooctadiene lignans with nitric oxide production inhibitory activity from the roots of Kadsura longipedunculata

Xinzhu Qi Jiabao Liu Jiabao Chen Qi Hou Shuai Li

Citation:  Qi Xinzhu, Liu Jiabao, Chen Jiabao, Hou Qi, Li Shuai. New seco-dibenzocyclooctadiene lignans with nitric oxide production inhibitory activity from the roots of Kadsura longipedunculata[J]. Chinese Chemical Letters, 2020, 31(2): 423-426. doi: 10.1016/j.cclet.2019.06.006 shu

New seco-dibenzocyclooctadiene lignans with nitric oxide production inhibitory activity from the roots of Kadsura longipedunculata

English

  • Kadsura longipedunculata Finet et Gagnep is widely distributed in the middle and southwest region of China. Its roots and stems have been used in Chinese folk medicine, and have the effect of promoting blood circulation and dispersing swelling, dispelling wind and activating collaterals, regulating qi-flowing for relieving pain, and have been used for the treatment of rheumatoid arthritis, traumatic injury, canker, gastroenteritis, etc. [1]. Phytochemical studies showed that the main principal bioactive constituents of Kadsura were lignans and triterpenoids. Schisandraceae lignans mainly contain dibenzocyclooctadiene lignans, tetrahydrofurans, cyclolignans, and simple lignans [2]. As the characteristic component of genus Kadsura and Schizandra, dibenzocyclooctadiene lignans have the effect of anti-inflammatory [3-6], antineoplastic [7-9], and anti-HIV activities [10-13], and its anti-inflammatory activity has been a hot research field for natural product researchers during recent years [3-6]. As the study to seek components with anti-inflammatory activity from K. longipedunculata, four new seco-dibenzocyclooctadiene lignans, named kadlongilignans A–D (1–4) (Fig. 1), were isolated from the active fraction (Experimental section in Supporting information). Their inhibitory activity of NO (nitric oxide) production of LPS (lipopolysaccharide)-induced murine macrophages were evaluated. The isolation, structural identification, and bioactivity evaluation of these compounds were reported in the text.

    Figure 1

    Figure 1.  Structures of compounds 1–4.

    Compound 1 had the molecular formula of C29H30O10, as deduced by HRESIMS (Fig. S4 in Supporting information), which showed a quasi-molecular ion peak at m/z 561.1736 [M + Na]+ (calcd. for C29H30O10Na: 561.1731) and 13C NMR data. The UV spectrum (Fig. S1 in Supporting information) with λmax values at 210 and 279 nm, along with its IR spectrum (Fig. S3 in Supporting information) with absorption bands at 1613, 1582, and 1503 cm-1 (aromatic moiety), indicated the presence of a biphenyl moiety. The IR (υmax 3419 and 1716 cm-1) bands revealed hydroxyl and carbonyl groups of 1. The 1H NMR spectrum (Fig. S5 in Supporting information) of 1 displayed two aromatic singlets for a octasubstituted biphenyl moiety at δH 6.93 (H-4) and 6.70 (H-11), five aromatic proton signals for a mono-substituted benzene system at δH 8.04 (dd, 2H, J = 8.0, 1.5 Hz, H-30 and H-70), 7.57 (tt, 1H, J = 8.0, 1.5 Hz, H-50), and 7.44 (t, 2H, J = 8.0 Hz, H-40 and H-60), three singlets for methoxy groups at δH 3.98 (3 H), 3.94 (3 H), 3.82 (3 H), a signal of methylenedioxy at δH 5.99 and 5.96, an oxymethine at δH 5.69 (d, 1H, J = 6.0 Hz, H-9), an oxymethylene at δH 4.24 (br d, 2H, J = 6.0 Hz, H-6), a methine at δH 3.15 (m, 1H, H-8), an acetyl methyl at δH 2.02 (s, 3H, H-17) and a methyl at δH 0.96 (d, 3H, J = 7.0 Hz, H-18) (Table 1). The 13C NMR data of 1 indicated 29 carbon signals (Table 1), including a ketone carbonyl (δC 209.8), an ester carbonyl (δC 165.9), 18 aromatic carbons [δC 152.1, 149.4, 147.0, 141.6, 137.2, 136.8, 134.4, 133.5, 132.0, 129.9 (2), 129.5, 128.6 (2), 120.8, 112.7, 104.2, 101.0], a methylenedioxy carbon (δC 101.5), an oxygenated methine carbon (δC 75.4), an oxygenated methylene carbon (δC 62.4), three methoxy carbons (δC 61.1, 59.9, 55.7), a methine carbon (δC 51.1), and two methyl carbons (δC 30.6, 14.0). The HMBC correlations of the aromatic protons at δH 6.93 (H-4) with δC 134.4 (C-2), 152.1 (C-3), 137.2 (C-5), 112.7 (C-16), 147.0 (C-1), 120.8 (C-15) and δH 6.70 (H-11) with δC 149.4 (C-12), 136.8 (C-13), 120.8 (C-15), 132.0 (C-10), 141.6 (C-14), 112.7 (C-16) further proved the biphenyl moiety. The HMBC correlations of the methylenedioxyl protons at δH 5.99, 5.96 (H-19) with the aromatic carbons of the biphenyl moiety at δC 149.4 (C-12) and 136.8 (C-13) suggested the methylenedioxyl group was connected on C-12 and C-13. The HMBC correlations of 2-OCH3 C-2, 3-OCH3 with C-3 and 14-OCH3 with C-14 suggested that the three methoxy groups were located at C-2, C-3 and C-14 of biphenyl moiety, respectively. The HMBC correlations of OH signal at δH 5.86 with δC 147.0 (C-1), 134.4 (C-2) and 112.7 (C-16) showed that the hydroxyl group was linked to C-1. The HMBC correlations of oxygenated methylene signal at δH 4.24 (H-6) with δC 104.2 (C-4), 137.2 (C-5), 112.7 (C-16) assigned the methylene group on C-5 of the biphenyl moiety. The HMBC correlations of the methyl at δH 2.02 (H-17) with the carbonyl of δC 209.8 (C-7) and 51.1 (C-8), and the methyl at δH 0.96 (H-18) with δC 209.8 (C-7), 51.1 (C-8) and 75.4 (C-9), and the methine at δH 3.15 (H-8) with δC 209.8 (C-7), 75.4 (C-9), 132.0 (C-10), 30.6 (C-17) and 14.0 (C-18), and δH 5.69 (H-9) with δC 209.8 (C-7), 51.1 (C-8), and 14.0 (C-18) suggested the presence of a C-7 keto-isoprene moiety. Furthermore, the HMBC correlations of H-9 with C-10, C-11 (δC 101.0), C-15 indicated that the C-7 keto-isoprene moiety was attached on C-10 of the biphenyl moiety. The HMBC correlations of mono-substituted benzene aromatic protons of H-30 and H-70 (δH 8.04) with the ester carbonyl of C-10 (δC 165.9) showed a benzoyloxy group, and the HMBC correlations of H-9 with C-10 suggested that the benzoyloxy moiety was attached on C-9 of the C-7 keto-isoprene moiety (Fig. 2). The interpretation above indicated that 1 is a 6, 7-seco-dibenzocyclooctadiene lignan.

    Table 1

    Table 1.  1H (500 MHz) and 13C (125 MHz) NMR data of 1 in CDCl3.
    DownLoad: CSV

    Figure 2

    Figure 2.  Key HMBC (H→C) correlations of 1.

    The ECD curve of 1 exhibited a negative Cotton effect near 240 nm (Fig. S2 in Supporting information), which consequently reflected a P-biphenyl absolute configuration [14-16]. After defining the biphenyl axial chirality, the absolute configurations of C-8 and C-9 of 1 were determined to be 8S and 9R by comparison of the experimental and calculated ECD curves (Fig. 3). Thus, the structure of 1, and its absolute configuration (P, 8S, 9R) were established as shown in Fig. 1, and it was named as kadlongilignan A.

    Figure 3

    Figure 3.  Experimental and calculated ECD spectra of 1.

    Compounds 2 and 3, belonging to a pair of isomers, were obtained by separation of chiral HPLC, and had the same molecular formula of C24H32O7 by HRESIMS and ESIMS ion at m/z 433.2219 [M + H]+ (calcd.: 433.2221) (Figs. S13 and S22 in Supporting information) and 13C NMR data. The IR spectrum (Figs. S12 and S21 in Supporting information) showed the presence of hydroxyl (3399 cm-1), carbonyl (1711 cm-1), arylalkenyl (1661 cm-1) and aromatic (1593, 1511 and 1458 cm-1) groups. The 1H NMR data (Table 2) showed the presence of two aromatic methine protons at δH 6.42 (d, 1H, J = 2.0 Hz) and 6.26 (d, 1H, J = 2.0 Hz) indicating the presence of one 1, 3, 4, 5-tetrasubstituted benzene system, two olefinic protons at δH 5.78 (br s, 1 H) and 5.10 (br s, 1H), three methoxy groups at δH 3.87 (s, 3 H), 3.85 (s, 3 H), 3.70 (s, 3H), two methylenes at δH 2.06 (dd, 1H, J = 13.0, 10.0 Hz, H-7a) and 2.47 (dd, 1H, δH = 13.0, 4.5 Hz, H-7b), 2.34 (dd, 1H, J = 14.0, 8.5 Hz, H-70a) and 2.58 (dd, 1H, J = 14.0, 6.5 Hz, H-70b), two methines at δH 1.81 (m, 2H, H-8 and H-80), two methyls at δH 0.91 (d, 3H, J = 7.0 Hz, H-9) and 0.87 (d, 3H, J = 6.5 Hz, H-90). The 13C NMR data of 2 (Table 2) displayed signals for one ketone carbonyl carbon at δC 199.3, ten aromatic or olefin carbons at δC 166.4, 161.9, 152.3, 149.0, 137.5, 133.6, 115.2, 108.5, 104.7 and 96.4, a quaternary carbon at δC 75.4, two methylenes at δC 40.7 and 39.8, two methines at δC 35.2 and 39.3, and two methyls at δC 16.8 and 15.9, which suggested that 2 was a deformed simple lignan with one cyclohexadienone ring. Additionally, a methylene at δH 2.85 (s, 2H), a methyl at δH 2.22 (s, 3H) of the 1H NMR data and a ketone carbon at δC 205.8, a methylene at δC 53.2, a methyl at δC 31.7 of the 13C NMR data indicated that an acetonyl group was in 2. The HMBC correlations of δH 2.85 (H-1") with δC 199.3 (C-3), 75.4 (C-4), 166.4 (C-5), 205.8 (C-2"), and 31.7 (C-3") indicated that the acetonyl group was connected at C-4 of the lignan. The HMBC correlations of three methoxyl signals at δH 3.70 (5-OCH3), 3.85 (3'-OCH3), 3.87 (4'-OCH3) with δC 166.4 (C-5), 152.3 (C-3') and 133.6 (C-4') showed that they were located at C-5, C-3' and C-4', respectively (Fig. 4). The mainly difference between compounds 2 and 3 was the absolute configuration of C-4. By comparison of the experimental and calculated ECD curves, the absolute configurations of C-4 of 2 and 3 were assigned as 4R and 4S, respectively (Fig. 5). Meanwhile, according to the octant rule of cyclohexanone [17, 18], using the cotton effect at around 360 nm (n→π*, R band), the absolute configurations of C-4 of 2 and 3 was determined to be R and S, too. Since the C-C bonds rotated freely, the configurations of C-8 and C-8' of 2 and 3 could not be determined exactly. Thus, the structures of 2 and 3 were determined as 15, 16-seco-dibenzocyclooctene lignans in Fig. 1 and named as kadlongilignan B and kadlongilignan C.

    Table 2

    Table 2.  1H (500 MHz) and 13C (125 MHz) NMR data of 2–4 in CDCl3.
    DownLoad: CSV

    Figure 4

    Figure 4.  Key HMBC (H→C) correlations of 2 and 4, 1H-1H COSY (–) correlations of 4.

    Figure 5

    Figure 5.  Experimental and calculated ECD spectra of 2 and 3.

    Compound 4 was given a molecular formula of C20H26O5 based on HRESIMS ion at m/z 369.1673 [M + Na]+ (calcd. 369.1672) (Fig. S27 in Supporting information). The UV bands (207, 289 nm) (Fig. S25 in Supporting information) and IR absorptions (Fig. S26 in Supporting information) at 1593, 1507 cm-1 indicated the presence of biphenyl moiety. The 1H NMR data of 4 (Table 2) showed three AMX coupling aromatic protons at δH 6.86 (d, 1H, J = 8.0 Hz, H-2'), 6.84 (d, 1H, J = 2.0 Hz, H-50) and 6.72 (dd, 1H, J = 8.0, 2.0 Hz, H-1') indicating the presence of one 1, 3, 4-trisubstituted benzene system, two singlet aromatic methine protons at δH 6.86 (s, 1H, H-2) and 6.67 (s, 1H, H-5) indicating the presence of one 1, 2, 4, 5-tetrasubstituted benzene system, two methoxy groups at δH 3.87 (s, 3H, 3-OCH3) and 3.88 (s, 3H, 4'-OCH3), an oxymethylene at δH 3.36 (m, 1H, H-9') and 3.19 (m, 1H, H-9'), a methylene at δH 2.77 (dd, 1H, J = 14.0, 5.0 Hz, H-7) and 2.28 (dd, 1H, J = 13.5, 10.0 Hz, H-7), two methyls at δH 0.78 (d, 3H, J = 7.0 Hz, H-70) and 0.69 (d, 3H, J = 7.0 Hz, H-9), and two methines at δH 1.66 (m, 1H, H-8) and 1.44 (m, 1H, H-8'). The 1H-1H COSY correlations of H-7/H-8/H-8'/H-9', H-8/H-9, and H-7'/H-8', along with the HMBC correlations of H-7 (δH 2.28, 2.77) with C-8 (δC 36.5), C-9 (δC 16.0), and C-80 (δC 40.4), H-90 (δH 3.19, 3.36) with C-8', C-7' (δC 13.2), and C-8 suggested the structural unit of 2, 3-dimethylbutan-1-ol was in 4 (Fig. 4). The structural unit was attached on C-1 of the aromatic ring by the HMBC correlations of the aromatic proton at δH 6.86 (H-2) with δC 130.3 (C-1) and 35.7 (C-7). The HMBC correlations of one aromatic proton at δH 6.67 (H-5) with δC 135.3 (C-6) and 133.7 (C-6') and another aromatic proton at δH 6.72 (H-1') with δC 135.3 (C-6) (Fig. 4) indicated the presence of bibenzyl by the C-C bond connection between C-6 and C-60. Because of the free rotation of C-C bonds, the configurations of C-8 and C-8' of 4 were not be determined. Thus, the planar structure of 4, determining as shown in Fig. 1, was 9, 10-seco-dibenzocyclooctene lignan and named as kadlongilignan D.

    In summary, kadlongilignans A–D (1–4) were four new seco-dibenzocyclooctadiene lignans from the roots of K. longipedunculata. Notably, compound 1 was a rare 6, 7-seco-dibenzocyclooctadiene lignan, and 2 and 3 possessed a novel cyclohexadienone structure. In a view of biosynthesis, the 6, 7-seco-, 9, 10-seco-and 15, 16-seco-type structures deriving from dibenzocyclooctadiene lignans may be degradated by the oxidases in this plant [19]. The original 3, 4-dihydroxy moiety of 2 and 3 was first oxidized to be o-quinone unit and then coupled with acetoacetyl-CoA to form acetonylcyclohexadienone structure [20]. The four compounds were tested for their capacity to inhibit the production of NO through LPS-induced murine macrophages (Table 3). Compounds 3 and 4 exhibited inhibition effect on the NO production with the inhibition rates of 36.3% and 26.9% at the concentration of 10 μmol/L, respectively (dexamethasone as positive control).

    Table 3

    Table 3.  Inhibition effects of compounds 1–4 on LPS-induced NO production.
    DownLoad: CSV

    This work was financially supported by CAMS Initiative for Innovative Medicine (No. CAMS-2016-I2M-1-010) and the Drug Innovation Major Project (No. 2018ZX09711001-001-003).

    Supplementarymaterial related to this article can befound, in the online version, at doi:https://doi.org/10.1016/j.cclet.2019.06.006.


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  • Figure 1  Structures of compounds 1–4.

    Figure 2  Key HMBC (H→C) correlations of 1.

    Figure 3  Experimental and calculated ECD spectra of 1.

    Figure 4  Key HMBC (H→C) correlations of 2 and 4, 1H-1H COSY (–) correlations of 4.

    Figure 5  Experimental and calculated ECD spectra of 2 and 3.

    Table 1.  1H (500 MHz) and 13C (125 MHz) NMR data of 1 in CDCl3.

    下载: 导出CSV

    Table 2.  1H (500 MHz) and 13C (125 MHz) NMR data of 2–4 in CDCl3.

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    Table 3.  Inhibition effects of compounds 1–4 on LPS-induced NO production.

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  • 发布日期:  2020-02-01
  • 收稿日期:  2019-05-05
  • 接受日期:  2019-06-04
  • 修回日期:  2019-06-03
  • 网络出版日期:  2019-06-05
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