Secondary metabolites from the Chinese liverwort Diplophyllum apiculatum

Phytochemistry Letters 31 (2019) 92–95

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Secondary metabolites from the Chinese liverwort Diplophyllum apiculatum a

a

b

a

a

a

a

Shenghua Fan , Yi Li , Jinchuan Zhou , Yanan Qiao , Chunyang Zhang , Yun Gao , Xueyang Jin , ⁎ Jiaozhen Zhanga, Wang Chenc, Hongxiang Loua, a b c

T

Department of Natural Products Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, Jinan, 250012, People’s Republic of China School of Pharmacy, Linyi University, Linyi, 276000, People’s Republic of China Vitamin D Research Institute, Shaanxi University of Technology, No. 1 Dongyi Road, Hanzhong, Shaanxi, 723000, People’s Republic of China

ARTICLE INFO

ABSTRACT

Keywords: Diplophyllum apiculatum (A. Evans) Stephani Scapaniaceae Liverwort Clerodane-type diterpenoids Diplapiculin A–C

Three new clerodane-type diterpenoids, diplapiculins A–C (1-3), together with five known compounds (4-8) were isolated from the Chinese liverwort Diplophyllum apiculatum (A. Evans) Stephani. Their structures were determined by detailed analysis of HRMS and NMR data, coupled with single-crystal X-ray diffraction crystallography and electronic circular dichroism (ECD). They were found no antifungal and anticancer effects in preliminary biotests in vitro.

1. Introduction That liverworts (Hepaticae) are abundant in lipophilic terpenoids and aromatic compounds has been convincingly investigated extensively (Xie and Lou, 2008, 2010; Asakawa et al., 2010, 2013; Na et al., 2018). Previous investigations on chemical constituents of Diplophyllum, belonging to family Scapaniaceae, revealed the presence of a series of ent-eudesmane-type sesquiterpenoids (Ohta et al., 1977; Asakawa et al., 1979; Toyota et al., 1994; Adio and König, 2007; Wang et al., 2016). To our best knowledge, this is the first chemical study on the liverwort Diplophyllum apiculatum (A. Evans) Stephani, which is mainly distributed in China and North America. This article reports three new clerodane-type diterpenoids, diplapiculins A–C (1-3), along with five known compounds (4-8) from the Chinese liverwort D. apiculatum, collected from the Jiulong mountain national forest park, Zhejiang Province, People’s Republic of China, in May 2018. So far, this represented the first isolation of clerodane-type diterpenoids from Diplophyllum species. Structural elucidation of new compounds was achieved by spectroscopic methods, comparisons of experimental ECDs and single-crystal X-ray diffraction analyses (Fig. 1). 2. Results and discussion 2.1. Isolation and identification of undescribed compounds The EtOH–H2O (95:5, v/v) extract of D. apiculatum was fractionated by chromatography over MCI gel, silica gel and Sephadex LH-20 and

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was then further purified by semipreparative HPLC to afford 8 compounds. Compound 1 was obtained as colorless needles following crystallization from MeOH. Its molecular formula C21H26O6 (m/z 375.1807 [M +H]+, calcd 375.1802), with nine degrees of unsaturation, was established based on HRESIMS and 13C NMR spectroscopic data. The 1D NMR spectra (Tables 1 and 2) indicated the presence of two methyl groups [δH 2.10 (s, H3-17) and 1.29 (s, H3-19)], one oxygenated methyl [δH 3.66 (s, H3−OCH3)], one oxygenated methine [δH 5.36 (t, J =7.1 Hz, H-12)]; six methylenes [δC 25.3 (C-1), 23.4 (C-2), 21.9 (C-3), 33.1 (C-6), 38.0 (C-7), 37.1 (C-11)], a double bond [δC 120.1 (C-9) and 160.3 (C-10)] and three carbonyl groups [δC 174.4 (C-18), 171.0 (C-20) and 207.9 (C-8)]. In addition, the analysis of 1D NMR data exhibited signals for a typical β-monosubstituted furan ring [δH 6.40 (s, H-14), 7.43 (d, J =1.7 Hz, H-15) and 7.47 (s, H-16); δC 125.3 (C-13), 108.3 (C14), 144.2 (C-15), 139.9 (C-16)] Rui-Juan et al., 2013. Above data indicated that the structure of compound 1 was a highly oxygenated clerodane diterpenoid which was similar to jamesoniellide J Tazaki et al., 1999) except for the substituent group linked to C-8. The existence of the carbonyl group [δC 207.9 (C-8)] located at C-8 was confirmed by HMBC correlations from H3-17 to C-8; from H-7 to C-6 and C-8. Therefore, compound 1 was a secoclerodane diterpene cleaved between C-8 and C-9. Its relative configuration was partially established by the application of NOE experiment (Fig. S31) and confirmed by a single-crystal X-ray diffraction analysis (Fig. 3, CCDC 18896361,889,636), which indicated (4R,5S,12R) absolute configurations for 1, named diplapiculin A.

Corresponding author. E-mail address: [email protected] (H. Lou).

https://doi.org/10.1016/j.phytol.2019.03.018 Received 23 January 2019; Received in revised form 21 March 2019; Accepted 25 March 2019 1874-3900/ © 2019 Published by Elsevier Ltd on behalf of Phytochemical Society of Europe.

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Table 2 13 C NMR (150 MHz) spectroscopic data (CDCl3) for compounds.1–3.

Fig. 1. Structures of compounds 1–3. Table 1 1 H NMR (600 MHz) spectroscopic data (CDCl3) for compounds.1–3. Position

1

2

3

1a 1b 2a 2b 3a 3b 4 5 6 7a 7b 8 9 10 11a

4.26 dt (15.0, 3.6)

2.89 m (2 H)

1.97 m 1.84 m 1.79 m 1.62 m 2.69 t (5.6)

1.92 m (2 H)

3.94 dt (17.0, 3.6) 2.33 m 1.93 m 1.66 m 2.08 m 1.77 m 2.90 dd (12.3, 6.8)

2.16 m (2 H) 2.29 m (2 H)

6.88 d (16.2) 6.07 d (16.2)

4.76 d (10.0) 1.53 m 1.48 m 4.00 m

3.57 ddd (15.9, 7.7, 2.2) 2.92 ddd (15.7, 6.9, 3.2) 5.36 t (7.1)

2.82 ddt (16.0, 7.7, 2.2) 3.17 dd (15.9, 7.2)

3.24 ddd (16.1, 8.0, 3.4) 2.98 m

5.22 t (7.0)

5.46 t (6.8)

6.40 s 7.43 t (1.7) 7.47 s 2.10 s (3 H)

6.36 d (0.9) 7.42 t (1.7) 7.44 m 2.22 s (3 H)

6.45 d (1.1) 7.45 t (1.7) 7.57 m 1.16 d (6.3) (3 H)

1.29 s (3 H)

1.50 s (3 H)

1.36 s (3 H)

3.66 s

3.55 s

11b 12 13 14 15 16 17 18 19 20 OMe

1.81 m 1.64 m 2.75 dd (11.7, 4.6)

Position

1

2

3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OMe

25.3 t 23.4 t 21.9 t 52.0 d 43.9 s 33.1 t 38.0 t 207.9 s 120.1 s 160.3 s 37.1 t 70.5 d 125.3 s 108.3 d 144.2 d 139.9 d 30.3 q 174.4 s 24.1 q 171.0 s 51.7 q

24.4 t 23.4 t 22.4 t 51.1 d 46.8 s 152.5 d 128.5 d 197.8 s 120.9 s 158.4 s 37.0 t 70.7 d 124.7 s 108.2 d 144.3 d 140.1 d 28.0 q 173.0 s 17.6 q 170.4 s 51.5 q

25.6 t 18.2 t 15.4 t 41.6 d 47.9 s 83.5 d 38.1 t 64.4 d 120.4 s 156.8 s 34.9 t 71.0 d 125.0 s 108.8 d 144.2 d 140.2 d 24.7 q 175.3 s 19.5 q 169.8 s

Chemical shifts (δ) are expressed in ppm, and J values are presented in Hz.

two methyl groups [δH 1.16 (d, J =6.3 Hz, H3-17) and 1.36 (s, H3-19)], three oxygenated methines [δH 5.46 (t, J =6.8 Hz, H-12), 4.76 (d, J =10.0 Hz, H-6) and 4.00 (m, H-8)]; five methylenes [δC 25.6 (C-1), 18.2 (C-2), 15.4 (C-3), 38.0 (C-7), 34.9 (C-11)], a double bond [δC 120.4 (C-9) and 156.8 (C-10)], three carbonyl groups [δC 174.4 (C-18), 171.0 (C-20) and 207.9 (C-8)] and a typical β-monosubstituted furan ring [δH 6.45 (d, J =1.1 Hz, H-14), 7.45 (t, J =1.7 Hz, H-15), 7.57 (m, H-16); δC 125.0 (C-13), 108.8 (C-14), 144.2 (C-15), 140.2 (C-16)]. The planar structure of 3 was determined by extensive analyses of its 2D NMR spectra. The presence of a lactone ring between C-18 and C-6 was proved by HMBC correlations from H-4 to C-3, C-5, C-10, C-18 and C19. The location of the lactone carbonyl group [δC 175.3 (C-18)] was confirmed by the HMBC correlations from H-6 to C-4, C-5, C-10, C-18 and C-19; from H-4 to C-18. And the HMBC correlations from H3-17 to C-7 and C-8 confirmed the location of the hydroxyl group at C-8 (Fig. 2). The relative configuration of 3 was partially defined via NOESY data (Fig. S31). NOE between H-11 and H3-19 indicated geometric isomerism at the C-9/C-10 double bond was E configuration. Correlation of H3-19 with H-4 indicated that they were co-facial orientation. The NOE signals observed between H-6 and H-8 proved that these two protons have the same orientation. This conclusion was validated by a single-crystal X-ray diffraction analysis using Cu Kα radiation (Fig. 3, CCDC 1,889,640). Moreover, the experimental ECD data of 1 and 3 (Fig. S30) were concordant, which confirmed the absolute configuration. Thus, the absolute structure of compound 3 was identified as (4R,5R,6R,8R,12R) configurations and named diplapiculin C. The following known compounds (Fig. S32.) were also isolated, as determined by comparison of their spectroscopic data to those reported in the literature: drimenol (Brown, 1994) (4), (1R,4aR,8aR)-5,5,8aTrimethyl-2-methylenedecahydro-naphthalen-1-yl-methanol (Pollini et al., 2004) (5), chiloscyphenols A (Ma et al., 2007) (6), Fusicoauritone (Zapp et al., 1994) (7), 2,6-dihydroxy-3,4-dimethylbenzoic acid methyl ester (Tzong-Huei et al., 2010) (8).

Chemical shifts (δ) are expressed in ppm, and J values are presented in Hz.

Compound 2, a colorless oil, has the molecular formula C21H24O6, with ten indices of hydrogen deficiency according to HRESIMS (m/z 373.1643 [M+H]+, calcd 373.1646) and 13C NMR spectroscopic data. Comparison of the NMR data (Tables 1 and 2) indicated that the structure of 2 was closely similar to those of 1, with the exception that two methylenes in 1 were replaced by two vinylic carbons. The presence of double bond was also supported by the extra degree of unsaturation and the NMR data analyses of C-6 [(δC 152.8), δH 6.88 (d, J =16.2 Hz)] and C-7 [(δC 128.6), δH 6.07 (d, J =16.2 Hz)], which confirmed an E configuration bond at C-6/C-7. Moreover, NOE correlations between H-6 with H-4 established that they were co-facial oriented (Fig. S31). Correspondingly, comparing the experimental ECD data (Fig. S20) with that of 1 (Fig. S10), determined (4R,5S,12R) absolute configurations for 2, named diplapiculin B. Compound 3 was obtained as colorless needles following crystallization from MeOH. Its molecular formula, C20H24O6 (m/z 361.1649 [M+H]+, calcd 361.1646), with nine degrees of unsaturation, was established based on HRESIMS and 13C NMR spectroscopic data. Its 1D NMR spectra (Tables 1 and 2) indicated the presence of signals due to

3. Experimental section 3.1. General experimental procedures Melting points were measured with an X-6 micromelting point apparatus. Optical rotations were acquired on a Anton Paar polarimeter. UV data were recorded using a Shimadzu UV-2450spectrophotometer. 93

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Fig. 2. Main HMBC (arrow) and 1H-1H COSY (bold) correlations of compound 1 and 3.

ECD spectra were performed on a Chirascan spectropolarimeter. IR spectra were measured on a Nicolet iN 10 Micro FTIR spectrometer. NMR spectra were recorded on a Bruker Avance DRX-600 spectrometer (1H: 600 MHz, 13C: 150 MHz) and Bruker Avance AV-400 spectrometer (1H: 400 MHz, 13C: 100 MHz) in CDCl3 with tetramethylsilane as the internal standard. TMS was used as internal standard. HRESIMS were obtained using an LTQ-Orbitrap XL. HPLC was carried out on an Agilent 1200 series instrument with Eclipse XDB-C18 5 mm columns (4.6 × 250 mm and 9.4 × 250 mm). All solvents used were of analytical grade. MCI gel (CHP20 P, 75–150 mm, Mitsubishi Chemical Industries Ltd.), silica gel (200–300 mesh; Qingdao Haiyang Chemical Co. Ltd.), Sephadex LH-20 (25–100 mm; Pharmacia), and reversed–phase C18 silica gel (150–200 mesh, Merck) were used for column chromatography. Compounds were visualized under UV light and by spraying with H2SO4−EtOH (1:9, v/v) followed by heating.

Pharmaceutical Sciences, Shandong University, People’s Republic of China. 3.3. Extraction and isolation The air-dried and milled plant material from D. apiculatum (286 g) was extracted with 95% EtOH (3 × 1.5 L, each for two days) at room temperature and filtered. The filtrate was evaporated under reduced pressure at 40 °C to afford a residue. The crude extract (7.19 g) was separated by MCI gel column chromatography (MeOH/H2O, 3:7 to 9:1) to give fractions 1–5. Fraction 2 (584.6 mg) was separated by silica gel column chromatography [petroleum ether (60–90 °C)-ethyl acetate, 200:1 to 0:1] and gave subfractions 2A-2I. Subfraction 2B (20.3 mg) was purified using HPLC (MeOH/H2O, 68:32, 1.5 mL/min), to afford 8 (1.2 mg). Subsraction 2E (64.2 mg) was chromatographed using a Sephadex LH-20 column (MeOH) and gave subfractions E1-E6. Subfraction E3 (16.9 mg) was purified using HPLC (MeOH/H2O, 60:40, 1.5 mL/min), to afford 1 (1.2 mg). Subfraction E5 (13.5 mg) was purified using HPLC (CH3CN/H2O, 45:55, 1.5 mL/min), to afford 2 (1.5 mg). Subsraction 2 F (63.9 mg) was chromatographed using a Sephadex LH-20 column (MeOH) and gave subfractions F1-F5. Subfraction F3 (13.9 mg) was purified using HPLC (MeOH/H2O, 57:43, 1.5 mL/min) to afford 3 (1.6 mg). Fraction 3 (316.5 mg) was separated

3.2. Plant material Whole plants of D. apiculatum were collected from the Jiulong mountain national forest park, Zhejiang Province, People’s Republic of China, in May 2018, and identified by Jinchuan Zhou (Linyi University). A voucher specimen (No. 20,180,515,021) has been deposited at the Department of Natural Products Chemistry, School of

Fig. 3. X-ray ORTEP drawings of 1 and 3. 94

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by silica gel column chromatography [petroleum ether (60 – 90 °C)ethyl acetate, 200:1 to 0:1] and gave subfractions 3A-3I. Subfraction 3A (120.8 mg) was purified using HPLC (MeOH/H2O, 80:20, 1.5 mL/min), to afford 4 (4.8 mg) and 6 (1.7 mg). Subfraction 3A-4 (8.1 mg) was again purified using HPLC (MeOH/H2O, 87:13, 1.5 mL/min) to afford 5 (2.7 mg). Subfraction 3D (31.4 mg) was separated using HPLC (MeOH/ H2O, 78:22, 1.5 mL/min). Then, subfraction 3D-3 (22.1 mg) was purified using HPLC (MeOH/H2O, 85:15, 1.5 mL/min) to afford 7 (1.9 mg).

3.5. Cytotoxicity and antifungal activity tests All the isolated compounds have been tested for cytotoxic activity against three human cancer cell lines (A549, DU145 and PC-3) by MTT assay with adriamycin used as a positive control (Qiao et al., 2018). Moreover, they were evaluated for antifungal activities against Candida albicans SC5314 (the wild-type strain) and DSY654 (the Cdr1, Cdr2 efflux pumps deficient strain), and fluconazole served as the positive antifungal agent (Cui et al., 2018). Unluckily, they were found no antifungal and anticancer effects in biotests in vitro.

3.3.1. Diplapiculin A Colorless needles (MeOH); mp 130–132 °C; [α]25 D −7.22 (c 0.04 MeOH); UV (MeOH) λmax (log ε) 238 (2.84) nm; ECD (MeOH) 240 (Δε 13.39) nm; IR νmax 3421, 2943, 2873, 1716, 1618, 1444, 1240 cm−1; 1 H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 375.1807 [M +H]+ (calcd for C21H27O6, 375.1802).

Acknowledgment This work was supported financially by the National Natural Science Foundation of China (Nos. 81874293 and 81630093).

3.3.2. Diplapiculin B Colorless oil (MeOH); [α]25 D −47.63 (c 0.04 MeOH); UV (MeOH) λmax (log ε) 223 (2.70) nm; ECD (MeOH) 264 (Δε 5.85) nm; IR νmax 3386, 2875, 2854, 1732, 1621, 1435, 1198, 1020 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 373.1643 [M+H]+ (calcd for C21H25O6, 373.1646).

Appendix A. Supplementary data

3.3.3. Diplapiculin C Colorless needles (MeOH); mp 136–138 °C; [α]25 D 27.06 (c 0.04 MeOH); UV (MeOH) λmax (log ε) 233 (2.72) nm; ECD (MeOH) 266 (Δε 3.16) nm; IR νmax 3510, 2923, 2884, 1745, 1649, 1445, 1191, 873 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 361.1649 [M+H]+ (calcd for C20H25O6, 361.1646).

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Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.phytol.2019.03.018. References

3.4. X-ray crystal structure analysis Colorless needles of 1 and 3 were obtained from a MeOH solution. All crystallographic data were collected on a Bruker D8 venture diffractometer equipped with an APEXII CCD using Cu Kα radiation (λ = 1.541 78 Å) at 293(2) K. The APEX2 Software Suite was used for cell refinement and data reduction. The structure was refined with fullmatrix least-squares calculations on F2 using SHELXL-2014/7. Crystal Data for Compound 1. C21H26O6, M = 374.42, monoclinic system, space group P21, a = 7.3435(3) Å, b = 8.4690(4) Å, c = 30.9011(14) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 1921.80(15) Å3, Z = 4, Dcalcd =1.294 g/cm3, μ (Cu Kα) = 1.542 mm−1, F(000) = 800, 9612 reflections measured (5.416° ≤ 2θ ≤ 68.410°), 3329 unique which were used in all calculations. The final R1 was 0.0549 (> 2sigma(I)) and wR2 was 0.1372 (all data). The flack parameter was 0.12(11). Details of crystallographic data for 1 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1,889,636. The data can be obtained free of charge via www.ccdc.cam.ac.uk/products/csd/ request. Crystal Data for Compound 3. C20H24O6, M = 360.39, monoclinic system, space group P21, a = 6.8263(7) Å, b = 11.6250(13) Å, c = 23.005(2) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 1825.6(3) Å3, Z = 4, Dcalcd =1.311 g/cm3, μ (Cu Kα) = 1.542 mm−1, F (000) = 768, 4020 reflections measured (3.843° ≤ 2θ ≤ 66.592°), 1830 unique which were used in all calculations. The final R1 was 0.0720 (> 2sigma(I)) and wR2 was 0.1337 (all data). The flack parameter was 0.0(5). Details of crystallographic data for 1 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1,889,640. The data can be obtained free of charge via www.ccdc.cam.ac.uk/products/csd/request.

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