Indole Alkaloid Glycosides from the Aerial Parts of Strobilanthes cusia

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Indole Alkaloid Glycosides from the Aerial Parts of Strobilanthes cusia Wei Gu,†,‡ Yu Zhang,§ Xiao-Jiang Hao,§ Fu-Mei Yang,‡ Qian-Yun Sun,‡ Susan L. Morris-Natschke,⊥ Kuo-Hsiung Lee,⊥,∥ Yue-Hu Wang,*,† and Chun-Lin Long*,†,# †

Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China ‡ The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550002, People’s Republic of China § State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China ⊥ Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States ∥ Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan # College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, People’s Republic of China S Supporting Information *

ABSTRACT: Three indole alkaloid glycosides, strobilanthosides A−C (1−3), two known indole alkaloid glucosides (4 and 5), and five phenylethanoid glycosides (8−10) were isolated from the aerial parts of Strobilanthes cusia. The structures of the new compounds were elucidated by spectrometric analysis, and the absolute configurations of 1 and 2 were established by ECD spectrocsopy. N′β-D-Glucopyranosylindirubin (5) showed weak antibacterial activity (MIC 62.5− 125 μM) against Staphylococcus aureus.

alkaloids, strobilanthosides A−C (1−3), along with seven known compounds (4−10). The antibacterial activity of these compounds against Staph. aureus was also evaluated.

Strobilanthes cusia (Nees) Kuntze (Baphicacanthus cusia (Nees) Bremek.), a member of the family Acanthaceae, is an herbaceous plant native to northeast India, Myanmar, Thailand, and southern China.1 This plant has been widely used as a traditional herbal medicine and dye in southwest China. Its root is a famous traditional Chinese medicine commonly known as “Nan-Ban-Lan-Gen”, often used to treat viral hepatitis, influenza, cold, pneumonia, inflammation, herpes, erysipelas, and snakebite. The stems and leaves of S. cusia are used in the dye known as indigo blue.2 Diverse structures, including indigoid indole alkaloids, quinazolinone alkaloids, monoterpenes, triterpenes, flavonoids, sterols, anthraquinones, benzoxazinones, and lignans, have been reported from the extracts of S. cusia.3,4 The plant has been shown to possess various pharmacological activities such as antimicrobial, antiviral, antitumor, and anti-inflammatory effects.3,5−7 In the ethnobotanical research and bioactivity screening for antibacterial activity from medicinal and edible plants in Xishuangbanna, Yunnan Province, China, the crude extract of S. cusia showed weak activity against Staphylococcus aureus,8 which was in accord with a previous report.9 Subsequently, the chemical constituents of the aerial parts S. cusia were investigated and led to the identification of three new indole © XXXX American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION A 95% EtOH extract of the aerial parts of S. cusia was suspended in H2O and partitioned successively with petroleum ether and EtOAc. The EtOAc-soluble part was subjected to column chromatography over silica gel, RP C18 silica gel, and Sephadex LH-20 followed by semipreparative HPLC to afford three new indole alkaloids, strobilanthosides A−C (1−3), two known indole alkaloid glucosides, cephalandole C (4)10 and N′β-D-glucopyranosylindirubin (5),11 and five phenylethanoid glycosides, jionoside D (6),12 acteoside (7),13 martynoside (8),14 isomartynoside (9),15 and 3,4-dihydroxyphenethoxy-Oα-L-rhamnopyanosyl-(1→3)-β-D-(4-O-caffeoyl)galactopyranoside (10).13 Compounds 1 and 2 are a pair of stereoisomers with a molecular formula of C45H44N2O17, as established by 13C NMR spectroscopic and HREIMS data, indicating 25 indices of Received: April 15, 2014

A

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C NMR data (Table 1) with those of acteoside (7),13 the compound was recognized as a phenylethanoid glycoside derivative. In addition to the 29 carbon signals comparable to those of acteoside, the remaining 16 carbon signals were similar to those of indigo.16 However, some signals [δC 201.5 (C-3⁗′), 198.0 (C-3⁗), 164.0 (C-7⁗′a), and 163.0 (C-7⁗a)] in 1 were deshielded concomitant with some shielded signals [δC 99.7 (C-2⁗) and 77.6 (C-2⁗′)], implying that the C-2⁗−C-2⁗′ double bond in the indigo moiety might be reduced. The acteoside moiety was easily established by the correlations of H2-8 to C-1′, H-3′ to C-1″, H-4′ to C-9‴, and H-1″ to C-3′ in the HMBC spectrum of 1 (Figure 1). In addition, a weak correlation between H-2 and C-2⁗′ indicated the linkage between C-2⁗′ and C-6. The deshielding of C-2⁗ (δC 99.7) compared with C-2⁗′ (δC 77.6) indicated that an oxygenated group was linked to C-2⁗. Since the above moieties possess only 21 indices of hydrogen deficiency, the linkage of C-5-C-6C-2⁗′-C-2⁗-O led to formation of a dihydrofuran ring. Thus, the planar structure of 1 was determined as shown in Figure 1. The 1H and 13C NMR data of 2 (Table 1) were similar to those of 1, implying that compound 2 might be an isomer of compound 1 at C-2⁗ and C-2⁗′. The planar structure of 2 was also elucidated from its 1H−1H COSY and HMBC spectra (Figure 2). The absolute configuration of the acteoside moiety in 1 and 2 was assumed to be the same as acteoside (7), which was also isolated from the plant. The absolute configurations of C-2⁗ and C-2⁗′ in 1 and 2 were established by comparison of the experimental electronic circular dichroism (ECD) spectra of 1 and 2 with time-dependent density functional theory (TDDFT)-calculated ECD spectra. A simplified structure of 11 (Figure S1 in the Supporting Information), in which a methyl group replaced the glucosyl group in 1 and 2, was used for calculations, because the chromophores of the indigo moiety were the main contributors to the ECD spectra.17−19 Four diastereoisomers (11a, 2⁗R,2⁗′S; 11b, 2⁗S,2⁗′R; 11c, 2⁗S,2⁗′S; 11d, 2⁗R,2⁗′R) were used for systematic conformational analysis using MMFF94S molecular mechanics force field calculations (Supporting Information). ECD calculations were performed with the Gaussian09 program using the TD-DFT-B3LYP/6-31G(d,p) level of theory on B3LYP/6-31G(d)-optimized geometries. The calculated ECD spectra of 11a and 11b were comparable with those of the experimental ECD spectra of 1 and 2 (Figure 3 and Figure S2 in the Supporting Information), respectively. Therefore, in 1, named strobilanthoside A, the absolute configurations of C-2⁗ and C-2⁗′ were determined as R, S, and in 2, named strobilanthoside B, as S, R. Compound 3 was obtained as a colorless, amorphous solid. Its molecular formula was established as C18H21NO8 by 13C NMR and HREIMS data at m/z 379.1258 [M]+ (calcd 379.1267). The IR spectrum revealed the presence of hydroxy (3430 cm−1), carboxylic (1689 cm−1), and aromatic (1628 and 1434 cm−1) groups. By comparison of its 1H and 13C NMR spectra with those of cephalandole C (4) and other indole alkaloid glycosides,10,20 it was deduced that the compound has an indole core with a glucopyranosyl group [δH 4.75 (d, J = 7.9 Hz, H-1′)] and a methyl acrylate group [δH 8.05 (d, J = 16.1 Hz), 6.31 (d, J = 16.1 Hz), and 3.94 (3H, s); δC 170.1, 133.7, 113.6, and 52.3]. In the HMBC spectrum of 3, the correlation of H-1′ to C-3 indicated that the oxygen at the anomeric carbon of glucose was located at C-3, while those of H-8 to C-3 and H-9 to C-2 indicated that the methyl acrylate group was 13

hydrogen deficiency. The IR spectrum of compound 1 showed absorption peaks for hydroxy (3440 cm−1), carbonyl (1696 cm−1), and aromatic (1618, 1514, 1488, and 1468 cm−1) groups. The 1H NMR and 13C NMR data of 1 (Table 1) showed the characteristic signals for three carbonyl groups (δC 201.5, 198.0, and 163), β-glucopyranosyl [δH 4.08 (d, J = 7.9 Hz)] and α-rhamnopyranosyl [δH 5.17 (br s) and 1.10 (3H, d, J = 6.2 Hz)] moieties, and a trans double bond [δH 7.59 (d, J = 15.8 Hz) and 6.28 (d, J = 15.8 Hz)]. By comparing its 1H and Table 1. 1H (600 MHz) and 13C (150 MHz) NMR Data of 1 and 2 in Methanol-d4 (δ in ppm, J in Hz) 1 δH

position 1 2 3 4 5 6 7 8 1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″ 3″ 4″ 5″ 6″ 1‴ 2‴ 3‴ 4‴ 5‴ 6‴ 7‴ 8‴ 9‴ 2⁗ 3⁗ 3⁗a 4⁗ 5⁗ 6⁗ 7⁗ 7⁗a 2⁗′ 3⁗′ 3⁗′a 4⁗′ 5⁗′ 6⁗′ 7⁗′ 7⁗′a

6.67, d (8.3) 6.75, d (8.3)

2.44, 3.90, 3.47, 4.08, 3.34, 3.75, 4.88, 3.41, 3.57, 3.48, 5.17, 3.93, 3.59, 3.30, 3.57, 1.10,

m m m d (7.9) m t (9.2) m m m m br s m m overlapped m d (6.2)

7.06, d (1.9)

6.77, 6.96, 7.59, 6.28,

overlapped m d (15.8) d (15.8)

7.49, 6.78, 7.40, 6.79,

m m m m

7.55, 6.84, 7.50, 6.96,

d (7.7) t (7.7) m d (8.0)

2 δC 128.0, 124.2, 118.8, 142.0, 148.7, 127.8, 31.5, 71.4,

C CH CH C C C CH2 CH2

104.0, 76.0, 81.6, 70.4, 76.0, 62.4,

CH CH CH CH CH CH2

103.0, 72.4, 72.1, 73.9, 70.6, 18.5, 127.7, 115.3, 146.9, 149.9, 116.6, 123.2, 148.0, 114.8, 168.3, 99.7, 198.0, 119.7, 126.0, 120.7, 139.5, 113.1, 163.0, 77.6, 201.5, 120.1, 125.7, 120.4, 139.6, 114.0, 164.0,

CH CH CH CH CH CH3 C CH C C CH CH CH CH C C C C CH CH CH CH C C C C CH CH CH CH C

δH 6.69, d (8.4) 6.76, d (8.4)

2.40, 3.89, 3.63, 4.15, 3.35, 3.81, 4.90, 3.44, 3.60, 3.53, 5.19, 3.97, 3.60, 3.30, 3.56, 1.10,

m m m d (7.9) m t (9.2) m m m m br s m m overlapped m d (6.1)

7.06, d (2.0)

6.78, 6.97, 7.60, 6.29,

overlapped m d (15.8) d (15.8)

7.52, 6.79, 7.42, 6.81,

m m m m

7.56, 6.86, 7.51, 6.96,

d (7.6) t (7.6) m m

δC 127.6, 124.2, 118.8, 142.0, 148.5, 127.9, 31.6, 71.3,

C CH CH C C C CH2 CH2

103.9, 76.1, 81.6, 70.4, 76.0, 62.4,

CH CH CH CH CH CH2

103.0, 72.3, 72.0, 73.9, 70.5, 18.5, 127.9, 115.1, 146.9, 149.9, 116.5, 123.3, 148.1, 114.6, 168.3, 99.7, 198.4, 119.5, 126.2, 120.7, 139.6, 113.1, 163.2, 77.5, 201.3, 119.8, 125.8, 120.3, 139.8, 114.3, 164.1,

CH CH CH CH CH CH3 C CH C C CH CH CH CH C C C C CH CH CH CH C C C C CH CH CH CH C B

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Figure 1. Chemical structure of compounds 1−10.

located at C-2. Thus, the structure of 3 was determined to be (E)-methyl 3-O-β-D-glucopyranosyl-1H-indol-2-yl acrylate, named strobilanthoside C. In an antibacterial assay, the 95% EtOH extract from the aerial parts of S. cusia inhibited the growth of Staph. aureus with a minimum inhibitory concentration (MIC) value of 250 μg/ mL. Thus, all isolates from the plant were further evaluated for antibacterial activity. Compound 5 showed weak inhibitory activity against Staph. aureus (MIC 62.5−125 μM) with gentamicin as a positive control (MIC 0.1 μM). The remaining compounds exhibited no activity.

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Figure 2. Selected 1H−1H COSY (bold) and HMBC (arrows) correlations of compounds 1 and 2.

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotation values were determined on a Jasco P-1020 polarimeter. UV spectra were recorded on a Shimadzu double-beam 210A spectrometer (Shimadzu Co., Shimadzu, Japan). ECD spectra were recorded on an Applied Photophysics spectropolarimeter. IR spectra were recorded on a Bruker Tensor 27 Fourier transform infrared spectrometer (Bruker, Karlsruhe, Germany) with KBr pellets. 1D and 2D NMR spectra were performed on Bruker AM-400, DRX-500, and Avance III-600 spectrometers (Bruker Bio-Spin GmbH, Rheinstetten, Germany) with TMS as the internal standard. ESIMS and HREIMS analyses were carried out on an API Qstar-Pulsar-1 mass spectrometer (Applied Biosystems/MDS Sciex, Ontario, Canada) and Waters AutoSpec Premier P776 (Waters, Milford, MA, USA), respectively. Semipreparative HPLC was performed on an Agilent 1200 series pump (Agilent Technologies, Santa Clara, CA, USA) equipped with a diode array detector and a Zorbax SB-C18 column (5.0 μm, ⦶ 9.4 × 250 mm). Column chromatography was performed using silica gel 80−

Figure 3. Selected 1H−1H COSY (bold) and HMBC (arrows) correlations of compound 3.

C

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(4.45), 217 (4.94), 204 (4.94) nm; ECD Δε (c = 0.0088, MeOH) −1.74 (399), 0 (368), +0.90 (346), 0 (294), −0.65 (271), −2.69 (242); IR (KBr) νmax 3440, 1696, 1618, 1514, 1488, 1468, 1446, 1384, 1271, 1157, 1064, 1043 cm−1; 1H and 13C NMR, see Table 1; ESIMS (positive) m/z 907 [M + Na]+; HREIMS m/z 884.2643 [M]+ (calcd for C45H44N2O17, 884.2640). Strobilanthoside B (2): C45H44N2O17, yellow, amorphous solid; [α]13D = +10 (c = 0.11, MeOH); UV (MeOH) λmax (log ε) 332 (3.91), 298 (3.84), 216 (4.44) nm; ECD Δε (c = 0.020, MeOH) +1.01 (398), 0 (370), −1.09 (344), 0 (285), −0.32 (271), +1.72 (242); IR (KBr) νmax 3432, 1628, 1515, 1456 cm−1; 1H and 13C NMR, see Table 1; ESIMS (positive) m/z 907 [M + Na]+; HREIMS m/z 884.2643 [M]+ (calcd for C45H44N2O17, 884.2640). Strobilanthoside C (3): C18H21NO8, colorless, amorphous solid; [α]24D = −11 (c = 0.3, MeOH); UV (MeOH) λmax (log ε) 458 (1.75), 344 (3.39), 254 (3.02), 208 (3.54) nm; IR (KBr) νmax 3430, 1689, 1628, 1434, 1384, 1072 cm−1; 1H and 13C NMR, see Table 2; ESIMS (negative) m/z 378 [M − H]−; HREIMS m/z 379.1258 [M]+ (calcd for C18H21NO8, 379.1267).

Figure 4. Calculated ECD spectra for full and simplified 1 (MeOH) and experimental ECD of 1 in MeOH.

Table 2. 1H (600 MHz) and 13C (150 MHz) NMR Data of 3 in Methanol-d4 (δ in ppm, J in Hz)

100; 300−400 mesh; GF-254 (SiO2; Qingdao Meigao Chemical Co.), C18 reversed-phase silica gel (SiO2, 40−75 μm; Fuji Silysia Chemical Ltd.), and Sephadex LH-20 gel (GE Healthcare Bio-Sciences AB). Fractions were monitored by TLC (GF254, Qingdao Marine Chemical Co. Ltd., Qingdao, China). Plant Material. The aerial parts of S. cusia were collected during February 2011 from Xishuangbanna, Yunnan Province, China. The plant was identified by one of the authors (C.-L.L.). A voucher specimen (BN0045) was deposited in the Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences. Extraction and Isolation. The air-dried and powdered aerial parts of S. cusia (10 kg) were extracted three times with regulating 95% EtOH (3 × 50 L) under reflux. The filtrate was evaporated under reduced pressure to give a residue, which was extracted with petroleum ether and EtOAc. The EtOAc-soluble fraction (154 g) was subjected to silica gel column chromatography (80−100 mesh) with a gradient elution of CHCl3−MeOH [20:1, 10:1, 5:1, 2:1, 1:1 (v/v)] to afford five fractions. Fraction 2 was loaded onto a C18 reversed-phase column and eluted with a MeOH−H2O step gradient (20% MeOH → 90% MeOH) to give subfractions 2A−2D. Subfraction 2D was fractionated on a Sephadex LH-20 column (MeOH) followed by column chromatography (CHCl3−MeOH, 15:1) on 300−400 mesh SiO2 to obtain compound 4 (42.7 mg). Fraction 3 was subjected to a C18 reversed-phase column and eluted with a MeOH−H2O step gradient (20% MeOH → 90% MeOH) to give subfractions 3A−3H. Subfraction 3D was subjected to column chromatography on Sephadex LH-20 (MeOH) and 300−400 mesh SiO2 (CHCl3−MeOH, 30:1) and purified by semipreparative HPLC (MeOH−H2O, 40:60) to afford 3 (3.1 mg, tR = 20.2 min). Subfraction 3E was fractionated by column chromatography on Sephadex LH-20 (MeOH) and 300−400 mesh SiO2 (CHCl3−MeOH, 10:1) and then by semipreparative HPLC (MeCN−H2O, 20:80) to yield compounds 8 (11.1 mg, tR = 20.9 min) and 9 (14.2 mg, tR = 28.1 min). Subfraction 3F was subjected to column chromatography on Sephadex LH-20 (MeOH) and 300−400 mesh SiO2 (CHCl3−MeOH, 16:1) to afford 5 (5.1 mg). Fraction 4 was fractionated by C18 reversed-phase column chromatography (20% MeOH → 90% MeOH). The 40% and 50% MeOH fraction was fractionated by Sephadex LH-20 column chromatography (MeOH) to give subfractions 4A−4F. Subfraction 4A was purified by silica gel column chromatography (CHCl3−MeOH, 18:1) and semipreparative HPLC (MeCN−H2O, 30:70) to yield compounds 1 (9.2 mg, tR = 27.3 min) and 2 (7.3 mg, tR = 36.2 min). Subfraction 4C was subjected to silica gel column chromatography (CHCl3−MeOH, 10:1) to give compound 6 (9.0 mg). Subfraction 4D was purified with silica gel column chromatography (CHCl3−MeOH, 10:1) and semipreparative HPLC (MeOH−H2O, 40:60) to yield compounds 7 (11.0 mg, tR = 13.6 min) and 10 (14.3 mg, tR = 20.2 min). Strobilanthoside A (1): C45H44N2O17, yellow, amorphous solid; [α]13D = −395 (c = 0.08, MeOH); UV (MeOH) λmax (log ε) 332

δH

position 2 3 3a 4 5 6 7 7a 8 9 10 1′ 2′ 3′ 4′ 5′ 6′ OMe

7.83, 7.02, 7.20, 7.28,

d (8.0) t (8.0) t (8.0) d (8.0)

8.05, d (16.1) 6.31, d (16.1) 4.75, 3.54, 3.44, 3.49, 3.28, 3.87, 3.76, 3.79,

d (7.9) dd (9.5, 7.9) t (9.5) t (9.5) m dd (12.0, 2.2) dd (12.0, 5.0) s

δC 124.4, 141.8, 121.8, 120.5, 120.7, 126.1, 112.5, 137.4, 133.7, 113.6, 170.1, 106.8, 75.3, 78.0, 71.2, 78.1, 62.5,

C C C CH CH CH CH C CH CH C CH CH CH CH CH CH2

52.3, CH3

Antibacterial Activity Assay. The measurement of growth inhibition was carried out by the disc diffusion method with slight modification.21 Bacterium inoculum (0.05 mL) was inoculated with Mueller−Hinton agar (5 mL) and placed onto plates (6 mm in diameter). Sterile 6 mm filter paper discs were placed on the plates, and immediately six portions of the 40 μL sample solutions (concentration 10 mg/mL) were added. Gentamicin was used as control. The plates were incubated at 37 °C for 24 h. The inhibition zone was measured in millimeters, and the assay was carried out three times for each sample. The minimum inhibitory concentration of the sample was determined using a broth microdilution assay in line with CLSI (formerly NCCLS) guidelines.22 Each well containing 100 mL of antimicrobial agent was inoculated with 100 mL of Staph. aureus suspension containing 1 × 106 cfu/mL, and plates were incubated at 37 °C for 24 h. The MIC was defined as the lowest concentration that did not show visible growth.

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ASSOCIATED CONTENT

S Supporting Information *

1D and 2D NMR, IR, and MS spectra of compounds 1−3 and ECD calculation for the simplified structure 11. These materials D

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are available free of charge via the Internet at http://pubs.acs. org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: (86) 871-65223318. Fax: (86) 871-65223318. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the National Natural Science Foundation of China (31161140345, 31070288), the Ministry of Science & Technology of China (2012FY110300), the JSPS Asian Core Program (JSPS/AP/109080), and the Ministry of Education of China through its 111 and 985 projects (B08044, MUC985).

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