Chinese Journal of Natural Medicines 2014, 12(8): 06280631

Chinese Journal of Natural Medicines

Triterpenes from the stem bark of Mitragyna diversifolia and their cytotoxic activity CAO Xing-Fen, WANG Jun-Song, WANG Peng-Ran, KONG Ling-Yi* State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China Available online 20 August 2014

[ABSTRACT] AIM: To study the chemical constituents and bioactivity of the stem bark of Mitragyna diversifolia. METHO D: Compounds were isolated by various chromatographic methods. T heir structures were elucidated on the basis of spectroscopic techniques (IR, UV, MS, and NMR), and they were evaluated for their cytotoxic activities by the MT T method. RESULTS: Eight triterpenes were isolated and identified as 3 , 6 , 19 -trihydroxy-urs-12-en-28-oic acid (1), 3β, 6β, 19 - trihydroxy-urs-12-en-28-oic acid (2), 3-oxo-6 -19 -dihydroxy-urs-12-en-28-oic acid (3), 3β, 6β, 19α-trihydroxy-urs-12-en-24, 28-dioic acid 24-methyl ester (4), 3 , 6, 19 , 24-tetrahydroxy-urs-12-en-28-oic acid (5), rotundic acid (6), 23-nor-24-exomethylene- 3β, 6β, 19α-trihydroxy-urs-12-en-28-oic acid (7), and pololic acid (8), respectively. All of the isolates were tested against two human t umor cell lines, MCF-7 (breast) and HT-29 (colon). CO NCLUSIO N: Compound 1 was a new triterpene. Compounds 5−7 exhibited potent inhibitory effects on the growth of MCF-7 and HT-29 cells, and the others showed no cytotoxicity. [KEY WO RDS] Mitragyna diversifolia; Rubiaceae; T riterpenes; Cytotoxicity

[CLC Number] R284.1

[Document code] A

[Article ID] 2095-6975(2014)08-0628-04

Introduction Mitragyna diversifolia (Wall ex G. Don) Havil (Rubiaceae) is mainly distributed in M alaysia, Thailand, and Yunnan province of China and has particular medicinal importance [1]. The leaves of this plant have been traditionally used to treat diarrhea, and for weaning addicts off morphine [2] . Previous phytochemical investigations on its constituents led to the isolation of indole alkaloids and triterpenes [3-4]. The secondary metabolites from Mitragyna species often vary with different ecological environments. As part of a program searching for novel and bioactive chemical constituents, the stem bark of M. diversifolia was investigated. This paper describes

[Re ceive d on] 22 -Apr.-20113 [Research funding] This project was supported by the National Science Foundation of China (No. 21272275), and the Program for Changjiang Scholars and Innovative Research Team in Un iversity (No. PCSIRT-IRT1193). [ *Corresponding author] KONG Ling-Yi: Prof., Tel/Fax: 86-25-83271405, E-mail: [email protected] T hese authors have no conflict of interest to declare. Copyright © 2014, China Pharmaceutical University. Published by Elsevier B.V. All rights reserved

the extraction, isolation, and structural characterization of a new triterpene 1 and seven known ones, 2−8 (Fig. 1), and their cytotoxic activities against M CF-7 and HT-29 cells.

Results and Discussion Compound 1 w as obt ained as a white powder. The HRESI-M S of 1 suggested the elemental formula C30H47O5 from a pseudomolecular ion peak at m/z 487.343 1 [M − H]− . The IR spectrum showed absorption bands for hydroxyl (3 432 cm−1) and olefin (1 631 cm−1) groups. The 1H NMR (Table 1) of 1 revealed the presence of six tertiary methyl ( 1.28, 1.27, 1.17, 1.15, 1.02, and 0.95, 3H, each signal), a secondary methyl [ 0.87 (d, J = 6.5 Hz, 3H)] and a trisubstituted olefinic double bond ( 5.27, brs, 1H). The occurrence of a signal at  2.45 for H-18, as well as a characteristic downfield shifted doublet of triplets signal [ 2.50 (dt, 13.5, 4.5 Hz, 1H)] assignable to H-16 , due to the anisotropic effect of a 19 -hydroxyl group, suggested that compound 1 was an urs-12-ene derivative possessing an  -OH group at C-19 [6]. The presence of two additional oxymethine protons resonating at  3.22 (t, J = 3.0 Hz, 1H) and 4.32 (brs, 1H) were revealed in the 1H NM R spectrum, indicating the presence of two

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Fig. 1

Structures of compounds 1−8

Table 1 1 H (500 MHz) and 13C NMR (125 MHz) data of compound 1 in methanol-d 4 Position

Compound 1 C

1

36.6

2

27.3

H , multi (J in Hz) 1.35, m 1.22, m 1.69, overlap

3

78.5

3.22, t (3.0)

4

39.2

5

50.3

1.30, m

6

69.4

7

41.8

4.32, brs 1.73, m 1.46, overlap

8

40.3

9

48.4

10

37.7

11

24.5

1.98, overlap

12

129.9

5.27, brs

13

139.2

14

43.1

15

29.5

1.84, m

16

26.6

2.50, dt (13.5, 4.5)

17

49.0

18

55.1

19

73.6

20

43.2

21

26.2

22

39.0

23

29.1

1.29, overlap 1.96, overlap 1.42, overlap 1.65, m 1.56, m 0.95, s

24

24.9

1.17, s

25

17.1

1.27, s

26

18.5

1.02, s

27

24.8

1.28, s

28

182.2

29

27.1

1.15, s

30

16.5

0.87, d (6.5)

ylic group at  182.2 (C-28), and three oxygenated carbons at  78.5 (C-3), 69.4 (C-6), and 73.6 (C-19). In the HM BC spectrum, the correlations of H 3-23 ( 0.95, s) and H 3-24 ( 1.17, s) with a carbon bearing an OH group at  78.5 placed this OH group at C-3 in the ursane skeleton (Fig. 2). Another hydroxyl group was located to C-6 according to the cross-peaks from H-5 to C-6 ( 69.4) and from H-6 to C-5 (50.3) and C-7 ( 41.8). Detailed analyses of the 1D- and 2D-NM R (1H, 13C NM R spectra, HM QC, and HM BC) of 1, and comparison with compound 2 [7] , suggested that 1 and 2 had the same planar structure. ROESY correlations (Fig. 2) from H-3 to H3-25 and H 3-26, indicated the α-orientation of the 3-OH. This suggestion was strongly supported by the small coupling constant (J = 3.0 Hz) between H-3 and H-2. Since the 13 C NM R data of C-3 (78.5), C-5 (50.3), and C-24 (24.9) of 1 were superimposable with those of urs-12-ene3α, 11α-diol [8] , the α-orientation of 3-OH in 1 was further confirmed. The  -orientation of the hydroxyl group at C-6 was deduced from the shape of the proton signal of H-6 (4.32, brs) in the 1H NM R spectrum, which was further verified by the cross peaks of H-6\H 3-27 and H-6\H-5 in the ROESY spectrum. Hence, the structure of 1 w as established as 3α, 6 , 19α-trihydroxy-urs-12-en-28-oic acid.

1.80, overlap

Fig. 2

2.45, s

Selected (a) HMBC and (b) RO ESY correl ations of 1

Seven known compounds were identified to be 3β, 6β, 19αtrihydroxy-urs-12-en-28-oic acid (2) [7], 3-oxo-6 -19α- dihydroxy-urs-12-en-28-oic acid (3) [9], 3β, 6β, 19α-trihydroxyurs-12-en-24,28-dioic acid 24-methyl ester (4) [7], 3 , 6 , 19α,24-tetrahydroxy-urs-12-en-28-oic acid (5) [10], rotundic acid (6) [11] , 23-nor-24-exomethylene-3β, 6β, 19α-trihydroxyurs-12-en-28-oic acid (7) [6] , and pololic acid (8) [12] by comparison of the NM R and M S data with those reported in the literature. Compounds 1−8 w ere evaluated for cytotoxic act iv ities against two tumor cell lines (M CF-7 and HT-29) by the M TT test, with cisplatin as the posit ive control (Table 2). Compounds 5−7 show ed potent inhibitory activities comparable to thos e of cisplatin. The other compounds showed no cytotoxicity (IC50 > 50 mol· L−1).

additional hydroxyl groups in an ursane skeleton. The 13C NM R of 1 (Table 1) revealed thirty carbons containing an olefinic group at  129.9 (C-12) and 139.2 (C-13), a carbox-

Experimental General Experimental Procedures Optical rotations were measured with a JASCO P-1020

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Table 2 Cytotoxicity of compoun ds 1−8, given as IC 50 values (mol· L-1 ) Compound

MCF-7

HT-29

1

> 50

> 50

2

> 50

> 50

3

> 50

> 50

4

> 50

> 50

5

35.4 ± 1.4

> 50

6

> 50

33.3 ± 2.1

7

24.4 ± 0.9

24.3 ± 1.7

8

> 50

> 50

Cisplatin

18.7 ± 0.3

6.4 ± 0.2

polarimeter. UV spectra were obtained on a Shimadzu UV2450 spectropolarimeter (Tokyo, Japan). IR spectra (KBr disks) were recorded on a Bruker Tensor 27 spectrometer (Ettlingen, Germany). NMR spectra were recorded on a Bruker ACF-500 NM R instrument (1H: 500 MHz, 13C: 125 MHz), with TM S as internal standard. M ass spectra were obtained on an M S Agilent 1100 series LC/M SD ion-trap mass spectrometer (ESIM S) and HR-ESI-M S was done on an Agilent 6520B Q-TOF spectrometer, respectively. Silica gel (Qingdao Haiyang Chemical Co., Ltd.), Sephadex LH-20 (Pharmacia), and Rp-C18 (40-63 µm, Fuji) were used for column chromatography (CC). Preparative HPLC was performed on a Shimpack Rp -C18 column (5 µm, 20 mm × 200 mm) monitored by a 1100 Series multiple wavelength detector. All solvents used were of analytical grate (Jiangsu Hanbang Sci. & Tech. Co., Ltd., China). Plant material The stem bark of M. diversifolia w as collected in M ay 2011 from Xishuangbanna, Yunnan Province, and was ide ntified by Prof. ZHANG Shun-Cheng, Xishuangbanna Botanical Garden, Chinese Academy of Sciences. A voucher specimen (No. M D-201105) has been deposited in the D epartment of Natural M edicinal Chemistry, China Pharm aceutical University. Extraction and isolation The stem bark of M. diversifolia (10 kg) was extracted three times with 95% EtOH at 100 °C (each 10 L, 2 h. After removal of the solvent under vacuum, the viscous concentrate was suspended in water, and was then partitioned successively with petroleum ether (PE), CH2Cl2, EtOAc, and n-BuOH. The CH 2Cl2 layer (64 g) was chromatographed over D101 porous resin eluted with gradient aqueous ethanol to afford three fractions (A−C). Fraction C (10 g) was fractionated by silica gel CC eluting with PE-EtOAc (50 : 1 to 0 : 1) to give six fractions (Fractions CA−CF). Fraction CD (2.6 g) was subjected to M CI, eluted with M eOH-H2O (2 : 8 to 1 : 0), purified by ODS with M eOH-H2O (2 : 8 to 1 : 0), and Sephadex LH-20 (M eOH) chromatography, and then subjected to preparative HPLC using M eOH-H2O (73 : 27) as mobile phase at a flow rate of

10 mL·min−1 to afford 1 (4 mg), 2 (28 mg), and 6 (5 mg). Fraction CE (2.5 g) was separated over reversed-phase C18 silica gel eluted with M eOH-H2O (3 : 7 to 8 : 2) to give five fractions (CEa-CEe). Fraction CEc was further isolated and purified by repeated silica gel CC (CH2Cl2-M eOH, 10 : 1), and then preparative HPLC was carried out using M eOH-H2O (70 : 30) as an eluent at a flow rate of 10 mL·min−1 to afford 3 (8 mg) and 4 (13 mg). Fraction CEd was further purified by Sephadex LH-20 open column chromatography (M eOH), and finally subjected to preparative HPLC to yield 5 (15 mg), 7(9 mg), and 8 (5 mg). Cytotoxicity assay The cytotoxicity assays were performed according to the MTT method in 96-well microplates [5], using two human tumor cell lines M CF-7 (breast cancer) and HT-29 (colon tumor).

Identification 3α, 6β, 19α-Trihydroxy-urs-12-en-28-oic acid (1) White powder; [α]20D + 9.0 (c 0.12, M eCN); UV (M eCN) λmax (log ε) 250 (2.66), 194 (3.66) nm; IR (KBr)  max 3 442, 1 631, 1 396, 1 060 cm−1; 1H and 13C NM R data, see Table 1; HRESI-M S m/z 487.343 1 [M − H]− (Calcd. for C30H47O5, 487.342 9). 3β, 6β, 19α-Trihydroxy-urs-12-en-28-oic acid (2) White powder; 1H NM R (CD3OD, 500 MHz):  5.34 (1H, s, H-12), 4.51 (1H, s, H-6), 3.10 (1H, dd, 11.5, 4.0 Hz, H-3), 2.58 (1H, dt, 13.5, 4.0 Hz, H-16), 2.54 (1H, s, H-18), 1.33 (3H, s, H-27), 1.32 (3H, s, H-25), 1.22 (3H, s, H-23), 1.18 (3H, s, H-29), 1.10 (3H, s, H-26), 1.06 (3H, s, H-24), 0.95 (3H, d, 6.5 Hz, H-30); 13C NMR (CD 3OD, 125 M Hz): 40.8 (C-1), 27.2 (C-2), 80.3 (C-3), 40.3 (C-4), 57.3 (C-5), 69.1 (C-6), 42.0 (C-7), 39.1 (C-8), 48.8 (C-9), 37.7 (C-10), 24.7 (C-11), 129.9 (C-12), 139.3 (C-13), 43.1 (C-14), 29.7 (C-15), 28.6 (C-16), 48.9 (C-17), 55.2 (C-18), 73.8 (C-19), 43.2 (C-20), 26.8 (C-21), 42.2 (C-22), 27.4 (C-23), 18.6 (C-24), 16.7 (C-25), 17.7 (C-26), 24.9 (C-27), 182.3 (C-28), 28.2 (C-29), 17.4 (C-30). 3-Oxo-6, 19-dihydroxy-urs-12-en-28-oic acid (3) White powder; 1H NM R (pyridine-d5, 500 M Hz): 5.70 (1H, s, H-12), 4.70 (1H, br s, H-6), 3.15 (1H, dt, 15.0, 4.0 Hz, H-16), 3.12 (1H, s, H-18), 2.90 (1H, dt, 15.0, 6.0 Hz, H-2), 2.49 (1H, dt, 15.0, 5.5 Hz, H-2), 1.74 (3H, s, H-25), 1.72 (3H, s, H-24), 1.71 (3H, s, H-29), 1.69 (3H, s, H-23), 1.49 (3H, s, H-27), 1.37 (3H, s, H-26), 1.15 (3H, d, 7.0 Hz, H-30); 13C NM R (pyridine-d5, 125 M Hz): 40.2 (C-1), 35.1 (C-2), 216.1 (C-3), 49.7 (C-4), 57.6 (C-5), 68.8 (C-6), 41.8 (C-7), 38.8 (C-8), 48.1 (C-9), 37.3 (C-10), 24.5 (C-11), 128.5 (C-12), 139.9 (C-13), 42.8 (C-14), 29.7 (C-15), 26.2 (C-16), 48.7 (C-17), 55.1 (C-18), 73.1 (C-19), 43.1 (C-20), 26.8 (C-21), 42.4 (C-22), 24.5 (C-23), 27.3 (C-24), 16.7 (C-25), 18.8 (C-26), 25.1 (C-27), 181.0 (C-28), 27.5 (C-29), 17.1 (C-30). 3β, 6β, 19α-Trihydroxy-urs-12-en-24, 28-dioic acid 24-methyl ester (4) White powder; 1H NM R (pyridine-d5, 500 MHz):  5.69 (1H, s, H-12), 4.51 (1H, dd, 12.0, 4.0, H-3),

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4.44 (1H, s, H-6), 3.60 (3H, s, 24-OCH 3), 3.13 (1H, dt, 13.0, 4.0 Hz, H-16), 3.10 (1H, s, H-18), 2.17 (3H, s, H-23), 1.73 (3H, s, H-25), 1.70 (3H, s, H-26), 1.65 (3H, s, H-27), 1.48 (3H, s, H-28), 1.15 (3H, s, H-29), 1.13 (3H, d, 7.5 Hz, H-30); 13 C NM R (Pyridine-d5, 125 M Hz): 41.6 (C-1), 28.4 (C-2), 76.7 (C-3), 56.4 (C-4), 54.0 (C-5), 71.3 (C-6), 42.2 (C-7), 40.8 (C-8), 49.1 (C-9), 37.2 (C-10), 24.6 (C-11), 128.7 (C-12), 139.8 (C-13), 43.1 (C-14), 29.8 (C-15), 26.9 (C-16), 48.8 (C-17), 55.2 (C-18), 73.3 (C-19), 42.8 (C-20), 27.4 (C-21), 38.9 (C-22), 13.6 (C-23), 179.5 (C-24), 17.8 (C-25), 18.8 (C-26), 25.2 (C-27), 181.1 (C-28), 27.6 (C-29), 17.2 (C-30), 52.0 (24-OCH 3). 3 , 6 , 19α, 24-Tetrahydroxy-urs-12-en-28-oic acid (5) White powder; 1H NM R (CD 3OD, 500 M Hz):  5.31 (1H, brs, H-12), 4.38 (1H, br s, H-6), 3.59 (1H, d, 11.0 Hz, H-24a), 3.55 (1H, dd, 12.0, 4.0, H-3), 3.46 (1H, d, 11.0 Hz, H-24b), 2.55 (1H, dt, 13.0, 4.5 Hz, H-16), 2.51 (1H, s, H-18), 1.31 (3H, s, H-23), 1.30 (3H, s, H-25), 1.19 (3H, s, H-26), 1.07 (3H, s, H-27), 1.06 (3H, s, H-29), 0.92 (3H, d, 6.5 Hz, H-30); 13 C NM R (CD 3OD, 125 M Hz): 41.6 (C-1), 27.7 (C-2), 74.2 (C-3), 44.3 (C-4), 50.1 (C-5), 69.0 (C-6), 41.8 (C-7), 40.3 (C-8), 49.2 (C-9), 37.5 (C-10), 24.7 (C-11), 129.9 (C-12), 139.4 (C-13), 43.2 (C-14), 29.7 (C-15), 26.8 (C-16), 49.8 (C-17), 55.3 (C-18), 73.8 (C-19), 49.0 (C-20), 27.2 (C-21), 39.1 (C-22), 14.1 (C-23), 67.2 (C-24),17.8 (C-25), 18.6 (C-26), 24.9 (C-27), 182.4 (C-28), 27.4 (C-29), 16.7 (C-30). Rotundic acid (6) White powder; 1H NM R (CD 3OD, 500 MHz):  5.30 (1H, s, H-12), 3.60 (1H, dd, 10.0, 5.0, H-3), 3.52 (1H, d, 10.0 Hz, H-24a), 2.56 (1H, dt, 13.0, 4.5 Hz, H-16), 2.48 (1H, s, H-18), 1.33 (3H, s, H-27), 1.18 (3H, s, H-29), 0.96 (3H, s, H-25), 0.92 (3H, d, 7.0 Hz, H-30), 0.79 (3H, s, H-23), 0.70 (3H, s, H-26); 13C NM R (CD 3OD, 125 MHz): 41.2 (C-1), 27.6 (C-2), 74.5 (C-3), 42.8 (C-4), 43.4 (C-5), 16.9 (C-6), 33.8 (C-7), 39.6 (C-8), 50.4 (C-9), 38.0 (C-10), 24.8 (C-11), 129.6 (C-12), 140.1 (C-13), 43.2 (C-14), 29.7 (C-15), 26.8 (C-16), 49.8 (C-17), 55.2 (C-18), 73.8 (C-19), 49.0 (C-20), 27.2 (C-21), 39.1 (C-22), 68.0 (C-23), 12.8 (C-24), 17.7 (C-25), 19.4 (C-26), 24.9 (C-27), 182.3 (C-28), 27.4 (C-29), 16.7 (C-30). 23-Nor-24-exomethylene-3β, 6β, 19α-trihydroxy-urs12-en-28-oic acid (7) White powder; 1H NM R (pyridine-d5, 500 MHz):  6.08 (1H, s, H-23), 6.02 (1H, s, H-23), 5.73 (1H, s, H-12), 4.77 (1H, s, H-6), 3.36 (1H, dd, 11.0, 5.0, H-3), 3.12 (1H, dt, 13.5, 4.5 Hz, H-16), 3.12 (1H, s, H-18), 1.50 (3H, s, H-25), 1.46 (3H, s, H-26), 1.80 (3H, s, H-27), 1.78 (3H, s, H-29), 1.14 (3H, d, 7.5 Hz, H-30); 13C NMR (Pyridine-d5, 125 MHz): 40.8 (C-1), 33.9 (C-2), 73.2 (C-3), 153.7 (C-4), 53.3 (C-5), 70.0 (C-6), 40.9 (C-7), 38.8 (C-8), 46.4 (C-9), 39.2 (C-10), 25.2 (C-11), 129.3 (C-12), 140.1 (C-13), 42.9 (C-14), 27.4 (C-15),

25.5 (C-16), 48.9 (C-17), 55.5 (C-18), 73.6 (C-19), 41.8 (C-20), 27.0 (C-21), 43.6 (C-22), 105.8 (C-23), 17.2 (C-25), 19.5 (C-26), 27.6 (C-27), 181.0 (C-28), 29.7 (C-29), 17.1 (C-30). Pololic acid (8) White powder; 1H NMR (DM SO, 500 MHz):  5.15 (1H, br s, H-12), 4.27 (1H, d, 7.0 Hz, 3-OH), 3.73 (1H, s, 19-OH), 3.00 (1H, m, H-3), 2.35 (1H, s, H-18), 1.27 (3H, s, H-27), 1.06 (3H, s, H-29), 0.88 (3H, s, H-23), 0.84 (3H, s, H-25), 0.83 (3H, d, 7.0 Hz, H-30), 0.69 (3H, s, H-26), 0.67 (3H, s, H-24); 13C NM R (DM SO, 125 MHz): 39.5 (C-1), 28.2 (C-2), 77.0 (C-3), 38.5 (C-4), 55.0 (C-5), 18.2 (C-6), 32.8 (C-7), 41.2 (C-8), 47.0 (C-9), 37.3 (C-10), 24.0 (C-11), 126.9 (C-12), 138.7 (C-13), 41.5 (C-14), 28.4 (C-15), 26.5 (C-16), 46.8 (C-17), 53.3 (C-18), 71.8 (C-19), 38.3 (C-20), 27.1 (C-21), 36.7 (C-22), 26.0 (C-23), 16.7 (C-24), 16.4 (C-25), 16.1 (C-26), 23.2 (C-27), 179.0 (C-28), 25.3 (C-29), 15.2 (C-30).

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Cite this article as: CAO Xing-Fen, WANG Jun-Song, WANG Peng-Ran, KONG Ling-Yi. Triterpenes from the stem bark of Mitragyna diversifolia and their cytotoxic activity [J].Chinese Journal of Natural Medicines, 2014, 12 (8): 628-631.

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Triterpenes from the stem bark of Mitragyna diversifolia and their cytotoxic activity.

To study the chemical constituents and bioactivity of the stem bark of Mitragyna diversifolia...
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