advpub_c15-00055

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE DOI:10.1248/cpb.c15-00055

2015 The Pharmaceutical Society of Japan

Advance Publication

March 12, 2015

Chem. Pharm. Bull.

Note

Catunaroside I-L, Four New Triterpenoid Saponins from the Stem Bark of

Catunaregam Spinosa

Jun Li,b Xuan Huang,

a Xiao-Hong Jiang,

a Qi-Feng Zhu,

a Yun Yang,

a and

Guang-Chun Gao *

,a

a Key Laboratory of Natural Medicine and Health Food R & D Technology, College of

Medicine, Jiaxing University; NO.118, JiaHang Road, Jiaxing 314001, P. R. China: b Jiaxing

Academy of Agricultural Sciences;ShuangQiao Road, Jiaxing 314016, P. R. China.

* To whom correspondence should be addressed. E-mail: [email protected]

Chemical and Pharmaceutical Bulletin Advance Publication

Abstracts: Four new triterpenoid saponins, Catunaroside I

[3-O--D-glucopyranosyl-(13)--D-glucopyranosyl-arjunic acid

28-O--D-glucopyranoside] (1), Catunaroside J

[3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D -glucopyranosyl-arjunic

acid 28-O--D-glucopyranoside] (2), Catunaroside K

[3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucopyranosyl-tormenti

c acid] (3), and Catunaroside L

[3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucopyranosyl-pomolic

acid] (4), and two known triterpenoid saponin Arjunetoside (5) and RandiasaponinVII (6),

were isolated from the stem bark of Catunaregam spinosa. Their structures were elucidated

on the basis of their spectral data and chemical evidence.

Key words: Catunaroside I-L, triterpenoid saponin, Catunaregam spinosa, Rubiaceae.


Catunaregam spinosa T. (Rubiaceae), distributed in tropical and semitropical areas, was

known as a folk medicine in India and Brazil for its antispasmodic, antidysenteric,

anti-inflammatory, immunomodulatory and antifertility properties.1-4)

Many phytochemical

research has been done on this plant, and coumarin glucosides,5)

iridoid glucosides, 1)

and

triterpenoid saponins4, 6, 7)

were found. Our previous investigations on this plant had led to the

isolation of iridioid,8)

norneolignans,9)

triterpenoid saponins.10, 11)

In continuation of our

studies on the plants, four new triterpenoid saponins, Catunaroside I-L, together with

Arjunetoside and RandiasaponinVII, were isolated from the n-BuOH extract of its stem bark

by preparative HPLC. The isolation and structure determination of those triterpenoid saponins

were elucidated in this paper.

Results and Discussion

Compound 1 was obtained as a colorless amorphous powder. The molecular formula

C48H78O20 was determined by a combination of NMR spectra and HR-ESI-MS which

exhibited a molecular ion peak at m/z: 997.4980 [M + Na] + (Calcd for C48H78O20Na:

977.4984). On acid hydrolysis, 1 afforded only glucose as sugar moiety that was identical to

an authentic sample by Silica gel TLC. The IR spectrum showed absorption bands at 3417

cm 1

(OH), 1726 cm 1

(C = O), 1643 cm 1

(C = C). The 13

C-NMR spectrum exhibited 48

signals, of which 30 were assigned to the aglycone moiety and 18 to the sugars. In the

1H-NMR spectrum, seven methyl protons ( 1.37, 1.05, 0.96, 1.14, 1.63, 1.14 and 0.98 ppm;

each 3H, s), one olefinic methine proton ( 5.49, br s), and three anomeric protons ( 4.91, d,

8.0 Hz; 5.29, d, 7.5Hz; 6.38, d, 8.0 Hz) were observed. The 13

C-NMR spectrum also showed


seven methyl carbons at 28.4, 18.0, 16.6, 17.6, 24.9, 28.7 and 24.6 ppm, two olefinic

carbons at 122.9 and 144.3 ppm, three oxygenated methine carbons at 66.6, 95.7 and 81.0

ppm, and three anomeric carbons at 106.0, 105.9 and 95.9. Based on the above data, it was

deduced that 1 was an olean-12-ene type triterpenoid glycoside with three units of glucose.

The comparison of 1H- and

13C-NMR spectrum data of aglycone part of 1 with that of arjunic

acid 12)

indicated that compound 1 possessed a 2, 3, 19-trihydroxyolean-12-ene-28-oic

acidic aglycone. The chemical shifts of C-3 ( 95.7) and C-28 ( 177.2) 13) implied that 1 was

a 3, 28-bisdesmosidic glycoside. This hypothesis was also in agreement with the relatively

downfield shifts of anomeric protons ( 4.91, 6.38 ppm) and the corresponding upfield shifts

of anomeric carbons ( 106.0, 95.9 ppm). In the HMBC spectrum, significant correlations

between signals at 4.91(H-1) and 95.7 (C-3), 5.29 (H-1) and 88.9 (C-3), and 6.37

(H-1) and 177.2 (C-28) were observed. The -anomeric configurations of glucose units

were determined by the relatively large 3JH1, H2 coupling constants (7.5-8.0 Hz). Considering

above information compound 1 was elucidated as

3-O--D-glucopyranosyl-(13)--D-glucopyranosyl-arjunic acid

28-O--D-glucopyranoside.

Compound 2, a colorless amorphous powder, was analyzed to have the molecular formula

of C54H88O25 by its HR-ESI-MS spectrum (m/z: 1159.5563 [M + Na] +). Acid hydrolysis of 2

afforded glucose as the only sugar unit. The 13

C-NMR spectrum revealed 54 signals, of which

30 were assigned to the aglycone and 24 to the sugars. The 1H-NMR spectrum showed seven

methyl protons ( 1.28, 1.18, 0.92, 1.12, 1.60, 1.14, 0.97 ppm; each 3H, s), one olefinic


methine proton ( 5.47, br s), and four sugar anomeric protons ( 4.82, d, J = 7.5 Hz; 5.38, d,

J = 7.5 Hz; 5.85, d, J = 7.5 Hz; 6.37, d, J = 8.0 Hz). The signals of seven methyl carbons at

28.2, 17.6, 16.7, 17.7, 24.9, 28.7 and 24.7 ppm, two olefinic methine carbons at 123.1 and

144.3 ppm, four sugar carbons at 104.5, 104.6, 103.6 and 95.9 ppm, and two carbons at

177.3 and 96.5 ppm linked to glycan part were also observed in the 13

C-NMR spectrum. The

above evidence revealed that 2 was a bisdesmosidic glycoside. And the aglycone part of this

compound was determined as 2, 3, 19-trihydroxyolean-12-ene-28-oic acid comparing the

1H and

13C NMR signals of 2 with those of 3-O--D-glucopyranosyl-2, 3,

19-trihydroxyolean-12-en-28-oic acid-28-O--D-glucopyranoside. 12) According to the 1H

and 13

C-NMR signals, the aglycone and sugar moieties of 2 were assigned based on the

2D-NMR spectra, and the exact glycosidic linkages were unambiguously confirmed by the

following HMBC correlations between H-1 ( 6.37) of a glucose and C-28 ( 177.3) of

aglycone part; H-1 ( 4.82) of the inner glucose and C-3 ( 96.5) of aglycone part; H-1 (

5.38) of the 3-O-glucose and C-3 ( 88.9) of inner glucose; H-1 ( 5.85) of the

2-O-glucose and C-2 ( 78.3) of inner glucose. The -anomeric configurations of the glucose

units were established by its 3JH1, H2 coupling constants (7.5-8.0 Hz). On the basis of above

results compound 2, named as Catunaroside J, was determined as

3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucopyranosyl-arjunic

acid 28-O--D-glucopyranoside.

Compound 3, also an amorphous powder, has the molecular formula of C48H78O20 as

indicated from its HR-ESI-MS (m/z 997.5001 [M + Na]+) spectrum. Acid hydrolysis implied


that compound 3 only contained glucose by comparing Rf value with that of authentic sample.

The 13

C-NMR spectrum revealed 48 signals, of which 30 were assigned to the aglycone and

18 to the sugars. The 1H-NMR spectrum exhibited signals for seven methyl protons ( 1.28 s,

1.17 s, 0.88 s, 1.06 s, 1.70 s, 1.43 s and 1.12 d J= 6.5 Hz), one olefinic methine proton ( 5.56,

br s) and three sugar anomeric protons ( 4.82, d, J = 7.5 Hz; 5.38, d, J = 7.5 Hz; 5.85, d, J =

8.0 Hz). In the 13

C-NMR spectrum, the signals of seven methyl carbons at 28.2, 17.8, 16.6,

17.2, 24.7, 27.1 and 16.8 ppm, two olefinic methine carbons at 128.0 and 139.9 ppm, three

sugar carbons at 104.4, 104.7 and 103.6 ppm were observed. The above evidence suggested

that 3 may be an urs-12-ene type triterpenoid glycoside with three glucose residue. The NMR

characteristic carbon signals ( 66.6, 72.8 ppm) and proton signal ( 1.12 d J= 6.5 Hz)

suggested that the aglycone part was tormentic acid, then it was proved by comparing with

NMR data from reference.14)

The carbon signals in 13

C-NMR spectrum at 96.4 (C-3) and

180.6 (C-28) inferred compound 3 was a 3-O-monodesmosidic saponin. The -anomeric

configurations of the glucose units were established according to its 3JH1, H2 coupling

constants (7.5-8.0 Hz). The sequence of the glycan part connected to C-3 of the aglycone was

deduced from the following HMBC correlations: H-1 ( 4.82) of inner glucose with C-3 (

96.4) of aglycone part, H-1 ( 5.38) of 3-O-glucose with C-3 ( 88.9), and H-1 ( 5.85) of

2-O-glucose with C-2 ( 78.3). From the above evidence, compound 3 was identified as

3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucopyranosyl-tormentic

acid, named as Catunaroside K.


Compound 4, obtained as an amorphous powder, was deduced to have the molecular

formula C48H78O19 as indicated from HR-ESI-MS (m/z: 981.5080 [M + Na]+) data. The IR

spectrum showed the presence of C=O group at 1741 cm-1

and a C=C group at 1659 cm-1

. The

1H-NMR spectrum revealed signals due to seven methyl protons ( 1.25 s, 1.20 s, 0.80 s, 1.02

s, 1.74 s, 1.45, s and 1.07 d, J = 7.0 Hz), an olefinic proton ( 5.59 br s) and three anomeric

protons ( 4.84, d, J = 7.6 Hz; 5.38, d, J = 7.6 Hz; 5.73, d, J = 7.6 Hz). The corresponding

signals at 28.0, 16.7, 15.5, 17.2, 24.7, 27.2 and 16.8 (seven methyl carbons) ppm, 128.0

and 140.0 (an olefinic carbons) ppm, and 105.1, 104.7 and 103.8 (three anomeric carbons)

ppm were also observed in 13

C-NMR spectrum. Based on above observations, the NMR

signals of 4 were in good agreement with those of sibiricasaponins B (pomolic acid

3-O-(3-O-sulfo)--L-arabinopyranoside) 15) except for the signals of 3-O-substituted sugar

moieties. Acid hydrolysis of 4 showed the only existence of glucose. The exact sugar

arrangement was determined to be

3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucose according to the

reported NMR data of aralia saponin V. 16)

The conclusion was then proved by the HMBC

correlations between signals at 4.84 (H-1) of inner glucose and 96.4 (C-3) of aglycone

part, 5.38 (H-1) of 3-O-glucose and 88.6 (C-3), and 5.73 (H-1) of 2-O-glucose and

79.3 (C-2). Thus compound 4 was elucidated as

3-O--D-glucopyranosyl-(12)-[-D-glucopyranosyl-(13)]--D-glucopyranosyl-pomolic

acid, named as Catunaroside L.


Compound 5 and 6 were elucidated as Arjunetoside and RandiasaponinVII separately by

comparison of their spectrum data with data reported in the literatures (IR, MS, 1H and

13C-NMR).

12, 17)

Experimental

General

Silica gel (100-200 mesh and 200-300 mesh, Qingdao Haiyang Chemical Co., Ltd.),

Macroporous resin D101, Lichroprep RP-18 (Merck) and Sephadex LH-20 (Pharmacia) were

used for column chromatography. TLC was performed on precoated silica gel 60 F254 plates

(Qingdao Haiyang Chemical Co., Ltd.), and detection was achieved by 10% H2SO4-EtOH.

Semipreparative HPLC was carried out using an ODS column (YMC-Pack ODS-5-A, 250

10 mm i.d., 5m; YMC) on a Waters-600 HPLC system equipped with a Waters-996

photodiode array detector. IR spectra were measured with a Bruker EQUINOX55 infrared

spectrometer. 1

H and 13

C-NMR spectra were recorded on a Bruker DRX-500 spectrometer

(SiMe4 as internal standard). MS were obtained on MDS SCIEX API 2000 LC/MS/MS

instrument for ESI and Bruker BioTOF Q spectrometer for HR-ESI. GC analysis were done

on Agilent 1200 with HP-5 column (0.32 mm30 mm, 0.25 m) and 1200 FID detector.

Plant Material

The stem bark of C. spinosa, collected from Sanya, Hainan Province, P.R.China in

February 2006, was identified by professor Si Zhang (South China Sea Institute of

Oceanology, Chinese Academy of sciences). And a voucher specimen has been deposited in


the South China Sea Institute of Oceanology, Chinese Academy of Sciences (accession

number: GKLMMM020).

Extraction and Isolation

The n-BuOH extract (170 g), obtained from air-dried and powered plant material using

method reported previously9)

, was passed through a macroporous resin (D101) column eluted

with H2O and EtOH-H2O (30:70, 60:40, 95:5) in turn. The EtOH-H2O (60:40) eluted portion

(35 g) from n-BuOH soluble fraction was subjected to silica gel CC eluted with

CHCl3-MeOH (90:10-50:50) to give fractions a-f. Fraction b was separated by Sephadex

LH-20 eluting with MeOH, then fractions 2-10 and 11-20 were purified by preparative HPLC

eluting with MeOH-H2O (45:55) and MeOH-H2O (50:50) to obtain compounds 1 (15 mg), 5

(12 mg) and 6 (12 mg) separately; Fraction f was rechromatographed to silica gel CC eluted

with CHCl3-MeOH-H2O (80:20:5), then fraction 12 was purified by preparative HPLC using

MeOH-H2O (48:52) to yield compound 2 (21 mg); The EtOH-H2O (95:5) eluted portion (10 g)

was subjected to silica gel CC eluted with CHCl3-MeOH (98:2-50:50) to give fractions A-G.

Fraction E was purified by sephadex LH-20 (MeOH), then separated by preparative HPLC to

obtain compound 3 (19 mg) using MeOH-H2O (65:35) and compound 4 (10 mg) using

MeOH-H2O (68:32).

Catunaroside I (1)

Colorless amorphous powder, []20D = + 12.7 (c = 0.5, MeOH). IR (KBr, cm1

) max: 3417,

1726, 1643. 1H-NMR (500 MHz, pyridine-d5) and

13C-NMR (125 MHz, pyridine-d5) data: see


table 1 and table 2. ESIMS m/z: 997 [M + Na]+, 1013 [M + K]

+. HR-ESI-MS m/z: 997.4980

[M + Na]+ (Calcd for C48H78O20Na, 997.4984).

Catunaroside J (2)


) max: 3420,



table 1 and table 2. ESI-MS m/z: 1159[M + Na]+. HR-ESI-MS m/z: 1159.5563 [M + Na]

+

(Calcd for C54H88O25Na, 1159.5512).

Catunaroside K (3)


) max: 3419,



table 1 and table 2. ESI-MS m/z: 997 [M + Na]+, 1013 [M + K]

+. HR-ESI-MS m/z: 997.5001


Catunaroside L (4)


) max: 3422,



table 1 and table 2. ESI-MS m/z: 981 [M + Na]+, 997 [M + K]

+. HR-ESI-MS m/z: 981.5080


Acid Hydrolysis of 1-6 and determination of the absolute configuration of glucoses.


Acid hydrolysis of Compounds 1-6 was done using the method reported previously. 10)

The

sugars were identified by comparing of the Rf value with that of glucose on TLC plate eluted

with CHCl3-MeOH-H2O (8:7:1) solvent system, visualized with ethanol-10% H2SO4 spraying

and then heating. The sugar residue and the authentic samples of D-glucose and L-glucose

were dissolved in 0.2 ml anhydrous pyridine and L-cysteine methyl ester hydrochloride, then

warmed at 60oC for 1 h. The trimethylsilylation reagent trimethylsilylimidazole was added,

followed by warming at 60oC for 1 h. After drying the residue was partition between H2O and

cyclohexane. The cyclohexane layer was analyzed by GC using a HP-5 column. The

temperatures of the injector and detector were 270 and 280 oC, respectively. A temperature

gradient system used for the oven was started with 160 oC for 4 min and increased up to 240

oC at a rate of 6

oC/min. The retention time (24.15 min) of sugar residue were the same with

that of D-glucose.

Acknowledgments

This work was financially supported by the Grant of the 12th Five-year Plan for University

Key Academic Subject (Pharmacology), Zhejiang Province, CHINA, the Science and

Technology Program of Jiaxing (2013AY21047) and the 2011 Annual Jiaxing Key Science

and Technology Innovation Team.

Conflict of Interest

The authors declare no conflict of interest.


References

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(1989).

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53, 530-531 (1987).

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542-544 (2008).

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Acta., 93, 339-344 (2010).

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2200-2205 (2011).

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Prod. Res., 3, 207-212 (2001).

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H., Tokuda H., Nishino H., Sugita D., Shimura S., Yoshida T., Phytochemistry, 59

315-323 (2002).

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Table 1. Selected 1H-NMR Spectroscopic Data of 1-4 in Pyridine-d5 (500, 125MHz )

Table 2. 13

C-NMR Spectroscopic Data of 1-4 in Pyridine-d5 (500, 125MHz )

Fig. 1. Structures of Compounds 1-6


Table 1. Selected 1H-NMR Spectroscopic Data of 1-4 in Pyridine-d5 (500, 125MHz )

Position 1 2 3 4

2 4.00 3.94 3.93 2.04 m

3 3.24 (d, 9.5) 3.14 (d, 9.0) 3.16 (d, 9.0) 3.28 (dd, 4.4, 11.5)

12 5.49 (br s) 5.47 (br s) 5.54 (br s) 5.59 (br s)

18 3.53 (br s) 3.51 (br s) 3.03 (br s) 3.05 (br s)

19 3.57(br s) 3.55(br s)

23 1.37 (s) 1.28 (s) 1.28 (s) 1.25 (s)

24 1.05 (s) 1.18 (s) 1.17 (s) 1.20 (s)

25 0.96 (s) 0.92 (s) 0.88 (s) 0.80 (s)

26 1.14 (s) 1.12 (s) 1.06 (s) 1.02 (s)

27 1.63 (s) 1.60 (s) 1.70 (s) 1.74 (s)

29 1.14 (s) 1.14 (s) 1.43 (s) 1.45 (s)

30 0.98 (s) 0.97 (s) 1.12 (d, 6.5) 1.07 (d, 7.0)

3-O-

1 4.91 (d, 8.0) 4.82 (d, 7.5) 4.82 (d, 7.5) 4.84 (d, 7.6)

2 4.09 4.42 4.41 4.42

3 4.23 4.26 4.27 4.25

4 4.10 4.00 3.99 4.01

5 4.22 3.93 3.92 3.92

6 4.42, 4.53 4.31, 4.48 4.31, 4.49 4.30, 4.48

3-O-

1 5.29 (d, 7.5) 5.38 (d, 7.5) 5.38 (d, 7.5) 5.38 (d, 7.6)

2 4.12 4.21 4.32 4.28

3 4.30 4.22 4.23 4.25

4 4.19 4.16 4.16 4.17

5 4.25 4.28 4.31 4.30

6 4.42, 4.53 4.43, 4.53 4.47, 4.54 4.42, 4.55

2-O-

1 5.85 (d, 7.5) 5.85 (d, 8.0) 5.73 (d, 7.6)

2 4.06 4.06 4.04

3 4.15 4.16 4.15

4 3.93 3.92 3.98

5 3.92 3.91 3.90

6 4.18, 4.26 4.18, 4.26 4.17, 4.26

28-O-

1 6.38 (d, 8.0) 6.37 (d, 8.0)

2 4.23 4.22

3 4.04 4.05

4 4.38 4.36

5 4.37 4.30

6 4.25,4.32 4.43, 4.53

Overlapped proton signals are reported without designated multiplicity.


Table 2. 13C-NMR Spectroscopic Data of 1-4 in Pyridine-d5 (500, 125MHz )

Position 1 2 3 4 Position 1 2 3 4

1 47.0 47.1 47.4 38.8 3-O-

2 66.6 66.6 66.6 26.4 1 106.0 104.5 104.4 105.1

3 95.7 96.5 96.4 89.5 2 75.5 78.3 78.3 79.3

4 40.7 41.0 40.3 39.6 3 88.8 88.9 88.9 88.6

5 55.7 55.8 55.7 55.9 4 69.7 69.9 69.9 70.1

6 18.7 18.8 18.7 18.6 5 78.1 78.0 78.0 77.7

7 33.0 33.1 33.4 33.5 6 62.2 63.5 63.5 63.4

8 40.2 40.2 40.9 40.3 3-O-

9 48.2 48.3 47.7 47.7 1 105.9 104.6 104.7 104.7

10 38.0 38.0 37.8 36.9 2 74.3 74.2 76.2 76.4

11 24.2 24.2 24.0 24.0 3 78.7 78.7 78.7 78.6

12 122.9 123.1 128.0 128.0 4 71.6 71.6 71.6 71.6

13 144.3 144.3 139.9 140.0 5 78.3 78.8 78.8 78.6

14 42.2 42.2 42.4 42.4 6 62.2 62.2 62.2 62.6

15 29.0 29.0 29.3 29.3 2-O-

16 28.0 28.0 26.4 26.4 1 103.6 103.6 103.8

17 46.5 46.5 48.3 48.3 2 75.5 75.5 75.4

18 44.6 44.6 54.6 54.6 3 78.6 78.6 78.6

19 81.0 81.1 72.8 72.7 4 72.8 72.7 72.7

20 35.5 35.6 42.1 42.1 5 77.9 77.9 77.8

21 28.9 29.0 26.9 27.0 6 62.4 62.3 62.4

22 33.1 33.2 38.5 38.5 28-O-

23 28.4 28.2 28.2 28.0 1 95.9 95.9

24 18.0 17.6 17.8 16.7 2 74.1 74.2

25 16.6 16.7 16.6 15.5 3 78.9 79.0

26 17.6 17.7 17.2 17.2 4 71.1 71.1

27 24.9 24.9 24.7 24.7 5 79.3 79.3

28 177.2 177.3 180.6 180.7 6 62.5 62.2

29 28.7 28.7 27.1 27.2

30 24.6 24.7 16.8 16.8


Fig. 1. Structures of Compounds 1-6

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