Paratrimerins A and B, Two New Dimeric Monoterpene-Linked Coumarin Glycosides from the Roots and Stems of Paramignya trimera

Abstract

Two new dimeric monoterpene-linked coumarin glucosides, paratrimerins A (1) and B (2), and three known coumarins, 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7-hydroxycoumarin (3), ostruthin (4), and ninhvanin (5), were isolated from the roots and stems of Paramignya trimera (OLIV.) GUILL. collected in Khanh Hoa province, Vietnam. Compound 1 comprises two 7-O-β-D-glucopyranoside coumarins linked at positions 6,6′ via a 1,3,4,4-tetrasubstituted cyclohexene containing a monoterpene bridge, whereas compound 2 is a β-D-apiofuranosyl(1→6)-β-D-glucopyranosyl derivative of 1. The chemical structures of these compounds were determined by one dimensional (1D) and 2D-NMR and high resolution-electrospray ionization (HR-ESI)-MS spectroscopy.

Paramignya is a genus (ca. 28 species)¹⁾ belonging to the Rutaceae family. Since the 1990 s, phytochemical studies have focused on two species, P. monophylla and P. griffithii. While flavanones, triterpenoid, and chromene derivatives have been isolated from the stems of P. griffithii,²⁾ tirucallane-triterpene and several new coumarins have been found in P. monophylla fruits³⁾ and stem bark.⁴⁾ In Vietnam, seven Paramignya species have been identified, distributed mostly in the South of the country.⁵⁾ Paramignya trimera (OLIV.) GUILL., local name “Than duoc” or “Xao tam phan,” is an endemic plant in South Vietnam. The stems and roots of the plant have been used in folk medicine to treat liver disease, especially cirrhotic ascites.⁶⁾ In the search for new natural compounds with biological activities relative to the treatment of liver disease, we isolated and structurally elucidated two new dimeric coumarin glycosides, namely paratrimerins A (1) and B (2), along with three known coumarins, 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7-hydroxycoumarin (3), ostruthin (4), and ninhvanin (5), from the roots and stems of P. trimera. Although monoterpene-linked biscoumarins have recently been isolated from rutaceous plants,^7–9)compounds 1 and 2 are the first monoterpene-linked biscoumarin glycosides isolated from nature.

Results and Discussion

Compound 1 was obtained as a white amorphous powderwith a negative optical rotation ([α]_D²⁵ −25.0°, c=0.02, MeOH). Its molecular formula was determined to be C₄₀H₄₄O₁₆ based on the quasi-molecular ion peak observed at m/z 781.2691 [M+H]⁺ (Calcd for C₄₀H₄₅O₁₆^±, 781.2702) and m/z 803.2548 [M+Na]⁺ (Calcd for C₄₀H₄₄O₁₆Na^±_, 803.2522) in the positive high resolution-electrospray ionization (HR-ESI)-MS spectrum. A further fragment ion was identified at m/z 457.1637 ([M−2×C₆H₁₀O₅+H]⁺, Calcd for C₂₈H₂₅O₆^±, 457.1646), indicating the presence of two glycosyl moieties in 1. The IR spectrum had bands at ν_max 3379, 1722 cm⁻¹, ascribable to hydroxyls and lactone carbonyl groups, respectively. The UV spectrum showed absorbtion maxima, λ_max at 204, 256, 292, and 330 nm, characteristic of a 7-oxygenated coumarinchromophore.⁷⁾ The ¹³C-NMR/distortionless enhancement by polarization transfer (DEPT) spectra of 1 (CD₃OD) contained 40 carbon signals (12×C, 22×CH, 4×CH₂, 2×CH₃), assignable to two glucosyl moieties, two coumarin nuclei, and a monoterpene ring (Table 1, Fig. 1). Its ¹H-NMR spectrum of 1, displayed patterns similar to those of ostruthin,⁶⁾ with characteristic signals of two pairs of cis-located olefinic protons H-3/H-4 and H-3′/H-4′ (d, J=9.5 Hz, each), as well as two pairs of para-singlet aromatic protons H-5/H-8, and H-5′/H-8′ (s, each), indicative of two 6,7-disubstituted coumarin nuclei. The structures of two coumarin nuclei in 1 were confirmed based on analysis of heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), correlation spectroscopy (COSY) and nuclear Overhauser effect spectroscopy (NOESY) spectra (Table 1, Fig. 2). Two anomeric proton signals in 1 were observed at δ_H 4.99 (d, H-1″) and δ_H 4.93 (d, H-1‴) (each J=8.0 Hz), together with six pair-wise carbon signals at δ_C 101.6 (C-1″)/102.5 (C-1‴), 74.8 (C-2″)/75.0 (C-2‴), 78.2 (C-3″)/78.3 (C-3‴), 71.7 (C-4″)/71.2 (C-4‴), 78.4 (C-5″)/78.4 (C-5‴) and 62.7 (C-6″)/62.5 (C-6‴) (Table 1). This indicated the presence of two glucosyl moieties in the β-D-configuration.¹⁰⁾ The positions of the glucopyranosyl moieties at oxygenated carbons C-7/C-7′ of the two coumarin rings was determined based on the HMBC correlations (Fig. 2) between the anomeric protons H-1″ (δ_H 4.99, d, J=8.0 Hz) and H-1‴ (δ_H 4.93, d, J=8.0 Hz) to carbons C-7 (δ_C 158.3) and C-7′ (δ_C 160.0), respectively (Table 1, Fig. 2). The NOESY spectra of 1 also confirmed the location of two sugar units based on the cross-peaks from the anomeric protons H-1″ and H-1‴ to the singlet aromatic protons H-8 and H-8′, respectively (Fig. 2). The structure of the monoterpene (C₁₀) bridge, determined as an 1,4-dimethyl-4-vinylcyclohexene, was similar to that of some monoterpene-linked biscoumarins isolated from other rutaceous species, such as bisparasin⁷⁾ from Citrus paradise and thamnosin¹¹⁾ from Thamnosma montana. The coupling constant ³J_9,10=16.5 Hz was indicative of two vicinal protons H-9 (δ_H 6.41) and H-10 (δ_H 6.37) in the trans-position⁷⁾ (Fig. 2). Furthermore, the monoterpene bridge attached to two glucopyranosyl coumarin units at the non-protonated carbons C-6 (δ_C 127.7) and C-6′ (δ_C 131.6) could be directly determined based on the HMBC cross-peaks (³J-correlations) from the coumarinic protons H-5 (δ_H 7.47) and H-5′(δ_H 7.39) to the tertiary carbons of the vinylcyclohexene moiety C-9 (δ_C 121.2) and C-9′ (δ_C 44.3), respectively (Table 1, Fig. 2). Furthermore, two coumarinic protons H-5 and H-5′ have NOESY interactions with the vinylic proton H-9 (δ_H 6.41) and methine proton H-9′ (δ_H 4.13), respectively. These above spectroscopic evidences confirmed the linkage at C-6/C-9 and C-6′/C-9′ between the two glucosidic coumarins and the 1,4-dimethyl-4-vinylcyclohexene moiety.

Table 1. ¹H- and ¹³C-NMR Data of (−)-Paratrimerin A (1); (−)-Paratrimerin B (2)

Position	Compound (1)		Compound (2)
	13C-NMR	1H-NMR	13C-NMR	1H-NMR
2	163.3 (s)	—	163.3 (s)	—
3	114.3 (d)	6.28, d, 9.5 Hz	114.5 (d)	6.32, d, 9.5 Hz
4	146.0 (d)	7.95, d, 9.5 Hz	146.1 (d)	7.91, d, 9.5 Hz
4a	115.2 (s)	—	115.3 (d)	—
5	126.6 (d)	7.47, s	126.4 (d)	7.42, s
6	127.7 (s)	—	127.7 (s)	—
7	158.3 (s)	—	158.5 (s)	—
8	104.0 (d)	7.03, s	104.2 (d)	7.07, s
8a	155.2 (s)	—	155.1 (s)	—
2′	163.5 (s)	—	163.9 (s)	—
3′	114.1 (d)	6.22, d, 9.5 Hz	114.0 (d)	6.25, d, 9.5 Hz
4′	145.9 (d)	7.88, d, 9.5 Hz	146.0 (d)	7.91, d, 9.5 Hz
4′a	114.4 (s)	—	114.4 (s)	—
5′	131.0 (d)	7.39, s	131.0 (d)	7.39, s
6′	131.6 (s)	—	131.5 (s)	—
7′	160.0 (s)	—	160.0 (s)	—
8′	103.6 (d)	7.09, s	103.8 (d)	7.18, s
8′a	155.0 (s)	—	155.2 (s)	—
1,3,4,4,-Tetrasubstituted cyclohexene bridge
9	121.2 (d)	6.41, d, 16.5 Hz	121.0 (d)	6.49, d, 16.5 Hz
10	140.9 (d)	6.37, d, 16.5 Hz	140.9 (d)	6.23, d, 16.5 Hz
11	40.2 (s)	—	40.0 (s)	—
12	31.9 (t)	1.65, dt-like, 13.3, 5.9 Hz, 1.87, m, part. overlapped	31.7 (t)	1.61, dt-like, 13.3, 5.9 Hz, 1.83, m, part. overlapped
11-CH3	25.8 (q)	1.31, br s	25.3 (q)	1.33, br s
9′	44.3 (d)	4.13, s	44.3 (d)	4.11, s
10′	124.6 (d)	5.35, s	124.4 (d)	5.35, s
11′	135.6 (s)	—	136.0 (s)	—
12′	28.6 (t)	2.16, dt-like, 18.4, 7.0 Hz, 2.29, dt-like, 18.4, 5.7 Hz	28.5 (t)	2.18, dt-like, 18.2, 7.0 Hz, 2.27, dt-like, 18.2, 5.9 Hz
11′-CH3	23.7 (q)	1.85, br s	23.7 (q)	1.85, br s
1″	101.6 (d)	4.99, d, 8.0 Hz	102.0 (d)	5.03, d, 7.5 Hz
2″	74.8 (d)	3.39b, m	74.9 (d)	ca. 3.46a,e, m
3″	78.2 (d)	ca. 3.5a,d, m	78.4 (d)	ca. 3.46a,e, m
4″	71.7 (d)	3.23b, t, 9.0 Hz	71.2 (d)	ca. 3.41, m
5″	78.4 (d)	ca. 3.5a,d, m	78.4 (d)	ca. 3.46a,e, m
6″	62.7 (t)	3.85, dd, 12.0; 2.0 Hz, 3.37e	62.4 (t)	3.71, dd, 2, 12 Hz, 3.89, dd, 2, 12.5 Hz
1‴	102.5 (d)	4.93, d, 8.0 Hz	102.4 (d)	4.90c, d, 7.5 Hz
2‴	75.0 (d)	3.58, dd, 9.0, 8.0 Hz	75.0 (d)	ca. 3.61b, m
3‴	78.3 (d)	ca. 3.5a,d, m	78.60 (d)	ca. 3.46a,e, m
4‴	71.2 (d)	3.36b, m	72.1 (d)	3.15, t, 9.5 Hz
5‴	78.4 (d)	ca. 3.5a,d, m	77.2 (d)	ca. 3.66b, m
6‴	62.5 (t)	3.89, dd, 12.0, 2.0 Hz, 3.70, dd, 12.0, 6.0 Hz	69.4 (t)	3.22, dd, 2, 11 Hz, 3.96, dd, 2, 11 Hz
1″″	—	—	111.2 (d)	4.84, d, 2.5 Hz
2″″	—	—	78.3 (d)	4.03, 2.5 Hz
3″″	—	—	80.5 (s)	—
4″″	—	—	75.01 (t)	3.80, d, 9.5 Hz, 4.12, d, 10 Hz
5″″	—	—	65.7 (t)	3.68, d, 3.5 Hz

^a Strongly overlapped signals. ^b Chemical shift of HSQC correlation peak. ^c Overlapped by solvent signal. ^{d, e} May be interchanged; ¹H (500 MHz), ¹³C (125 MHz) recorded in CD₃OD.

Fig. 1. The Structures of Isolated Compounds (1–5) from Paramignya trimera

Fig. 2. Selected (COSY, NOESY and HMBC) Correlations of Compounds 1 and 2

The biscoumarins comprising a cyclohexene ring acting as a bridge between two coumarinsare quite common in nature.⁸⁾ The cyclohexene ring can be substituted by 4 to 5 substituents. The most common type is 1,3,4,4-tetrasubstituted cyclohexene (as in phebalin⁸⁾), whereas 1,3,4,5,5-pentasubstituted cyclohexene (as in toddalosin⁸⁾) is less common. Two coumarinnuclei can link through an 1,4-dimethyl-4-vinylcyclohexene chainat positions C-6/C-8′ as in isothamnosin A,⁸⁾ at C-8/C-6′ as in bisparasin,⁸⁾ C-8/C-8′ as in phebalin,⁸⁾ and at C-6/C-6′ as in thamnosin⁸⁾ and our new compound 1. The NOESY spectrum of 1 showed a correlation of the methyl signal 11-CH₃ (δ_H 1.31) to proton H-9′ (δ_H 4.13), indicative of a cis-configuration of the 11-CH₃ group and proton H-9′, as well as a cis-arrangement of two coumarin units on the 1,4-dimethyl-4-vinylcyclohexene ring, similar to the case of bisparasin, a biscoumarin isolated from Citrus plants.⁷⁾ Furthermore, the 11-CH₃ group has NOESY correlation to the methylene protons H-12 (δ_H 1.87, m) and H-12′ (δ_H 2.16, m) (Table 1), indicating that the cyclohexene ring adopts a half-chair conformation and the 11-CH₃ group and proton H-9′ are oriented axial- and pseudo-axial on the ring, respectively. Thus, the relative stereochemistry of paratrimerin A (1) was determined to be 9′S,11S or 9′R,11R. Acid hydrolysis of paratrimerin 1 gave the coresponding biscoumarin aglycone with molecular formula of C₂₈H₂₄O₆, determined from the HR-ESI-MS quasi-molecular ion peak observed at m/z 479.1460 [M+Na]⁺ (Calcd for C₂₈H₂₄O₆Na^±: 479.1465) and m/z 457.1642 [M+H]⁺ (Calcd for C₂₈H₂₅O₆^±: 457.1646).

Compound 2 appeared as an ivory powder with negative optical rotation ([α]_D²⁵ −67.5°, c=0.04, MeOH). The quasi-molecular ion peaks in positive HR-ESI-MS spectra at m/z 913.3101 [M+H]⁺ (Calcd for C₄₅H₅₃O₂₀^±, 913.3125) and m/z 935.2965 [M+Na]⁺ (Calcd for C₄₅H₅₂O₂₀Na^±, 935.2944) indicated the molecular formula of 2 as C₄₅H₅₂O₂₀. A comparison of the positive HR-ESI-MS and one dimensional (1D)- and 2D-NMR (HSQC, HMBC, COSY and NOESY in CD₃OD) spectral data of 2 to those of 1, suggested that compound 2 was an apiosyl derivative of 1 (Table 1, Fig. 2). The anomeric proton signals at δ_H 5.03 and δ_H 4.90 were assigned to H-1″ and H-1‴ of two glucoses, whereas, the signal at δ_H 4.84 (d, J=2.5 Hz) was assigned to anomeric proton H-1″″ of an apiose unit. The apiosyl anomeric proton H-1″″ had HMBC long-range correlations to glucosidic carbon C-6‴ (δ_C69.4) and also NOESY interactions with protons H-6‴ [(δ_H 3.22 (dd, J=2.0, 11.0 Hz), δ_H 3.96 (dd, J=2.0, 11.0 Hz)], confirming an apiofuranosyl(1→6)-glycopyranosyl linkage in 2.¹²⁾ The coupling constant of anomeric proton H-1″ (d, J=7.5 Hz) and H-1‴ (d, J=7.5 Hz) and their carbon signals confirmed the β-configuration of two D-glucose units. The anomeric apiosyl carbon C-1″″ (δ_C 111.2) was determined to be in the β-D-configuration by comparison with the ¹³C-NMR data of α-D-apiofuranoside (δ_C 104.5), and β-D-apiofuranoside (δ_C 111.5).¹³⁾ Based on these results, compound 2 was identified as new dimeric monoterpene-linked coumarin glycoside; namely, paratrimerin B. Thus, paratrimerins A and B are first two new monoterpene-linked biscoumarin glycosides isolated from natural source.

In addition, three other 6,7-disubstituted coumarins were isolated from the roots and stems of P. trimera and identified as the known coumarins 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7-hydroxycoumarin (3),¹⁴⁾ostruthin (4),^6,14) and ninhvanin (5)⁶⁾ (Fig. 1).

Experimental

General Experimental Procedures

¹H-NMR (500 MHz) and ¹³C-NMR (125 MHz) were measured on a Bruker Avance 500 MHz spectrometer. The HR-ESI-MS were obtained from a Varian FT-MS spectrometer and MicroQ-TOF III (Bruker Daltonics, Germany). Column chromatography was carried out on silica gel (Si 60 F₂₅₄, 230–400 mesh, Merck). All solvents were redistilled before use. Pre-coated TLC plates (Si 60 F₂₅₄) were used for analytical purposes. Compounds were visualized under UV radiation (254, 365 nm) and by spraying plates with 10% H₂SO₄ followed by heating with a heat gun.

Plant Material

The roots and stems of Paramignya trimera were collected in the Ninh Van commune, Khanh Hoa Province, South Vietnam. The plants were identified by botanist Ngo Van Trai, Institute of Medicinal Materials, Hanoi, Vietnam. A voucher specimen (C-503) is deposited in the Herbarium of the Institute of Natural Products Chemistry, VAST, Hanoi,Vietnam.

Extraction and Isolation

The air-dried roots and stems of P. trimera (5.0 kg) were boiled in water (2×10 L) for 4 h. The solution was cooled down to room temperature, filtered through a Whatman paper, and partitioned with ethyl acetate (2.0 L). The aqueous fraction was subjected to CC over Diaion HP-20 (500 g) and eluted with gradient solvent system of water–methanol [100 : 0, 80 : 20, 60 : 40, 40 : 60, 20 : 80, 0 : 100 (v/v, 2.0 L each)] to give six fractions (PW-1 to PW-6). The fraction PW-5 (32 g) was separated by normalphase silica gel (70–100 mesh) column chromatography (150 g) eluting with a gradient solvent system of chloroform–methanol [80 : 20, 60 : 40, 40 : 60, 20 : 80, 0 : 100 (v/v, 2 L each)] to give five fractions (PW-5A to PW-5E). The fraction PW-5D (10 g) was subjected to CC on silica gel (70–100 mesh) and eluted with chloroform–methanol–water (4 : 1 : 0.1, v/v/v) to obtain five fractions (PW-5D1 to PW-5D5). The sub-fraction PW-5D4 (772 mg) was firstly chromatographed on a Sephadex LH-20 column eluting with methanol–water (1 : 1, v/v) and further purified on YMC reverse phase column eluting with acetone–water (1 : 2, v/v) to yield compound 1 (43.7 mg). The fraction PW-5B (3.8 g) was subjected to CC on silica gel (70–100 mesh) and eluting with chloroform–methanol–water (4 : 1 : 0.1, v/v/v) to obtain three fractions (PW-5B1 to PW-5B3). The fraction PW-5B1 (345 mg) was separated by YMC reverse phase CC eluting with acetone–water (2 : 3, v/v) to get two sub-fractions (PW-5B1A and PW-5B1B). The sub-fraction PW-5B1A (98 mg) was purified over a Sephadex LH-20 CC and eluted with methanol–water (1 : 1, v/v) to yield compound 2 (23.0 mg).

In order to get more components from P. trimera, dried roots and stems (2.0 kg) were extracted with methanol (2×5 L) for 3 d at room temperature and concentrated under reduced pressure to yield a black crude methanol extract. The crude methanol extracts were successively partitioned in n-hexane, chloroform, and ethyl acetate, to give n-hexane (PH), chloroform (PC), and ethyl acetate (PE) residue, respectively. The precipitate from the n-hexane fraction (PH-1, 5 g) was washed with n-hexane–acetone (4 : 1, v/v) and filtered through a Whatman filter-paper to yield compound 4 as a white solid (200 mg). The filtrate (PH-2) was concentrated and subjected to CC on silica gel column (200–300 mesh) eluting with a gradient solvent system of n-hexane–acetone (20 : 1→10 : 1, v/v) to obtain eight fractions (PH-2A to PH-2H). The fraction PH-2D was re-chromatographed on RP-18 CC eluting with acetone–water (5 : 2, v/v) to yield 5 (120 mg). The chloroform fraction (5.0 g) was subjected for CC on silica gel eluting with chloroform–methanol (3 : 1, v/v) to yield compound 3 (6.0 mg).

Acid Hydrolysis of Compound 1

Compound 1 (2.5 mg) was added in 1 N HCl (2 mL) and then heated to 80°C in a water bath for 2.5 h. The acidic solution was extracted with chloroform (2 mL×2 times). The organic layer was washed with distilled water (2 mL×3 times), dried over Na₂SO₄, and evaporated in vacuo to give compound 6 (1.2 mg) as an ivory powder. C₂₈H₂₄O₆; HR-ESI-MS m/z: 479.1460 (100%) [M+Na]⁺, (Calcd for C₂₈H₂₄O₆Na^±: 479.1465), 457.1642 [M+H]⁺ (Calcd for C₂₈H₂₅O₆^±: 457.1646), [α]_D²⁵ +64° (c=0.4, MeOH). Rf (TLC): 0.4 (CHCl₃ : MeOH, 12/1).

Paratrimerin A (1)

White amorphous powder; C₄₀H₄₄O₁₆; ¹H-NMR (500 MHz, CD₃OD) and ¹³C-NMR (125 MHz, CD₃OD) are given in the Table 1; IR (KBr) cm⁻¹: 3379, 2935, 1722, 1646, 1088, 990, 746, 660, 514; UV λ_max (MeOH): 204, 256, 292, 330 nm; HR-ESI-MS m/z: 781.2691 [M+H]⁺ (Calcd for C₄₀H₄₅O₁₆^±: 781.2702), 803.2548 [M+Na]⁺ (Calcd for C₄₀H₄₄O₁₆Na^±: 803.2522), 457.1637 M−2×C₆H₁₀O₅+H]⁺; [α]_D²⁵ −25.0° (c=0.02, MeOH).

Paratrimerin B (2)

Ivory powder; C₄₅H₅₂O₂₀; ¹H-NMR (500 MHz, CD₃OD) and ¹³C-NMR (125 MHz, CD₃OD) are given in the Table 1; UV λ_max (MeOH): 207, 255, 294, 330 nm; HR-ESI-MS m/z: 913.3101 [M+H]⁺ (Calcd for C₄₅H₅₃O₂₀^±: 913.3125), 935.2965 [M+Na]⁺ (Calcd for C₄₅H₅₂O₂₀Na^±: 935.2944). [α]_D²⁵ −67.5° (c=0.04, MeOH).

Acknowledgments

This work was supported by a Grant from Vietnam Academy of Science and Technology, Vietnam (No. VAST 04.05/13-14). The authors are thankful to Dr. To Dao Cuong for specific rotation measurement and Dr. Andrea Porzel for her valuable comments and kind help.

Conflict of Interest

The authors declare no conflict of interest.

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