Isoprenylated flavonoids from the roots of Sophora tonkinensis

Phytochemistry Letters 1 (2008) 163–167

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Isoprenylated flavonoids from the roots of Sophora tonkinensis Xing-Nuo Li a,b, Na Sha a, Hai-Xia Yan b, Xiao-Yan Pang a, Shu-Hong Guan a, Min Yang a, Hui-Ming Hua b, Li-Jun Wu b, De-An Guo a,* a

Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 199 Guo Shoujing Road, Zhangjiang, Shanghai 201203, PR China b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 June 2008 Received in revised form 12 August 2008 Accepted 12 August 2008 Available online 12 September 2008

Two new isoprenylated flavanones, tonkinochromanes J (1) and K (2), and a new isoprenylated dihydrochalcone, tonkinochromane L (3), were isolated from the roots of Sophora tonkinensis along with four known compounds (4-7). Their structures were determined by means of spectroscopic analyses, including HRMS, IR, 1H and 13C NMR and 2D experiments (COSY, HSQC, and HMBC), and comparison with known related compounds. ß 2008 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

Keywords: Sophora tonkinensis Flavonoids Tonkinochromane J Tonkinochromane K Tonkinochromane L

1. Introduction In China, Sophora, a genus of the Leguminosae family, contains about 21 species, 14 varieties, and two forms that are mostly distributed in Southwest China, South China, and East China (The Flora of China, Vol. 40, 1994). Among them, Sophora tonkinensis is an important traditional Chinese herbal plant, named Shan-Dou-Gen in Chinese, distributed mainly in South China. Its roots and rhizomes were used for the treatment of acute pharyngolaryngeal infections and sore throats (The Pharmacopoeia of the People’s Republic of China, Vol. I, 2005). Phytochemical investigations have revealed that the plant accumulated isoprenyl-substituted flavonoids and lupin alkaloids as its main constituents (Ding and Chen, 2006, 2007). Pharmacological studies showed that the isoprenylated flavanones isolated from this species could inhibit cell growth and induce apoptosis in various cell lines from human solid tumors and in human leukemia U937 cells (Kajimoto et al., 2002). In the present work, the phytochemical study of Sophora tonkinensis allowed the isolation of two new isoprenylated flavanones (Fig. 1), tonkinochromanes J (1), K (2), and a new dihydrochalcone (Fig. 1), tonkinochromane L (3), together with four known compounds, 20 ,40 ,7-trihydroxy-6,8-bis(3-methyl-2butenyl)flavanone (4) (Kyogoku et al., 1973), 2-(20 ,40 -dihydroxy-

* Corresponding author. Tel.: +86 21 50271516; fax: +86 21 50272789. E-mail address: [email protected] (D.-A. Guo).

phenyl)-8,8-dimethyl-10-(3-methyl-2-butenyl)-8H-pyrano [2,3d]chroman-4-one (5) (Kyogoku et al., 1973), 6-[3-(20 ,40 -dihydroxyphenyl) acryloyl]-7-hydroxy-2,2-dimethyl-8-(3-methyl-2-butenyl)-2H-benzopyran (6) (Kyogoku et al., 1973), kushenol E (7) (Wu et al., 1985). To the best of our knowledge, this is the first report on the correction to the literature of compound 3 (Agarwal et al., 2006), and on the 13C NMR data of the known compounds 4, 5, and 6 (see Supplementary Data), whose 1H NMR data were merely listed in 1973 (Kyogoku et al., 1973). 2. Results and discussion Compound 1, obtained as yellow gums, was optically active (½aD 20 398 (c 0.07, MeOH)). Its molecular formula was established as C25H28O5 on the basis of its HR–EI–MS analysis (m/z 408.1947, calcd for 408.1937). The IR spectrum exhibited vibration bands for free hydroxyl (3415 cm1), conjugated carbonyl (1655 cm1), and olene (1597, 1587, 1501 cm1) functionalities. The 13C NMR and DEPT spectra resolved 25 carbon signals, which were classified by chemical shifts and HSQC spectrum as one carbonyl, eleven sp2 quaternary carbons, six sp2 methines, three sp3 methylenes, one sp3 methine, and four methyls. Among them, four sp2 quaternary carbons (dC 162.1; dC 161.6; dC 143.6; dC 144.8), and one sp3 methine (dC 80.2) were assigned to those bearing oxygen atoms (Table 1). The UV spectrum exhibited maximum absorptions at 284 and 310 (sh) nm, which indicated a flavanone skeleton (Xu, 1993). This was

1874-3900/$ – see front matter ß 2008 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.phytol.2008.08.001

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164

Fig. 1. Structures of compounds 1–3.

further supported by the 1H NMR signals [dH 5.31(H-2), dH 2.65 (H3a) and dH 2.94 (H-3b)], and 13C NMR signals [dC 190.9 (C-4), dC 80.2 (C-2) and dC 44.2(C-3)] (Table 1) (Xu, 1993). The 1H NMR spectrum of 1 (Table 1) showed the presence of a set of ortho-coupled aromatic signals [dH 7.56 (1H, d, J = 8.4 Hz, H-

5) and 6.62 (1H, d, J = 8.4 Hz, H-6)], a set of meta-coupled ones [dH 6.82 (1H, d, J = 2.0 Hz, H-60 ) and 6.91 (1H, d, J = 2.0 Hz, H-20 )], and two g,g-dimethylallyl groups (Matsuura et al., 1995) [dH 3.31 (2H, d, J = 7.6 Hz, H-100 ), 5.23 (1H, t, J = 7.6 Hz, H-200 ), 1.64 (3H, s, H-400 ), 1.61 (3H, s, H-500 ) and dH 3.34 (2H, d, J = 7.6 Hz, H-600 ), 5.35 (1H, m,

Table 1 1 H and 13C NMR Data of 1 and 2 (in acetone-d6) Positions

1

2

dH (mult, J, Hz) 2 3a 3b 4 5 6 7 8 9 10 10 20 30 40 50 60 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 a b

a

5.31 (m) 2.65 (dd, 2.8, 16.4) 2.94 (dd, 12.8, 16.4) 7.56 (d, 8.4) 6.62 (d, 8.4)

6.91 (d, 2.0)

6.82 (d, 2.0) 3.31 (d, 7.6) 5.23 (t, 7.6) 1.64 1.61 3.34 5.35

(s) (s) (d, 7.6) (m)

1.70 (s) 1.70 (s)

dC

b

dH (mult, J, Hz)a

80.2 d 44.2 t 190.9 125.9 109.9 162.1 116.0 161.6 114.8 130.9 111.4 144.8 143.6 128.4 119.3 22.4 122.7 131.3 17.6 25.6 28.7 123.3 132.0 17.5 25.6

s d d s s s s s d s s s d t d s q q t d s q q

5.45 (m) 2.70 (dd, 3.2, 16.4) 2.98 (m) 7.57 (d, 8.8) 6.62 (d, 8.8)

7.40 (br s)

7.30 (br s) 3.31 (m) 5.23 (t, 7.2) 1.64 1.62 5.45 4.34

(s) (s) (m) (d, 6.4)

1.44 1.49 3.35 5.35

(s) (s) (m) (t, 7.2)

1.75 (s) 1.71 (s) Recorded at 400 MHz. Recorded at 100 MHz.

dC b 80.2 d 44.3 t 190.9 125.9 110.0 162.2 116.0 161.6 114.8 132.1 121.7 124.1 158.4 130.6 128.5 22.4 122.8 131.2 17.7 25.6 73.1 90.0 72.2 27.1 26.9 28.4 122.5 132.7 17.5 25.6

s d d s s s s s d s s s d t d s q q d d s q q t d s q q

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165

Fig. 2. Key HMBC and 1H–1H COSY correlations of compounds 1–3.

H-700 ), 1.70 (6H, s, H-900 and H-1000 )] attached to rings A and B, respectively. This was confirmed by the EI–MS fragment ions at m/z 204 (A1+) and 204 (B3+), arising from Retro Diels-Alder (RDA) cleavage of the flavanone C-ring (Shirataki et al., 1982). The aromatic H-atom at dH 7.56, which correlated with dC 190.9 (C-4), 162.1 (C-7), and 161.6 (C-9) in the HMBC spectrum (Fig. 2), could be assigned to H-5. Since it coupled with the H-6, the substitution site at ring B was established at C-7 and C-8. And the correlations between dH 3.31 (H-100 ) and dC 162.1 (C-7), 116.0 (C-8), 161.6 (C-9) in a HMBC experiment indicated that one of the g,gdimethylallyl groups was located at C-8 position (Fig. 2). In addition, the HMBC spectrum showed that a 1H NMR signal at dH 3.34 (H-600 ) was correlated to 13C NMR signal at dC 119.3 (C-60 ), 128.4 (C-50 ) and 143.6 (C-40 ), and 1H NMR signal at dH 6.82 (H-60 ) showed correlations with 13C NMR signals at dC 80.2 (C-2), indicating that another g, g-dimethylallyl group was located at C-40 position (Fig. 2). Thus, with the aid of HSQC and HMBC experiments, all of the 1H and 13C NMR signals were fully assigned. And the absolute configuration at C-2 was determined as S from the circular-dichroism (CD) spectrum, which showed a positive Cotton effect at 333 nm, and a negative one at 303 nm (Desmond et al., 2005; Ding and Chen, 2006, 2007). Compound 2, obtained as yellow gums, was optically active (½aD 20 358 (c 0.07, MeOH)). Its molecular formula was established as C30H36O6 on the basis of its HR–EI–MS analysis (m/z 492.2521, calcd for 492.2512). The 13C NMR and DEPT spectra resolved 30 carbon signals, which were classified by chemical shifts and HSQC spectrum as one carbonyl, ten sp2 quaternary carbons, six sp2 methines, one sp3 quaternary carbon, three sp3 methylenes, three sp3 methines, and six methyls. Among them, three sp2 quaternary carbons (dC 162.1; dC 161.6; dC 154.5), one sp3 quaternary carbon (dC 72.2), and three sp3 methines (dC 90.0; dC 80.2; dC 73.0) were assigned to those bearing oxygen atoms (Table 1). Its UV and IR spectra were similar to those of 1. Comparison of the 1H NMR data of 2 with those of 1 revealed that the chemical-shift values and splitting patterns agreed well, except that the hydroxyl group at C-30 of 1 were replaced by a ‘4hydroxy-5-(2-hydroxyisopropyl)dihydrofuran’ moiety (Sigstad et al., 1996; Iinuma et al., 1995; Cao et al., 1998; Yap et al., 2005; Vilegas and Pozetti, 1993) [dH 5.45 (m), 4.34 (1H, d, J = 6.4 Hz), 1.49 (3H, s), and 1.44 (3H, s)], and that H-20 and H-60 of 2

were both shifted downfield by 0.50 ppm (Table 1). The 13C NMR data of 2 were also identical to those of 1, except for the corresponding replacement of the hydroxyl group at ring B of 2 by a ‘4-hydroxy-5-(2-hydroxyisopropyl)dihydrofuran’ moiety (Iinuma et al., 1995; Cao et al., 1998; Yap et al., 2005) (dC 73.0, 90.0, 72.2, 27.1, and 26.9), and for the upfield shift of C-30 (DdC =  24.7 ppm; Table 1), downfield shift of C-10 (DdC = + 1.2 ppm), C-20 (DdC = + 10.3 ppm), C-40 (DdC = + 4.8 ppm), C-50 (DdC = +2.2 ppm), and C-60 (DdC = + 9.2 ppm) (Table 1). This was supported by the fragment ions at m/z 433 ([M  59]+), 204 (A1+), and 212 ([B3– CH3COCH3–H2O]+) in the EI-MS (Tahara et al., 1984, 1985; Shirataki et al., 1982). The proposed structure was further confirmed by HSQC, HMBC spectra, and comparison with known related compounds (Sigstad et al., 1996; Takashima et al., 2002; Iinuma et al., 1995; Cao et al., 1998; Yap et al., 2005; Vilegas and Pozetti, 1993; Lo et al., 2002). ROESY correlations of H-600 to H-700 and the magnitude of J600 ,700 (6.4 Hz) indicated that the two groups on the furan ring were cis-orientated (Sigstad et al., 1996; Takashima et al., 2002; Iinuma et al., 1995; Cao et al., 1998; Yap et al., 2005; Vilegas and Pozetti, 1993; Lo et al., 2002). And the absolute configuration at C-2 was determined as S from the circular-dichroism (CD) spectrum, which showed a positive Cotton effect at 333 nm, and a negative one at 295 nm (Desmond et al., 2005; Ding and Chen, 2006, 2007). Compound 3 was obtained as yellow gum. Its molecular formula was established as C21H24O4 on the basis of its HR–EI–MS analysis (m/z 340.1684, calcd for 340.1675). The IR spectrum showed the presence of the hydroxyl (3415 cm1), conjugated carbonyl (1633 cm1), and olefine (1590, 1516 cm1) functionalities. The 1H NMR spectrum (Table 2) displayed signals of two methylene triplets at dH 2.90 (2H, t, J = 7.6 Hz, H2-b) and dH 3.24 (2H, t, J = 7.6 Hz, H2-a), which were coupled to each other, a methoxy group at dH 3.90 (3H, s, OCH3-40 ), a para-substituted aromatic ring at dH 7.09 (2H, d, J = 8.4 Hz, H-2 and H-6) and 6.75 (2H, d, J = 8.4 Hz, H-3 and H-5), a 1,2,4,5-tetrasubstituted aromatic ring at dH 6.44 (1H, s, H-30 ) and 7.64 (1H, s, H-60 ), and a g,gdimethylallyl group (Matsuura et al., 1995) at dH 3.22 (2H, d, J = 7.2 Hz, H-100 ), 5.25 (1H, t, J = 7.2 Hz, H-200 ), 1.68 (3H, s, H-400 ), 1.69 (3H, s, H-500 ). Also observed was a downfield exchangeable singlet at dH 12.8 (1H, s, OH-20 ), which is generally characteristic for the chelated hydroxyl group of flavonoids. Consistent with the

X.-N. Li et al. / Phytochemistry Letters 1 (2008) 163–167

166 Table 2 1 H and 13C NMR Data of 3 (in acetone-d6) Positions

3

dH (mult, J, Hz)a a b

3.24 (t, 7.6) 2.90 (t, 7.6)

C O 1 2/6 3/5 4 10 20 30 40 50 60 100 200 300 400 500 40 -OCH3 4-OH 20 -OH a b

7.09 (d, 8.4) 6.75 (d, 8.4)

6.44 (s)

7.64 (s) 3.22 (d, 7.2) 5.25 (t, 7.2) 1.68 (s) 1.69 (s) 3.90 (s) 8.48 (s) 12.8 (s)

dC b 40.3 29.8 204.9 132.2 129.8 115.7 156.2 113.0 164.2 99.4 164.5 122.0 131.0 28.1 122.9 132.6 17.4 25.5 55.9

t t s s d d s s s d s s d t d s q q q

Recorded at 400 MHz. Recorded at 100 MHz.

1

H NMR spectroscopic analysis, the 13C and DEPT NMR spectra (Table 2) also displayed the signals of two methylenes, one methoxy group, two aromatic rings, one g, g-dimethylallyl group, and a conjugated ketone at dC 204.9 (C O). Accordingly, this suggested that compound 3 is a dihydrochalcone (Jang et al., 2006). Thus, two hydroxy groups could be inferred from the molecular formula of C21H24O4. And the peaks in the EI–MS at m/z 107 (C7H7O), 233 (M-C7H7O), and 219 (M-C7H7O–CH2) resulting from a benzylic cleavage (Phuong et al., 2000) revealed the existence of a dihydrochalcone skeleton with an hydroxyl substituting ring B and the ring A substituted with one hydroxyl, one methoxyl, and one g,g-dimethylallyl group. In a HMBC experiment, the correlations between dH 3.22 (H-100 ) and dC 164.5 (C-40 ), 122.0 (C-50 ), 131.0 (C-60 ) indicated that the g,gdimethylallyl group was adjacent to C-50 (Fig. 2). In addition, the HMBC spectrum showed that a 1H NMR signal at dH 3.90 (OCH3-40 ) was correlated to 13C NMR signal at dC 164.5 (C-40 ), indicating that the methoxyl group was located at C-40 position (Fig. 2). Thus, with the aid of HSQC and HMBC experiments, all of the 1H and 13C NMR signals were fully assigned. To our knowledge, this is the first report on the correction to the literature (Agarwal et al., 2006) and the compound 3 was a new dihydrochalcone. Compounds 4-7 were identified as 20 ,40 ,7-trihydroxy-6,8-bis(3methyl-2-butenyl)flavanone (4), 2-(20 ,40 -dihydroxy-phenyl)-8,8dimethyl-10-(3-methyl-2- butenyl)-8H-pyrano[2,3-d]chroman-4one (5), 6-[3-(20 ,40 -dihydroxyphenyl)acryloyl]- 7-hydroxy-2,2dimethyl-8-(3-methyl-2-butenyl)-2H-benzopyran (6), and kushenol E (7) (see Supplementary Data) by means of spectroscopic analyses, including 1H, 13C NMR and 2D experiments (HSQC and HMBC), and comparison with the literatures (Kyogoku et al., 1973; Wu et al., 1985).

spectrophotometer and Alltima-C18 reversed-phase column (5 mm, 250  10 mm) with an Eclipse XDB-C18 guard column. Optical rotations: Perkin-Elmer 341 polarimeter. IR spectra: Nicolet-Magna-FT-IR 750 spectrometer. UV spectra: Shimadzu UV-2450 spectrophotometer. CD spectra: JASCO J-810 spectropolarimeter. EI–MS and HR–EI–MS: Finnigan-MAT-95 mass spectrometer. NMR spectra: Varian Mercury-plus 400 NMR spectrometer (1H 400 MHz, 13C 100 MHz); in acetone-d6 at room temperature (22 8C); d in ppm rel. to Me4Si, J in Hz. 3.2. Plant material The roots of Sophora tonkinensis were purchased from Shanghai Yanghetang Pharmaceutical Co. Ltd. The plants were authenticated by Prof. De-An Guo, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, People’s Republic of China. A voucher specimen (SC 0222006) was deposited in Shanghai Research Center for Modernization of TCM. 3.3. Extraction and isolation The air-dried and ground root material (9 kg) was extracted with 95% EtOH to give 1000 g of crude extract which was redissolved in 5 L of H2O. Then the solutions were adjusted to pH 3 with 2M HCl and paper filtered to afford 600 g of precipitations. The aqueous layer was then basified to pH 10 with 5% Na2CO3 and extracted with CHCl3 (4000 mL  3) to obtain 150 g of crude alkaloids (Li et al., 2008). The precipitations (600 g) were chromatographed on a silica gel column (petroleum ether/EtOAc, 30:1 to 0:1) to give six fractions 1–6. Fraction 4 (5:1; 3 g) was separated on a silica gel H column (petroleum ether/aceton, 20:1 to 5:1) to afford 7 fractions 10 –70 . Subfraction 30 (50 mg) was subjected to a Sephadex LH-20 column (3  100 cm) eluted with MeOH for eliminating the pigment and purified by semipreparative-HPLC using MeOH/H2O (87:13, 25 8C, 1.5 ml/min) to afford compound 1 (4 mg, tR = 29.12 min), and using MeOH/H2O (83:17, 25 8C, 1.5 ml/min) to afford compound 3 (4 mg, tR = 30.66 min) and 4 (10 mg, tR = 20.14 min). Compound 2 (2 mg) and 7 (10 mg) were obtained using the same approach as that of 1, 3 and 4 (after eliminating the pigment by Sephadex LH-20 column, purified by HPLC with MeOH/H2O 87:13, tR = 15.20 min, 25 8C and tR = 22.50 min, 25 8C, 1.5 ml/min) from subfraction 40 (20 mg). And Fraction 50 (130 mg) was separated using the same approach (after eliminating the pigment by Sephadex LH-20 column, purified by HPLC with MeCN/H2O 78:22, tR = 13.68 min, 25 8C and tR = 18.80 min, 25 8C, 1.5 ml/min) to yield 5 (20 mg) and 6 (14 mg). 3.4. Tonkinochromane J (1) Yellow gums, ½aD 20 398 (c 0.07, MeOH); UV (MeOH) lmax (log e) 310 (sh, 3.9), 284 (4.3), 236 (4.5), 220 (sh, 4.8) nm; CD (c 0.40, MeOH) [u]333 +9.928, [u]298 16.737; IR (KBr) 3415, 2968, 2922, 1655, 1597, 1508, 1441, 1375, 1333, 1286, 1209, 1045; 1H and 13C NMR data see Table 1; EI–MS: m/z 408 (M+); HR–EI–MS: m/z 408.1947 (calcd for C30H36O5, 408.1937).

3. Experimental

3.5. Tonkinochromane K (2)

3.1. General

Yellow gums, ½aD 20 358 (c 0.07, MeOH); UV (MeOH) lmax (log e) 313 (sh, 3.7), 285 (4.1), 238 (4.3), 221 (sh, 4.6) nm; CD (c 0.35, MeOH) [u]332 +8.865, [u]292 11.078; IR (KBr) 3417, 2970, 2924, 1658, 1601, 1508, 1487, 1442, 1375, 1286, 1045; 1H and 13C NMR data see Table 1; EI–MS: m/z 492 (M+); HR–EI–MS: m/z 492.2521 (calcd for C30H36O5, 495,2512).

All chemical solvents used were of anal. grade. Column chromatography (CC): Sephadex LH-20 (Amersham Biosciences); Silica gel (Qing Dao Marine Chemical Group Co.; 200–300 and 400– 600 mesh). HPLC: Agilent 1100 series with a Agilent DAD

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3.6. Tonkinochromane L (3) Yellow gums, UV (MeOH) lmax (log e) 316 (3.7), 280 (4.1), 228 (4.0), 220 (sh, 4.6) nm; IR (KBr) 3415, 2925, 2854, 1633, 1590, 1516, 1496, 1444, 1375, 1259, 1207, 1130, 831; 1H and 13C NMR data see Table 2; EI-MS: m/z 340 (M+); HR–EI–MS: m/z 340.1684 (calcd for C30H36O5, 340.1675). Acknowledgement We thank National Supporting Program for TCM from Ministry of Science and Technology of China (2006 BAI 08B03-03) for financial support of this work.

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