Two new dihydrobenzofuran-type neolignans from Breynia fruticosa

Phytochemistry Letters 6 (2013) 281–285

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Two new dihydrobenzofuran-type neolignans from Breynia fruticosa Yan-Ping Li a,b, Liao-Bin Dong c, Duo-Zhi Chen c, Hong-Mei Li b, Jin-Dong Zhong b, Fei Li b, Xing Liu b, Bei Wang b, Rong-Tao Li b,* a

The Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, People’s Republic of China The Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, People’s Republic of China c State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, People’s Republic of China b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 18 December 2012 Received in revised form 19 February 2013 Accepted 6 March 2013 Available online 26 March 2013

(7S,8R,70 S)-9,70 ,90 -Trihydroxy-3,4-methylenedioxy-30 -methoxy [7-O-40 ,8-50 ] neolignan (1) and (7S,8R,70 S)9,90 -dihydroxy-3,4-methylenedioxy-30 ,70 -dimethoxy [7-O-40 ,8-50 ] neolignan (2), two new natural dihydrobenzofuran-type neolignans, along with 9,90 -dihydroxy-3,4-methylenedioxy-30 -methoxy [7-O40 ,8-50 ] neolignan (3) and (-)-machicendiol (4), were isolated from the whole plants of Breynia fruticosa. The structures of 1 and 2, including the absolute configurations, were determined by spectroscopic methods and circular dichroism (CD) techniques. The absolute configuration of 4 was confirmed by calculations of the OR spectrum, together with OR and ECD spectra of its p-bromobenzoate ester (4a). ß 2013 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

Keywords: Breynia fruticosa Dihydrobenzofuran-type neolignans Absolute configuration

1. Introduction Lignans, widely distributed in the plant kingdom (Chang et al., 2005; Charlton, 1998; Pan et al., 2009; Zheng et al., 2011), have attracted much interest due to their diverse structures and various pharmacological effects (DellaGreca et al., 2011; Saarinen et al., 2007; Ward, 1999). The neolignans dihydrobenzofuran and benzofuran, as a subtype of lignans, are excellent examples of natural products with significant biological activities (Bitam et al., 2012; Botta et al., 2001; Rattanaburi et al., 2012). However, the determination of the absolute configuration of neolignan molecules, especially the C-70 hydroxy group substituent, remains a challenging task. Using existing experimental techniques (Schmidt et al., 2012; Seco et al., 2012) such as nuclear magnetic resonance (NMR), X-ray crystallography, circular dichroism (CD), optical rotatory dispersion (ORD), asymmetric total synthesis, etc., it is usually difficult to determine the absolute configuration of this type of chiral molecules. Breynia fruticosa (L.) Hook. f. is widely distributed in southern China and used as a Chinese folk medicine for the treatment of chronic bronchitis and inflammation (Liu et al., 2011; Meng et al., 2007). Further investigation of this plant led to the isolation of 4 neolignans (1–4), including 2 new ones (1 and 2) (Fig. 1). However, the absolute configurations of the known compounds 3 (Lin et al.,

* Corresponding author. Tel.: +86 871 65103845; fax: +86 871 65103845. E-mail address: [email protected] (R.-T. Li).

1999) and 4 (Schneiders and Stevenson, 1979) have not been reported. In this paper, we discuss the isolation and clarify the structure, including describing the absolute configurations, of compounds 1–4, which represents the first time the absolute configurations of C-70 hydroxy group substituted neolignans have been reported. 2. Results and discussion Compound 1, ½a26 D ¼ 18:8 (c 0.50, MeOH), was obtained as an amorphous powder. The molecular formula C20H22O7, with ten unsaturations, was established based on HREIMS (374.1366, calcd for: 374.1366) and NMR data. The IR spectrum indicated the presence of hydroxyl (3424 cm1), carbonyl group (1724 cm1) and carbon–carbon double bonds in benzene (1619, 1492, 1447 cm1) groups. The 1H NMR spectrum of 1 (Table 1) exhibited the characteristic signals of five aromatic protons, including an ABX spin system at dH 6.78 (d, J = 8.0 Hz), dH 6.86 (d, J = 8.0, 1.3 Hz), and dH 6.81 (d, J = 1.3 Hz) and two proton AB doublets at dH 6.91 (d, J = 3.0 Hz) and dH 6.87 (d, J = 3.0 Hz). In addition, the spectrum showed resonances due to a methoxyl (dH 3.88, s), two hydroxymethyl (dH 3.74, dd, J = 10.8, 7.7 Hz; dH 3.84, dd, J = 10.8, 5.1 Hz; dH 3.60, m; and dH 3.68, m), a methylene (dH 1.86, 1.98, m), two methines (dH 5.54, d, J = 5.6 Hz, and dH 4.74, dd, J = 8.0, 5.8 Hz), together with a –OCH2O– group (dH 5.93, dd, J = 5.3, 1.1 Hz). Analysis of the 13C NMR and DEPT spectra (Table 2) showed resonances for 20 carbons: seven olefinic quaternary carbons (including four oxygenated ones),

1874-3900/$ – see front matter ß 2013 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.phytol.2013.03.009

Y.-P. Li et al. / Phytochemistry Letters 6 (2013) 281–285

282 Table 1 1 H NMR data of 1–4 (d in ppm, J in Hz, CD3OD).

2 5 6 7 8 9

90 30 -OCH3 70 -OCH3 OCH2O b

2

3

4

dHb

dHb

dH b

6.81 6.78 6.86 5.54 3.44 3.74 3.84 6.91 6.87 4.74 1.86 1.98 3.60 3.68 3.88

20 60 70 80

a

1

dH a (d, 1.3) (d, 8.0) (dd, 8.0, 1.3) (d, 5.6) (m) (dd, 10.8, 7.7) (dd, 10.8, 5.1) (d, 3.0) (d, 3.0) (dd, 8.0, 5.8) (m) (m) (m) (m) (s)

5.93 (dd, 5.3, 1.1)

6.83 6.78 6.86 5.54 3.45 3.75 3.84 6.83 6.83 4.27 1.78 1.99 3.54 3.64 3.87 3.19 5.92

(overlapped) (d, 8.0) (dd, 8.0, 1.4) (d, 5.1) (m) (ddd, 10.8, 7.3, 4.3) (ddd, 10.8, 5.1, 4.3) (overlapped) (overlapped) (dd, 8.0, 5.4) (m) (m) (m) (m) (s) (s) (dd, 4.3, 1.1)

6.82 6.78 6.86 5.51 3.42 3.72 3.82 6.73 6.71 2.64 1.33 1.82 3.56

(d, 1.2) (d, 8.0) (dd, 8.0, 1.2) (d, 5.7) (m) (dd, 11.0, 7.6) (dd, 11.0, 5.2) (s) (s) (br t, 7.7) (m) (m) (m)

7.34 (d, 1.6) 6.91 (d, 8.1) 7.42 (dd, 8.1, 1.6) 6.98 (s)

3.86 (s)

6.89 7.14 4.86 1.92 2.03 3.61 3.70 4.02

(br s) (d, 0.9) (dd, 8.1, 5.3) (m) (m) (m) (m) (s)

5.93 (d, 4.3)

6.00 (br s)

Measured at 600 MHz. Measured at 500 MHz.

eight methines (five olefinic and two oxygenated), four methylenes (three oxygenated), and one methoxyl, of which 18 were assigned to the dihydrobenzofuran-type neolignan skeleton, and the remaining were ascribed to a methoxyl and a methylenedioxy. A close comparison of the 1H and 13C NMR data (Tables 1 and 2) of 1 with those of 3 (Lin et al., 1999) indicated that the two compounds were very similar, except for the presence of an oxygen group signal in 1 at C-70 , which is supported by the HMBC correlations from H-70 (dH 4.74, dd, J = 8.0, 5.8 Hz) to C-10 , C-20 , C-60 , C-80 , and C90 , from H-80 a (dH 1.98, m) and H-80 b (dH 1.86, m) to C-10 , C-70 , and C-90 , and from H-90 a (dH 3.68, m) and H-90 b (dH 3.60, m) to C-70 and C-80 . Moreover, the 1H–1H COSY correlations of H-70 /H2-80 /H2-90 indicated that the hydroxy group is located at C-70 . The threo relationship between H-7 and H-8 was inferred from their coupling constant (J7,8 = 5.6 Hz), which is similar to that reported in analogs based on X-ray analysis (Yuen et al., 1998). This arrangement was verified by the NOE correlations between H-7 and H-9 and between H-8 and H-2, 6 (Fig. 2). In addition, the absolute configurations of C-7 (dC 88.9) and C-8 (dC 55.8) were proved by the positive Cotton effect at 205 nm, and 222 nm and the negative Cotton effect at 240 nm and 290 nm, respectively (Antus et al., 2001; Kim et al., 2005; Van Dyck et al., 2001; Yuen et al., 1998). Therefore, the structure of 1 was established and named as (7S,8R,70 S)-9,70 ,90 -trihydroxy-3,4-methylenedioxy-30 -methoxy [7O-40 ,8-50 ] neolignan. Compound 2, ½a26 D ¼ 21:8 (c 0.50, MeOH), a yellow oil, exhibited the molecular formula C21H24O7, as derived from its HREIMS (388.1528, calcd for: 388.1522). The IR spectrum

exhibited the absorption of hydroxyls (3425, 3439 cm1) and aromatic rings (1620, 1492 cm1). The UV spectrum showed absorption maxima at 207, 238, and 286 nm. A comparison of its 1H and 13C NMR data (Tables 1 and 2) with those of compound 1 revealed similarities. The only difference was that the hydroxy group on C-70 in 1 was substituted by a methoxyl group in 2. This difference was supported by the HMBC correlations from H-70 (dH 4.27, dd, J = 8.0, 5.4 Hz) to C-10 , C-20 , C-60 , C-80 , and C-90 , from H-80 a (dH 1.99, m) and H-80 b (dH 1.78, m) to C-10 , C-70 and C-90 , from H-90 a (dH 3.64, m) and H-90 b (dH 3.54, m) to C-70 and C-80 , and 70 -OCH3 (dC 3.19, s) to C-70 (dC 82.3). Two new dihydrobenzofuran-type neolignans (1–2), and two known ones, 9,90 -dihydroxy-3,4-methylenedioxy-30 -methoxy [7O-40 ,8-50 ] neolignan (3) (Achenbach et al., 1987; DeAngelis and Wildman, 1969), and (-)-machicendiol (4) (Schneiders and Stevenson, 1979), were isolated from the whole plants of B. fruticosa. It is necessary to determine the absolute configurations of these biogenetic related compounds since the absolute configurations of the C-70 substituted neolignans were not Table 2 13 C NMR data of 1–4 (d in ppm, CD3OD).

1 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 80 90 30 -OCH3 70 -OCH3 OCH2O a

Fig. 1. Structure of compounds 1–2, and 4a.

b

1

2

3

4

d Ca

d Cb

d Cb

d Cb

137.5 107.1 149.5 148.7 109.2 120.4 88.9 55.8 65.2 139.2 111.8 145.5 148.9 129.6 115.8 72.5 42.9 60.3 56.8

137.3 107.0 149.4 148.8 109.1 120.4 88.9 55.5 65.1 136.9 112.5 145.6 148.8 129.9 116.6 82.3 42.1 59.5 56.7 56.8 102.5

137.7 107.1 149.5 147.5 109.2 120.4 88.7 55.9 65.2 129.6 114.1 145.4 148.9 137.2 118.0 33.0 36.0 62.3 56.8

126.0 109.9 149.7 149.6 106.1 120.1 157.5 101.6

102.6

102.8

102.6

Measured at 150 MHz. Measured at 125 MHz.

142.5 105.9 146.3 144.4 132.2 111.4 72.7 43.1 60.2 56.6

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283

Fig. 2. 1H–1H COSY (bold), selected HMBC (arrow) and key ROESY correlations of compound 1.

elucidated until now. It is interesting that compounds 1–3 exhibited a respective positive or negative Cotton effect, (Fig. 3) which indicates that the hydroxy group and methoxy group at C-70 in 1 and 2 may have no contribution to the CD spectrum, and the lack of CD absorption of compound 4 confirms the above mentioned conjecture. Thus, the question arises: how can the absolute configuration of the C-70 position in compounds 1, 2, and 4 be determine? Due to the amount of compound yielded (the isolation yield of 1 and 2 were very low) and the close biogenetic relationships of 1–4, compound 4 was chosen as the research target. The absolute configuration of 4 was established by calculations of the OR spectrum, together with OR and ECD spectra of its p-bromobenzoate ester (4a). A conformational search using molecular mechanics calculations was performed in the Discovery Studio 3.1 client (Dong et al., 2012). The corresponding minimum geometries were fully optimized at the B3LYP/6-31G(d) level in the gas phase. The OR of 4 was calculated at the B3LYP/6-311+G(2d,p) level of theory in methanol using the PCM solvent continuum model (Xu et al., 2010). The Boltzmann-weighted calculated value of S–4 was 4.4, which was close to the experimental value of 11.4 in methanol. However, it should be emphasized that the absolute configuration of 4 determined by computational techniques may result in inaccurate results (Mazzeo et al., 2010). Thus, the calculation of the OR spectrum of its p-bromobenzoate ester (4a) was necessary. The OR of 4a was calculated at the B3LYP/6-31G(d) level of theory in an acetonitrile solvent. The Boltzmann-weighted calculated value of S–4a was +168.5, which had the same sign as the experimental value of +35.3 in acetonitrile. To gain greater confidence that the absolute configuration of 4 was S, we continued to calculate the ECD spectrum of its p-bromobenzoate ester (4a). The Boltzmann-weighted timedependent DFT (TD-DFT)-calculated ECD spectrum for S–4a at the B3LYP/6-31G(d) level in the gas phase was carried out. A

Fig. 3. CD spectrum of compounds 1–3. (For interpretation of the references to color in figure legend, the reader is referred to the web version of the article.)

comparison of the observed ECD spectrum with the calculated one is shown in Fig. 4. There is an overall agreement between the experimental and TD-DFT-calculated ECD spectrum of 3S–1. Thus, based on these results, the absolute configuration of C-70 in 4 was established to be S. Because of their similar OR spectra (1 with ½a26 D ¼ 18:8 (c 0.50, MeOH), 2 with ½a26 D ¼ 21:8 (c 0.50, MeOH), 1 and 2 should have the same configuration at C-70 . Moreover, the close biogenetic relationships of 1–4 and the same coupling constant at H-70 of 1 (dd, J = 8.0, 5.8), 2 (dd, J = 8.0, 5.4), and 4 (dd, J = 8.1, 5.3) strongly indicate that 1, 2, and 4 might have the same C-70 configuration. Thus, 1 and 2 were also deduced to have a 70 S configuration. Compounds 1–4 were tested for in vitro cytotoxicity against A459, HCT116, MCF-7 and U87-MG human cancer cell lines using the MTT method (Alley et al., 1988); cis-platin was used as the positive control. However, none of them showed obvious cytotoxicities with values of IC50 > 50 mM. 3. Experimental 3.1. General experimental procedures Optical rotation was measured with a Jasco DIP-370 digital polarimeter (JASCO Corporation, Tokyo, Japan). IR spectra were recorded on a Bio-Rad FTS-135 spectrophotometer with KBr pellets (Bio-Rad Corporation, USA). 1D and 2D NMR spectra were recorded by using Bruker AM-400 and DRX-500 instruments, with tetramethylsilane (TMS) as an internal standard (Bruker BioSpin Group, German). HREIMS was performed on an API Qstar Pulsar

Fig. 4. Experimental and calculated ECD spectra of 4a. (For interpretation of the references to color in figure legend, the reader is referred to the web version of the article.)

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instrument (Applied Biosystem Corporation, Canada). CD spectra were obtained using a Jasco J715 spectropolarimeter. ECD spectra were measured on a Chirascan instrument. Semipreparative HPLC was performed on an Agilent 1200 liquid chromatography with a ZORBAX SB-C18 (5 mm, 9.4 mm  250 mm, Agilent, USA) column. Column chromatography (CC) was carried out on silica-gel (200– 300 mesh, 100–200 mesh, 80–100 mesh, Qingdao Marine Chemical Factory, China), Lichroprep RP-18 (43–63 mm, Merck, Darmstadt, Germany), and Sephadex LH-20 (Amersham Biosciences AB, Uppsala, Sweden) instruments. Fractions were monitored by TLC plates (Si gel GF254, Qingdao Marine Chemical Factory, Qingdao, China), and spots were visualized by heating silica-gel plates sprayed with 10% H2SO4-EtOH.

nature of all stationary points as minima and also provided values for computed free energies. Boltzmann statistics based on relative free energies at 298.15 K was used in the computations. The OR (589 nm) of 4 was calculated at the B3LYP/6311+G(2d,p) level of theory in methanol using the PCM solvent continuum model. The OR (589 nm) of 4a was calculated at the B3LYP/6-31G(d) level of theory in acetonitrile using the PCM solvent continuum model. Time-dependent DFT (TD-DFT) with the basis set B3LYP/631G(d) was used to calculate the excitation energies (E), oscillator strength (f), rotatory strength in velocity form (Rvel) and rotatory strength in length form (Rlen) of the lowest 50 excited states in the gas phase. The peak intensity, De(E), was calculated with the Gaussian function:

3.2. Plant material The whole plants of Breynia fruticosa were collected in Xishuangbanna in Yunnan Province, People’s Republic of China, and identified by Dr. Hai-zhou Li. A voucher specimen (KMUST 2009607003) was deposited at the Laboratory of Phytochemistry, Faculty of Life Science and Technology, Kunming University of Science and Technology. 3.3. Extraction and isolation The powdered whole plants of B. fruticosa (10 kg) were extracted with 75% aq. acetone (3  25 L) at room temperature (24 h  3). The filtrate was evaporated in vacuo to give a viscous residue, which was partitioned with EtOAc and H2O. The EtOAc layer (340 g) was subjected to chromatography using a Sephadex LH-20 and eluted with H2O and 30, 60, 90, and 100% MeOH to produce fractions A-E. Fraction B (38.5 g) was further separated over a silica-gel column using CHCl3/MeOH (30:1, 20:1, 10:1, 5:1 and 1:1) as an eluent to give five subfractions (B1–B5). Subfraction B2 (2.0 g) was separated by silica-gel CC (petroleum ether–Me2CO, 20:1 to 1:1) to obtain B2-1–B2-3. B2-2 gave compounds 1 (2.0 mg) and 4 (10.0 mg) after being chromatographed over silica gel with petroleum ether–Me2CO (10:1) and semipreparative HPLC with 38% CH3CN-H2O (3 mL/min). B2-3 was subjected to RP-18 chromatography and eluted with MeOHH2O 3:7 to 9:1, and then purified by Sephadex LH-20 chromatography (CHCl3-MeOH, 1:1) to yield 2 (4.5 mg). Subfraction B3 (2.8 g) was separated by silica-gel CC (CHCl3:Me2CO, 40:1 to 1:1) to afford 3 (3.0 mg). 3.4. Synthesis of compound 4a Compound 4 (2 mg) was dissolved in CH2Cl2 (1 mL). To this solution, p-bromobenzoyl chloride (2 mg) and DMAP (0.5 mg) were added in small portions over a period of 6 h with stirring at 60 8C; then, solvent was evaporated from the resulting mixture. The crude residue was purified by silica-gel column chromatography (500 mg, chloroform) to yield 4a (4 mg, 95%) as a white powder.

DeðEÞ ¼

1 39

2:297  10

A 2 1 X pffiffiffiffiffiffiffiffiffiffi DEi Ri e½ðEDEi Þ=ð2s Þ 2ps i

where s is the width of the band at a height of 1/e and DEi and Ri are the excitation energies and rotatory strengths for transition i, respectively; the values s = 0.20 eV and Rvel were used. 3.6. (7S,8R,70 S)-9,70 ,90 -Trihydroxy-3,4-methylenedioxy-30 methoxy[7-O-40 ,8-50 ]neolignan (1) Yellow oil. ½a26 D ¼ 18:8 (c 0.50, MeOH). UV (MeOH) lmax (log e): 206.8 (1.3), 286.0 (0.4); 1H NMR (CD3OD, 600 MHz) and 13C NMR (CD3OD, 150 MHz) see Tables 1 and 2; IR (KBr) nmax 3424, 2924, 2853, 1619, 1501, 1492, 1447, 1384, 1324, 1249, 1211, 1138, 1098, 1038, 969, 935, 860, 561 cm1; Positive EIMS: m/z 374; positive HREIMS m/z 374.1366 (calcd for C20H22O7, 374.1366). 3.7. (7S,8R,70 S)-9,90 -Dihydroxy-3,4-methylenedioxy-30 ,70 dimethoxy[7-O-40 ,8-50 ]neolignan (2) Yellow oil. ½a26 D ¼ 21:8 (c 0.50, MeOH). UV (MeOH) lmax (log e): 207.2 (1.4), 238.0 (0.8), 286.6 (0.5); 1H NMR (CD3OD, 500 MHz) and 13 C NMR (CD3OD, 125 MHz) see Tables 1 and 2; IR (KBr) nmax 3439, 3425, 2923, 1620, 1574, 1536,1502, 1492, 1446, 1360, 1324, 1249, 1207, 1138, 1101, 1037, 934 cm–1; Positive EIMS: m/z 388; positive HREIMS m/z 388.1528 (calcd for C21H24O7, 388.1522). 3.8. 9,90 -Dihydroxy-3,4-methylenedioxy-30 -methoxy[7-O-40 ,850 ]neolignan (3) 1 White powder. ½a26 D ¼ 13:0 (c 0.12, MeOH); For H and NMR data, see Tables 1 and 2.

13

C

13

C

3.9. (-)-Machicendiol (4) 1 White powder. ½a26 D ¼ 11:4 (c 0.22, MeOH); For H and NMR data, see Tables 1 and 2.

3.10. Compound 4a (4a) 3.5. Computational methods Theoretical OR and ECD spectra were obtained by density functional theory (DFT) and time-dependent DFT (TD-DFT), respectively, using Gaussian 09 (Gaussian 09) and were analyzed by using GUIs of the GaussView program (version 5.0). A conformational search using molecular mechanics calculations was performed in the Discovery Studio 3.1 client (for detailed procedures see supporting information). The corresponding minimum geometries were fully optimized at the B3LYP/631G(d) level in the gas phase. Frequency calculations (at 298.15 K) at the same level of theory were used to confirm the

1 White powder; ½a25 D ¼ þ35:3 (c 0.20, MeCN); H NMR data (400 MHz, CD3OD), dH 6.22 (br t, J = 6.7 Hz, H-70 ), 5.99 (s, H2OCH2O), 4.46 (dd, J = 11.0, 5.4 Hz, H2-90 ), 4.00 (s, H3-30 -OCH3), 2.60 (m, H-80 a), 2.46 (m, H-80 b), 6.87–7.90 (14 H), positive ESI: m/z 731, 733, 735 [M+Na]+ (1:2:1).

Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21262021, 21062008), the Fok YingTong Education Foundation (111040), and Specialized Research

Y.-P. Li et al. / Phytochemistry Letters 6 (2013) 281–285

Fund for the Doctoral (20095314110001).

Program

of

Higher

Education

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