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New Antiproliferative and Immunosuppressive Withanolides from The G Model PHYTOL 670 1–6 Phytochemistry Letters xxx (2014) xxx–xxx Contents lists available at ScienceDirect Phytochemistry Letters jo urnal homepage: www.elsevier.com/locate/phytol 1 2 New antiproliferative and immunosuppressive withanolides from the 3 seeds of Datura metel a,1 a,1 a b a a 4 Q1 Bing-You Yang , Yong-Gang Xia , Yan Liu , Li Li , Hai Jiang , Liu Yang , a a, 5 Qiu-Hong Wang , Hai-Xue Kuang * a 6 Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Ministry of Education, Harbin 150040, People’s Republic of China b 7 Q2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & 8 Peking Union Medical College, People’s Republic of China A R T I C L E I N F O A B S T R A C T Article history: Two new withanolides baimantuoluoside H (1) and baimantuoluoline K (2), and one known withanolide Received 28 September 2013 glycoside (3) were isolated and identified from the ethyl acetate-soluble fraction of ethanol extract of Received in revised form 10 February 2014 Datura metel seeds. The structures of the new compounds were determined using 1D and 2D NMR Accepted 14 February 2014 spectroscopy, and mass spectrometry. All isolated compounds were evaluated for their antiproliferative Available online xxx activity against human gastric adenocarcinoma (SGC-7901), human hepatoma (Hepg2), and human breast cancer (MCF-7) cells, as well as their immunosuppressive properties. It was determined that Keywords: compounds 1–3 exhibited medium antiproliferative and potential immunosuppressive effects. Datura metel L. ß 2014 Published by Elsevier B.V. on behalf of Phytochemical Society of Europe. Solanaceae Withanolides Antiproliferative Immunosuppressive 9 10 1. Introduction which mainly include withanolides, flavonoids and alkaloids. 28 Many reports have demonstrated that withanolides have anti- 29 11 Q3 Datura metel L. known as baimantuoluo in Chinese, has been proliferative activities in pancreatic cancer cells (Gu et al., 2013) 30 12 used as a popular traditional Chinese medicine for centuries to and HT29 cancer cell lines (Bouzidi et al., 2013), and showed 31 13 treat asthma, rheumatism, convulsions and relieve pain. Previous cytotoxicity against human breast (MCF7), lung (Lu1) and prostate 32 14 pharmacological studies have demonstrated that extracts of D. (LNCaP) cancer cell lines (Veras et al., 2004a,b). Additionally, some 33 15 metel have antifungal, anti-feeding, anti-insect, anti-hyperglycae- withanolides have significant immunosuppressive properties 34 16 mic, narcotic, anodyne and antispasmodic activities (Dabur et al., (Yang et al., 2013; Huang et al., 2009; Mirosława et al., 2001; 35 17 2004; Kaushik and Goyal, 2008; Krishna et al., 2004; Pascual- Solomon, 1997). This is the first report of the chemical constituents 36 18 Villalobos and Robledo, 1998; Zhou et al., 2008). The whole plant is of the seeds of Datura metel. The activities of the isolated 37 19 considered to be as narcotic, anodyne and antispasmodic. compounds were also evaluated. As a result, two new withanolides 38 20 Additionally, the bark, leaves, and seeds of D. metel are used in (1–2) and one known withanolide (3) were isolated and identified 39 21 Ayurveda for treating various diseases. Some studies have from the EtOAc-soluble partition of its ethanol extract. The isolated 40 22 demonstrated that its seeds have effects as an aphrodisiac and compounds were determined to have cytotoxic effects in SGC- 41 23 in treating leucoderma, skin disorders, ulcers, bronchitis, jaundice, 7901 cancer cells and exhibited potential immunosuppressive 42 24 piles and in diabetes (Krishna et al., 2004). Researchers have properties. 43 25 extensively studied the active constituents of the D. metel flower 26 (Yang et al., 2010a,b; Kuang et al., 2008, 2009, 2011; Yang et al., 2. Results and discussion 44 27 2008; Ma et al., 2006; Manickam et al., 1998; Bellila et al., 2011), Extracts of D. metel were separated and purified via multiple 45 chromatographic procedures including silica gel and octadecylsilyl 46 (ODS) column chromatography, as well as high-performance liquid 47 * Corresponding author. Tel.: +86 0451 82193001. chromatography (HPLC), and three withanolides were obtained 48 E-mail addresses: [email protected], [email protected] (H.-X. Kuang). 1 These authors contributed equally to this article. (Compounds 1–3, Fig. 1). 49 http://dx.doi.org/10.1016/j.phytol.2014.02.008 1874-3900/ß 2014 Published by Elsevier B.V. on behalf of Phytochemical Society of Europe. Please cite this article in press as: Yang, B.-Y., et al., New antiproliferative and immunosuppressive withanolides from the seeds of Datura metel. Phytochem. Lett. (2014), http://dx.doi.org/10.1016/j.phytol.2014.02.008 G Model PHYTOL 670 1–6 2 B.-Y. Yang et al. / Phytochemistry Letters xxx (2014) xxx–xxx 1 13 The H and C NMR spectra (Table 1) of 1 displayed 34 carbon 56 signals and several characteristic signals corresponding to the A–D 57 rings of the steroid skeleton. The four signals at dH 0.87 (s, 3H), 1.04 58 (d, J = 6.7 Hz, 3H), 1.25 (s, 3H) and 2.12 (s, 3H) were attributable to 59 1 Me-18, Me-19, Me-21 and Me-28, respectively. The H NMR signals 60 of five olefinic protons at dH 5.89 (d, J = 9.6 Hz, H-2); 7.11 (dd, 61 J = 9.6, 6.2, H-3); 6.04 (d, J = 6.2, H-4); 6.21 (dd, J = 9.9, 2.6 Hz, H-6); 62 5.89 (d, J = 9.6 Hz, H-7) indicated the presence of three olefinic 63 1 13 bonds. The H and C NMR data of 1 indicated the presence of a b- 64 0 configured glucosyl unit [dH 4.32 (d, J = 7.8 Hz, H-1 ), dC 104.0]. 65 Fig. 1. Structures of compounds 1–3. These data indicated that 1 was a withanolide glycoside that was 66 structurally similar to daturametelin H (Ma et al., 2006). The only 67 difference was the configuration of C-14. 68 The configuration of 1 was established based on the results of 69 NOESY experiments and coupling constants. The NOE cross-peaks 70 50 Compound 1 was obtained as an amorphous powder and between Me-18 and H-8, H-14 and H-8, respectively, indicated an 71 51 showed positive results with the Molish reagent and the uncommon withanolide skeleton with H-14 being b-oriented. 72 52 Liebermann-Burchard reaction, which indicated that it might be Assignments of all of the functional groups of 1 were achieved on 73 1 1 53 a triterpenoid or steroid. The molecular formula wsa assigned as the basis of H– HCOSY, HSQC and HMBC data (Fig. 2). Addition- 74 + 54 C34H46O9 based on the [M+Na] signal at m/z 621.3058 in the ally, the NOE correlations (Fig. 3) between H-18 and H-20/H-21/ 75 55 positive mode HRESIMS, indicating 12 degrees of unsaturation. Hb-16, H-20 and Hb-16/H-22 revealed that C-20 of compound 1 76 Table 1 1 13 1 13 H and C NMR data of 1–3 (400 MHz in H NMR and 100 MHz in C NMR, in CD3OD). No. 1 2 3 dC dH dC dH dC dH 1 207.2 73.5 3.85 (s) 211.5 2 125.8 5.89 d (9.6) 39.1 2.03 (m) 40.6 2.74 dd (4.0,20.4) 1.75 (m) 3.46 dt (3.4,21.2) 3 143.2 7.11 dd (6.2,9.6) 66.7 3.94 (m) 126.4 5.87ddd (3.0,4.6,9.6) 4 118.4 6.04 d (6.2) 42.4 2.35 (m) 130.2 6.18 dd (1.6,10.0) 5 157.5 144.3 146.5 6 128.5 6.21 dd (2.7,9.9) 127.3 5.74 d (5.4) 125.6 6.06 d (5.2) 7 136.2 5.89 d (9.6) 65.9 3.74 t (3.8) 74.0 3.51 t (4.3) 8 39.4 2.38 t (10.3) 35.1 1.92 (m) 38.0 1.64(m) 9 48.7 1.57 (m) 38.9 1.47 (m) 35.7 2.13(m) 10 52.3 43.3 54.2 11 25.0 1.83 (m) 21.0 1.60 (m) 23.4 1.83 (m) 1.36 (m) 1.52 (m) 1.76(m) 12 41.0 2.07 (m) 40.5 2.03 (m) 40.4 1.99 (m) 1.20 (m) 1.24 (m) 1.28 (m) 13 45.0 43.7 43.8 14 55.1 1.27(m) 50.7 1.60 (m) 50.4 1.64 (m) 15 23.7 2.19 (m) 25.2 1.84 (m) 25.1 1.76(m) 1.70 (m) 1.24 (m) 1.28 (m) 16 28.1 1.83(m) 28.3 1.84 (m) 28.2 1.83 (m) 1.46 (m) 1.43 (m) 1.45 (m) 17 53.1 1.26 (m) 53.1 1.24 (m) 53.2 1.28 (m) 18 12.2 0.87 (s, 3H) 12.0 0.80 (s, 3H) 12.0 0.80 (s, 3H) 19 20.5 1.25 (s, 3H) 18.9 1.03 (s, 3H) 20.1 1.39 (s, 3H) 20 40.4 1.98 (m) 40.4 1.97 (m) 40.5 1.99 (m) 21 13.6 1.04 d (6.7,3H) 13.8 1.07 d (6.6, 3H) 13.7 1.07 d (6.6, 3H) 22 80.0 4.49dt (3.4,13.2) 80.2 4.49 dt (3.4,13.3) 80.1 4,51dt (3.4,13.6) 23 30.8 2.55 (m) 30.7 2.56 (m) 30.8 2.60 (m) 2.19 (m) 2.23 (m) 2.25 dd (3.2,18.1) 24 160.3 157.9 160.4 25 123.7 126.4 123.6 26 168.6 168.6 168.6 27 63.6 4.62 d (11.2) 56.4 4.40 d (11.7) 63.6 4.65 d (11.2) 4.46 d (11.2) 4.33 d (11.7) 4.49 d (11.2) 28 20.8 2.12 (s, 3H) 20.3 2.13 (s, 3H) 20.8 2.16 (s, 3H) 0 1 104.0 4.32 d (7.8) 104.0 4.35 d (7.8) 0 2 75.0 3.16 t (8.4) 75.0 3.19 dd (8.0, 8.7) 0 3 78.0 3.34 (m) 78.0 3.36 (m) 0 4 71.6 3.27 (m) 71.5 3.27 (m) 0 5 78.0 3.27 (m) 78.0 3.28 (m) 0 6 62.7 3.85dd (1.8,11.9) 62.7 3.70 dd(1.9,11.9) 3.67dd (5.5,11.6) 3.88 dd (5.2,11.9) 7-OCH3 56.8 3.32(s, 3H) Please cite this article in press as: Yang, B.-Y., et al., New antiproliferative and immunosuppressive withanolides from the seeds of Datura metel.
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