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Phytochemical and chemotaxonomic studies on Dioscorea collettii
Biochemical Systematics and Ecology 71 (2017) 10e15
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Phytochemical and chemotaxonomic studies on Dioscorea collettii Song-Song Jing a, Ying Wang b, Xue-Jiao Li a, Xia Li a, Wan-Shun Zhao b, Bin Zhou a, Cheng-Cheng Zhao a, Lu-Qi Huang c, Wen-Yuan Gao a, * a
Tianjin Key Laboratory for Modern Drag Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China b Tianjin Key Laboratory of Chemistry and Analysis of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China c State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 November 2016 Received in revised form 15 January 2017 Accepted 21 January 2017
A chemical investigation of Dioscorea collettii led to the isolation of twenty-nine compounds, including six steroid saponins (1e6), thirteen monocyclic phenols (7e19), two flavonoids (20e21), three sterols (22e24), and five cyclodipeptides (25e29). The chemical structures of these compounds were elucidated using spectroscopic methods and by comparing their data to that reported in the literature. This study is the first report of compounds 2e4, 7, 14e17, 21, and 23e24 in D. collettii, while compounds 8e13, 18e20, and 25e29 were first isolated from the genus Dioscorea and the family Dioscoreaceae. The chemotaxonomic significance of the isolated compounds is discussed. © 2017 Elsevier Ltd. All rights reserved.
InChIKey: FXWXUNOOOBXAEM-GZSHDUAWSA-N Keywords: Dioscorea collettii Dioscorea Steroid saponins Diarylheptanoids Chemotaxonomy
1. Subject and source The genus Dioscorea (Dioscoreaceae), which is widely distributed in the tropical and temperate regions of the world, comprises over 600 species. There are approximately 49 species that grow in China. Dioscorea collettii Hook. f, a perennial herb, is mainly distributed in Myanmar, India, and the southwest areas of China. Rhizomes of D. collettii were collected from Mount Emei, Leshan City, Sichuan Province, China, in October 2013 and were authenticated by Prof. Wenyuan Gao (School of Pharmaceutical Science and Technology, Tianjin University). A voucher specimen (No. S20131103) was deposited in the School of Pharmaceutical Science and Technology, Tianjin University, China.
* Corresponding author. E-mail address: [email protected] (W.-Y. Gao). http://dx.doi.org/10.1016/j.bse.2017.01.010 0305-1978/© 2017 Elsevier Ltd. All rights reserved.
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2. Previous work The chemistry of D. collettii has received little previous attention. To date, phytochemical investigations of D. collettii have revealed the presence of several steroid saponins (Liu et al., 1983; Yang and Chen, 1983) and one sterol (Yang and Chen, 1983). Our recent study of D. collettii explored a novel diarylheptanoid derivative, along with five known diarylheptanoids (Jing et al., 2016). 3. Present study 3.1. Extraction and isolation The dried rhizomes of D. collettii (16.2 kg) were extracted with 90% and 60% aqueous ethanol under reflux three times (30 L, each for 2 h), sequentially. After removal of the solvent under reduced pressure in vacuo, the ethanol extracts were combined, suspended in water to a final volume of 10 L, and then sequentially partitioned with petroleum ether (PE, 60e90 C), ethyl acetate (EtOAc), and n-butyl alcohol (n-BuOH). The EtOAc extract (280.0 g) was subjected to silica gel column chromatography (CC) eluted with a step wise gradient of CH2Cl2eMeOH (10:0 / 0:10, v/v) to give 19 fractions (A-S). Fraction C was chromatographed using silica gel CC with a solvent system of PE-EtOAc (30:1 / 7:3, v/v) and was then repeatedly purified using silica gel CC eluted with PE-EtOAc (9:1 / 7:3, v/ v) to give compounds 22 (62 mg) and 24 (13 mg). Fraction E was separated by silica gel CC eluted with a PE-EtOAc gradient (1:0 / 7:3, v/v) followed by purification using semi-preparative HPLC (YMC C18, 250 20 mm, 5 mm, 10 mL/min) with elution in 35% aqueous MeOH to yield compound 18 (16 mg, tR ¼ 23 min). Fraction G was purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield five subfractions (G1-G5). Subfraction G1 was subjected to silica gel CC eluted with PE-EtOAc (9:1 / 7:3, v/v) followed by further purification with semi-preparative HPLC (90% CH3CN in H2O, 10 mL/min) to obtain compounds 1 (864 mg, tR ¼ 60 min) and 5 (635 mg, tR ¼ 57 min). Subfraction G2 was fractionated by silica gel CC eluted with PE-EtOAc (10:0 / 7:3, v/v), giving three subfractions (G2A-G2C). Subfractions G2A and G2B were subjected to silica gel CC eluted with PE-EtOAc (9:1, v/v) followed by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compounds 17 (32 mg) and 7 (21 mg), respectively. Subfraction G3 was separated by silica gel CC eluted with PE-EtOAc (10:0 / 7:3, v/v) and then purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to give compounds 9 (9 mg) and 12 (7 mg). Subfraction G4 was repeatedly purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compound 19 (12 mg). Fraction H was separated by silica gel CC eluted with PE-EtOAc (10:1 / 7:3, v/v) followed by Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and further purification using silica gel CC eluted with PE-EtOAc (10:1 / 7:3, v/v) to yield compounds 20 (6 mg) and 16 (43 mg). Fraction I was subjected to silica gel CC eluted with a PE-EtOAc solvent system with increasing polarity, giving five subfractions (I1eI5). Subfraction I3 was isolated by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and then purified by semi-preparative HPLC with 60% aqueous MeOH (10 mL/min) to yield compound 8 (11 mg, tR ¼ 9 min). Subfraction I5 was purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and washed with MeOH to yield compound 25 (36 mg). Fraction J was chromatographed over silica gel CC using a solvent system of PE-EtOAc (1:0 / 7:3, v/v) to obtain three subfractions (J1-J3). Subfraction J1 was separated using semi-preparative HPLC (65% MeOH in H2O, 10 mL/min) to yield compound 13 (21 mg, tR ¼ 20 min). Subfraction J2 was subjected to Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and then purified by semi-preparative HPLC using 35% MeOH in H2O (10 mL/min) to give compounds 14 (26 mg, tR ¼ 13 min), 10 (7 mg, tR ¼ 17 min), and 11 (13 mg, tR ¼ 22 min). Fraction L was separated using silica gel CC eluted with PE-EtOAc gradient (9:1 / 0:1, v/v) and then repeatedly purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compounds 23 (26 mg) and 21 (5 mg). Fraction M was subjected to silica gel CC eluted in a gradient of PE-EtOAc (20:1 / 5:5, v/v) followed by purification with semi-preparative HPLC (65% MeOH in H2O, 10 mL/min) to obtain compound 15 (18 mg, tR ¼ 16 min). Fraction N was repeatedly separated by silica gel CC eluted in a gradient of PE-EtOAc (10:1 / 7:3, v/v) to yield compound 2 (15 mg). Fraction P was subjected to silica gel CC eluted with PE-EtOAc (8:2 / 5:5, v/v) and then purified by semi-preparative HPLC with 75% aqueous CH3CN to yield compounds 6 (87 mg) and 3 (138 mg). Fraction Q was subjected to silica gel CC eluted with PE-EtOAc (8:2 / 5:5, v/v) and then purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to give compound 4 (56 mg). Fraction R was separated by Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and was then subjected to RP-C18 open CC eluted with isocratic 35% aqueous MeOH to obtain compounds 26 (3 mg) and 27 (5 mg). The n-BuOH extract (849.0 g) was fractionated using macroporous resin (D-101) sequentially eluted with H2O and 30% and 80% aqueous ethanol to obtain the 30% (212.0 g) and 80% (268.0 g) ethanol-eluted fractions. The 30% ethanol-eluted fraction (212.0 g) was separated with silica gel CC eluted with CH2Cl2eMeOH (100:1 / 0:100, v/v) followed by purification with Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and RP-C18 open CC eluted with isocratic 30% aqueous MeOH to give compounds 28 (7 mg) and 29 (4 mg). 3.2. Structure elucidation The twenty-nine compounds were determined to be diosgenin (1) (Farid et al., 2002), prosapogenin A of dioscin (2) (Liu et al., 2008), dioscin (3) (Zhao et al., 2013), gracillin (4) (Zhu et al., 2006), yamogenin (5) (Farid et al., 2002), collettinside III (6) (Zhao et al., 2013), raspberry ketone (7) (Trader and Carlson, 2013), (-)-rhododendrol (8) (Rojatkar et al., 1995), E-(4'hydroxyphenyl)-but-1-en-3-one (9) (Ducki et al., 1996), phloretic acid (10) (Simmler et al., 2014), trans-4-coumaric acid (11)
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(Zhou et al., 2013), trans-cinnamic acid (12) (Wei et al., 2013), 2,4-dichlorobenzoic acid (13) (Battula et al., 2015), 4hydroxybenzoic acid (14) (Refaat et al., 2015), protocatechuic acid (15) (Nguyen et al., 2014), vanillic acid (16) (Lee et al., 2010), 4-hydroxybenzaldehyde (17) (Luo et al., 2015), vanillin (18) (Du et al., 2010), syringaldehyde (19) (Wei et al., 2005), formononetin (20) (Ji et al., 2016), (þ)-catechin (21) (Kim et al., 2014), b-sitosterol (22), daucosterol (23), stigmasterol (24), cyclo-(L-Pro-L-Leu) (25) (Sansinenea et al., 2016), cyclo-(L-Leu-L-Ile) (26) (Laville et al., 2015), cyclo-(L-Leu-L-Leu) (27) (Shu et al., 2014), cyclo-(L-Phe-L-Val) (28) (Shu et al., 2014), and cyclo-(L-Phe-L-Tyr) (29) (Laville et al., 2015). The chemical structures of the isolated compounds (Fig. 1) were identified using spectroscopic methods (HR-ESI-MS, 1D NMR, 2D NMR, and optical rotation) and by comparing their spectroscopic data with that reported in the literature. Compounds 22e24 were identified by comparing their Rf values to those of authentic samples.
4. Chemotaxonomic significance This work revealed the presence of twenty-nine secondary metabolites, including six steroid saponins (1e6), thirteen monocyclic phenols (7e19), two flavonoids (20e21), three sterols (22e24), and five cyclodipeptides (25e29). Species of Dioscorea distributed in China are usually divided into eight groups, including sect. Stenophora Uline, sect. Stenocorea Prain & Burkill, sect. Combilium Prain & Burkill, sect. Shannieorea Prain & Burkill, sect. Opsophyton Uline, sect. Botryosicyos (Hochstetter) Uline, sect. Lasiophyton Uline, and sect. Enantiophyllum Uline. (Ding and Gilbert, 2000). Sect. Stenophora Uline is characterized as being rich in steroid saponins, while the other groups have little steroid saponin (Li et al., 2016; Pei et al., 1979). D. collettii belongs to sect. Stenophora Uline. Several steroid saponins from D. collettii have been reported (Liu et al., 1983; Yang and Chen, 1983), but these steroidal saponins were quite different from the common steroidal saponins identified from other species of sect. Stenophora Uline (Sautour et al., 2007). Chemical investigations of the genus Dioscorea have shown that steroidal saponins are the major secondary metabolites (Sautour et al., 2007). In this research, six steroid saponins (1e6) were obtained. These compounds can be divided into 25Rtype (1e4) and 25S-type (5e6) saponins. 25R-type saponins, especially dioscin (3) and gracillin (4), are widely distributed in species of sect. Stenophora Uline. This is the first report of prosapogenin A of dioscin (2), dioscin (3), and gracillin (4) in D. collettii. As the most common steroid saponins in sect. Stenophora Uline, the presence of prosapogenin A of dioscin (2), dioscin (3), and gracillin (4) in D. collettii confirms the general homogeneity of steroid saponins in the sect. Stenophora Uline and further supports the taxonomic assignment of D. collettii to sect. Stenophora Uline (Sautour et al., 2007). Because 25R-type saponins (1e4) are distributed in nearly all of the species of sect. Stenophora Uline, 25S-type (5e6) saponins are of greater taxonomic importance than 25R-type saponins. Yamogenin (5) has been reported in D. tokoro Makino (Tang and Wu, 1964), D. collettii var. hyplauca (Lou et al., 1984), and D. tenuipes (Akahori et al., 1973). Steroidal saponins such as collettinside III (6), which has a skeleton as yamogenin, were also found in D. zingiberensis (Tang and Jiang, 1987). These data indicate that there is a close chemotaxonomic relationship between D. collettii and the aforementioned four species of Dioscorea. Furthermore, steroidal saponins (1e6) were isolated in a high yields in the current study, confirming that steroidal saponins are the major component of D. collettii as well as the sect. Stenophora Uline. Our recent study of D. collettii explored a novel diarylheptanoid derivative, diocollettines A, along with five known diarylheptanoids (Jing et al., 2016). Diocollettines A could be used as a chemotaxonomic marker to differentiate D. collettii from other species of Dioscorea. Furthermore, many other different diarylheptanoids have been reported from various species of Dioscorea, not just in sect. Stenophora Uline, including D. nipponica (Woo et al., 2013), D. spongiosa (Yin et al., 2004), D. bulbifera (Wang et al., 2009), D. opposite (Yang et al., 2009), and D. villosa (Dong et al., 2012). Therefore, diarylheptanoids should be considered to be representative secondary metabolites of the genus Dioscorea, which further supports the view that diarylheptanoids are of great chemotaxonomic value in the species of Dioscorea (Li et al., 2016). Monocyclic phenols are common secondary metabolites in many plant species. The thirteen monocyclic phenols (7e19) isolated from D. collettii in this study can be divided into benzylacetone derivatives (C6eC4 type, 7e9), simple phenylpropanoids (C6eC3 type, 10e12), and benzoic acid derivatives (C6eC1 type, 13e19). Raspberry ketone (7) has also been described in D. nipponica (Woo et al., 2014) and D. japonica (Kim et al., 2011), which indicates that these three Dioscorea species share a similar biosynthetic pathway. The other two benzylacetone derivatives (8e9) and the three simple phenylpropanoids (10e12) were isolated from Dioscorea for the first time and may be used for D. collettii identification as they are easily detected. In addition, the benzylacetone derivatives (C6eC4 type, 7e9) and simple phenylpropanoids (C6eC3 type, 10e12) may be precursor derivatives for the formation of diarylheptanoids (Katsuyama et al., 2009). From this perspective, the simultaneous occurrence of benzylacetone derivatives, simple phenylpropanoids, and diarylheptanoids in D. collettii could outline the biosynthetic pathway of diarylheptanoids to a certain extent. Benzoic acid derivatives may derive from trans-4-coumaric acid (11) (El-Mawla and Beerhues, 2002) (Scheme S7). One benzoic acid derivative, 2,4-dichlorobenzoic acid (13), is usually reported as synthetic product and was only obtained as natural product in a few studies (Wright et al., 2005). Therefore, as the first chlorine-containing compound in Dioscorea, 2,4-dichlorobenzoic acid (13) could also be used as chemotaxonomic marker to differentiate D. collettii from other species of Dioscorea. Four benzoic acid derivatives (14e17) have also been obtained from D. nipponica (Lu et al., 2010; Woo et al., 2014, 14e17) and D. bulbifera (Gao et al., 2003; Wang et al., 2009, 15e16), which implies that D. collettii has a close genetic relationship with D. nipponica and D. bulbifera. Cyclodipeptides are mostly obtained from marine microorganisms and are rarely isolated from Dioscorea. Only two cyclodipeptides, cyclo-(Ser-Tyr) and cyclo-(Leu-Tyr), were previously obtained from D. nipponica (unpublished). The five
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Fig. 1. Chemical structures of compounds 1e29 from Dioscorea collettii.
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cyclodipeptides (25e29) in this study were isolated from Dioscorea for the first time, further confirming that D. collettii and D. nipponica share a similar biosynthetic pathway. Two flavonoids were isolated from D. collettii in this study, including an isoflavone (20) and a flavan-3-ol (21). Formononetin (20) is a new type of flavonoid isolated from the genus Dioscorea. The presence of formononetin (20) could be used for D. collettii identification. In addition to the family Dioscoreaceae, to the best of our knowledge, formononetin (20) has been previously reported only in the family Leguminosae (Ji et al., 2016). The occurrence of formononetin (20) suggests that there may be some similarities in the biosynthetic pathways in these two families. (þ)-Catechin (21) has been previously isolated from D. bulbifera (Gao et al., 2003) and D. antaly (Rakotobe et al., 2010). Sterols (22e24), especially b-sitosterol (22) and daucosterol (23), occurr extensively in species of Dioscorea, but they seem to be of little chemotaxonomic value. This study has further enriched our knowledge of D. collettii chemistry. Compounds 8e13, 18e20, and 25e29 were isolated from the genus Dioscorea for the first time and could be used as potential chemotaxonomic markers for species of Dioscorea. The chemical profile of D. collettii was generally consistent with the other species of sect. Stenophora Uline, further supporting the taxonomic assignment of D. collettii to sect. Stenophora Uline. From a phytochemical taxonomic viewpoint, many species of Dioscorea, especially D. nipponica, have close chemotaxonomic relationships with D. collettii. Acknowledgements This research was financially supported by the National Natural Science Foundation of China (Nos. 81373904 and 81673535). Appendix A. 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Phytochemical and chemotaxonomic studies on Dioscorea collettii Song-Song Jing a, Ying Wang b, Xue-Jiao Li a, Xia Li a, Wan-Shun Zhao b, Bin Zhou a, Cheng-Cheng Zhao a, Lu-Qi Huang c, Wen-Yuan Gao a, * a
Tianjin Key Laboratory for Modern Drag Delivery & High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China b Tianjin Key Laboratory of Chemistry and Analysis of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China c State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 November 2016 Received in revised form 15 January 2017 Accepted 21 January 2017
A chemical investigation of Dioscorea collettii led to the isolation of twenty-nine compounds, including six steroid saponins (1e6), thirteen monocyclic phenols (7e19), two flavonoids (20e21), three sterols (22e24), and five cyclodipeptides (25e29). The chemical structures of these compounds were elucidated using spectroscopic methods and by comparing their data to that reported in the literature. This study is the first report of compounds 2e4, 7, 14e17, 21, and 23e24 in D. collettii, while compounds 8e13, 18e20, and 25e29 were first isolated from the genus Dioscorea and the family Dioscoreaceae. The chemotaxonomic significance of the isolated compounds is discussed. © 2017 Elsevier Ltd. All rights reserved.
InChIKey: FXWXUNOOOBXAEM-GZSHDUAWSA-N Keywords: Dioscorea collettii Dioscorea Steroid saponins Diarylheptanoids Chemotaxonomy
1. Subject and source The genus Dioscorea (Dioscoreaceae), which is widely distributed in the tropical and temperate regions of the world, comprises over 600 species. There are approximately 49 species that grow in China. Dioscorea collettii Hook. f, a perennial herb, is mainly distributed in Myanmar, India, and the southwest areas of China. Rhizomes of D. collettii were collected from Mount Emei, Leshan City, Sichuan Province, China, in October 2013 and were authenticated by Prof. Wenyuan Gao (School of Pharmaceutical Science and Technology, Tianjin University). A voucher specimen (No. S20131103) was deposited in the School of Pharmaceutical Science and Technology, Tianjin University, China.
* Corresponding author. E-mail address: [email protected] (W.-Y. Gao). http://dx.doi.org/10.1016/j.bse.2017.01.010 0305-1978/© 2017 Elsevier Ltd. All rights reserved.
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2. Previous work The chemistry of D. collettii has received little previous attention. To date, phytochemical investigations of D. collettii have revealed the presence of several steroid saponins (Liu et al., 1983; Yang and Chen, 1983) and one sterol (Yang and Chen, 1983). Our recent study of D. collettii explored a novel diarylheptanoid derivative, along with five known diarylheptanoids (Jing et al., 2016). 3. Present study 3.1. Extraction and isolation The dried rhizomes of D. collettii (16.2 kg) were extracted with 90% and 60% aqueous ethanol under reflux three times (30 L, each for 2 h), sequentially. After removal of the solvent under reduced pressure in vacuo, the ethanol extracts were combined, suspended in water to a final volume of 10 L, and then sequentially partitioned with petroleum ether (PE, 60e90 C), ethyl acetate (EtOAc), and n-butyl alcohol (n-BuOH). The EtOAc extract (280.0 g) was subjected to silica gel column chromatography (CC) eluted with a step wise gradient of CH2Cl2eMeOH (10:0 / 0:10, v/v) to give 19 fractions (A-S). Fraction C was chromatographed using silica gel CC with a solvent system of PE-EtOAc (30:1 / 7:3, v/v) and was then repeatedly purified using silica gel CC eluted with PE-EtOAc (9:1 / 7:3, v/ v) to give compounds 22 (62 mg) and 24 (13 mg). Fraction E was separated by silica gel CC eluted with a PE-EtOAc gradient (1:0 / 7:3, v/v) followed by purification using semi-preparative HPLC (YMC C18, 250 20 mm, 5 mm, 10 mL/min) with elution in 35% aqueous MeOH to yield compound 18 (16 mg, tR ¼ 23 min). Fraction G was purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield five subfractions (G1-G5). Subfraction G1 was subjected to silica gel CC eluted with PE-EtOAc (9:1 / 7:3, v/v) followed by further purification with semi-preparative HPLC (90% CH3CN in H2O, 10 mL/min) to obtain compounds 1 (864 mg, tR ¼ 60 min) and 5 (635 mg, tR ¼ 57 min). Subfraction G2 was fractionated by silica gel CC eluted with PE-EtOAc (10:0 / 7:3, v/v), giving three subfractions (G2A-G2C). Subfractions G2A and G2B were subjected to silica gel CC eluted with PE-EtOAc (9:1, v/v) followed by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compounds 17 (32 mg) and 7 (21 mg), respectively. Subfraction G3 was separated by silica gel CC eluted with PE-EtOAc (10:0 / 7:3, v/v) and then purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to give compounds 9 (9 mg) and 12 (7 mg). Subfraction G4 was repeatedly purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compound 19 (12 mg). Fraction H was separated by silica gel CC eluted with PE-EtOAc (10:1 / 7:3, v/v) followed by Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and further purification using silica gel CC eluted with PE-EtOAc (10:1 / 7:3, v/v) to yield compounds 20 (6 mg) and 16 (43 mg). Fraction I was subjected to silica gel CC eluted with a PE-EtOAc solvent system with increasing polarity, giving five subfractions (I1eI5). Subfraction I3 was isolated by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and then purified by semi-preparative HPLC with 60% aqueous MeOH (10 mL/min) to yield compound 8 (11 mg, tR ¼ 9 min). Subfraction I5 was purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and washed with MeOH to yield compound 25 (36 mg). Fraction J was chromatographed over silica gel CC using a solvent system of PE-EtOAc (1:0 / 7:3, v/v) to obtain three subfractions (J1-J3). Subfraction J1 was separated using semi-preparative HPLC (65% MeOH in H2O, 10 mL/min) to yield compound 13 (21 mg, tR ¼ 20 min). Subfraction J2 was subjected to Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and then purified by semi-preparative HPLC using 35% MeOH in H2O (10 mL/min) to give compounds 14 (26 mg, tR ¼ 13 min), 10 (7 mg, tR ¼ 17 min), and 11 (13 mg, tR ¼ 22 min). Fraction L was separated using silica gel CC eluted with PE-EtOAc gradient (9:1 / 0:1, v/v) and then repeatedly purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to yield compounds 23 (26 mg) and 21 (5 mg). Fraction M was subjected to silica gel CC eluted in a gradient of PE-EtOAc (20:1 / 5:5, v/v) followed by purification with semi-preparative HPLC (65% MeOH in H2O, 10 mL/min) to obtain compound 15 (18 mg, tR ¼ 16 min). Fraction N was repeatedly separated by silica gel CC eluted in a gradient of PE-EtOAc (10:1 / 7:3, v/v) to yield compound 2 (15 mg). Fraction P was subjected to silica gel CC eluted with PE-EtOAc (8:2 / 5:5, v/v) and then purified by semi-preparative HPLC with 75% aqueous CH3CN to yield compounds 6 (87 mg) and 3 (138 mg). Fraction Q was subjected to silica gel CC eluted with PE-EtOAc (8:2 / 5:5, v/v) and then purified by Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) to give compound 4 (56 mg). Fraction R was separated by Sephadex LH-20 CC eluted with CH2Cl2eMeOH (1:1) and was then subjected to RP-C18 open CC eluted with isocratic 35% aqueous MeOH to obtain compounds 26 (3 mg) and 27 (5 mg). The n-BuOH extract (849.0 g) was fractionated using macroporous resin (D-101) sequentially eluted with H2O and 30% and 80% aqueous ethanol to obtain the 30% (212.0 g) and 80% (268.0 g) ethanol-eluted fractions. The 30% ethanol-eluted fraction (212.0 g) was separated with silica gel CC eluted with CH2Cl2eMeOH (100:1 / 0:100, v/v) followed by purification with Sephadex LH-20 CC with CH2Cl2eMeOH (1:1) and RP-C18 open CC eluted with isocratic 30% aqueous MeOH to give compounds 28 (7 mg) and 29 (4 mg). 3.2. Structure elucidation The twenty-nine compounds were determined to be diosgenin (1) (Farid et al., 2002), prosapogenin A of dioscin (2) (Liu et al., 2008), dioscin (3) (Zhao et al., 2013), gracillin (4) (Zhu et al., 2006), yamogenin (5) (Farid et al., 2002), collettinside III (6) (Zhao et al., 2013), raspberry ketone (7) (Trader and Carlson, 2013), (-)-rhododendrol (8) (Rojatkar et al., 1995), E-(4'hydroxyphenyl)-but-1-en-3-one (9) (Ducki et al., 1996), phloretic acid (10) (Simmler et al., 2014), trans-4-coumaric acid (11)
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(Zhou et al., 2013), trans-cinnamic acid (12) (Wei et al., 2013), 2,4-dichlorobenzoic acid (13) (Battula et al., 2015), 4hydroxybenzoic acid (14) (Refaat et al., 2015), protocatechuic acid (15) (Nguyen et al., 2014), vanillic acid (16) (Lee et al., 2010), 4-hydroxybenzaldehyde (17) (Luo et al., 2015), vanillin (18) (Du et al., 2010), syringaldehyde (19) (Wei et al., 2005), formononetin (20) (Ji et al., 2016), (þ)-catechin (21) (Kim et al., 2014), b-sitosterol (22), daucosterol (23), stigmasterol (24), cyclo-(L-Pro-L-Leu) (25) (Sansinenea et al., 2016), cyclo-(L-Leu-L-Ile) (26) (Laville et al., 2015), cyclo-(L-Leu-L-Leu) (27) (Shu et al., 2014), cyclo-(L-Phe-L-Val) (28) (Shu et al., 2014), and cyclo-(L-Phe-L-Tyr) (29) (Laville et al., 2015). The chemical structures of the isolated compounds (Fig. 1) were identified using spectroscopic methods (HR-ESI-MS, 1D NMR, 2D NMR, and optical rotation) and by comparing their spectroscopic data with that reported in the literature. Compounds 22e24 were identified by comparing their Rf values to those of authentic samples.
4. Chemotaxonomic significance This work revealed the presence of twenty-nine secondary metabolites, including six steroid saponins (1e6), thirteen monocyclic phenols (7e19), two flavonoids (20e21), three sterols (22e24), and five cyclodipeptides (25e29). Species of Dioscorea distributed in China are usually divided into eight groups, including sect. Stenophora Uline, sect. Stenocorea Prain & Burkill, sect. Combilium Prain & Burkill, sect. Shannieorea Prain & Burkill, sect. Opsophyton Uline, sect. Botryosicyos (Hochstetter) Uline, sect. Lasiophyton Uline, and sect. Enantiophyllum Uline. (Ding and Gilbert, 2000). Sect. Stenophora Uline is characterized as being rich in steroid saponins, while the other groups have little steroid saponin (Li et al., 2016; Pei et al., 1979). D. collettii belongs to sect. Stenophora Uline. Several steroid saponins from D. collettii have been reported (Liu et al., 1983; Yang and Chen, 1983), but these steroidal saponins were quite different from the common steroidal saponins identified from other species of sect. Stenophora Uline (Sautour et al., 2007). Chemical investigations of the genus Dioscorea have shown that steroidal saponins are the major secondary metabolites (Sautour et al., 2007). In this research, six steroid saponins (1e6) were obtained. These compounds can be divided into 25Rtype (1e4) and 25S-type (5e6) saponins. 25R-type saponins, especially dioscin (3) and gracillin (4), are widely distributed in species of sect. Stenophora Uline. This is the first report of prosapogenin A of dioscin (2), dioscin (3), and gracillin (4) in D. collettii. As the most common steroid saponins in sect. Stenophora Uline, the presence of prosapogenin A of dioscin (2), dioscin (3), and gracillin (4) in D. collettii confirms the general homogeneity of steroid saponins in the sect. Stenophora Uline and further supports the taxonomic assignment of D. collettii to sect. Stenophora Uline (Sautour et al., 2007). Because 25R-type saponins (1e4) are distributed in nearly all of the species of sect. Stenophora Uline, 25S-type (5e6) saponins are of greater taxonomic importance than 25R-type saponins. Yamogenin (5) has been reported in D. tokoro Makino (Tang and Wu, 1964), D. collettii var. hyplauca (Lou et al., 1984), and D. tenuipes (Akahori et al., 1973). Steroidal saponins such as collettinside III (6), which has a skeleton as yamogenin, were also found in D. zingiberensis (Tang and Jiang, 1987). These data indicate that there is a close chemotaxonomic relationship between D. collettii and the aforementioned four species of Dioscorea. Furthermore, steroidal saponins (1e6) were isolated in a high yields in the current study, confirming that steroidal saponins are the major component of D. collettii as well as the sect. Stenophora Uline. Our recent study of D. collettii explored a novel diarylheptanoid derivative, diocollettines A, along with five known diarylheptanoids (Jing et al., 2016). Diocollettines A could be used as a chemotaxonomic marker to differentiate D. collettii from other species of Dioscorea. Furthermore, many other different diarylheptanoids have been reported from various species of Dioscorea, not just in sect. Stenophora Uline, including D. nipponica (Woo et al., 2013), D. spongiosa (Yin et al., 2004), D. bulbifera (Wang et al., 2009), D. opposite (Yang et al., 2009), and D. villosa (Dong et al., 2012). Therefore, diarylheptanoids should be considered to be representative secondary metabolites of the genus Dioscorea, which further supports the view that diarylheptanoids are of great chemotaxonomic value in the species of Dioscorea (Li et al., 2016). Monocyclic phenols are common secondary metabolites in many plant species. The thirteen monocyclic phenols (7e19) isolated from D. collettii in this study can be divided into benzylacetone derivatives (C6eC4 type, 7e9), simple phenylpropanoids (C6eC3 type, 10e12), and benzoic acid derivatives (C6eC1 type, 13e19). Raspberry ketone (7) has also been described in D. nipponica (Woo et al., 2014) and D. japonica (Kim et al., 2011), which indicates that these three Dioscorea species share a similar biosynthetic pathway. The other two benzylacetone derivatives (8e9) and the three simple phenylpropanoids (10e12) were isolated from Dioscorea for the first time and may be used for D. collettii identification as they are easily detected. In addition, the benzylacetone derivatives (C6eC4 type, 7e9) and simple phenylpropanoids (C6eC3 type, 10e12) may be precursor derivatives for the formation of diarylheptanoids (Katsuyama et al., 2009). From this perspective, the simultaneous occurrence of benzylacetone derivatives, simple phenylpropanoids, and diarylheptanoids in D. collettii could outline the biosynthetic pathway of diarylheptanoids to a certain extent. Benzoic acid derivatives may derive from trans-4-coumaric acid (11) (El-Mawla and Beerhues, 2002) (Scheme S7). One benzoic acid derivative, 2,4-dichlorobenzoic acid (13), is usually reported as synthetic product and was only obtained as natural product in a few studies (Wright et al., 2005). Therefore, as the first chlorine-containing compound in Dioscorea, 2,4-dichlorobenzoic acid (13) could also be used as chemotaxonomic marker to differentiate D. collettii from other species of Dioscorea. Four benzoic acid derivatives (14e17) have also been obtained from D. nipponica (Lu et al., 2010; Woo et al., 2014, 14e17) and D. bulbifera (Gao et al., 2003; Wang et al., 2009, 15e16), which implies that D. collettii has a close genetic relationship with D. nipponica and D. bulbifera. Cyclodipeptides are mostly obtained from marine microorganisms and are rarely isolated from Dioscorea. Only two cyclodipeptides, cyclo-(Ser-Tyr) and cyclo-(Leu-Tyr), were previously obtained from D. nipponica (unpublished). The five
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Fig. 1. Chemical structures of compounds 1e29 from Dioscorea collettii.
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cyclodipeptides (25e29) in this study were isolated from Dioscorea for the first time, further confirming that D. collettii and D. nipponica share a similar biosynthetic pathway. Two flavonoids were isolated from D. collettii in this study, including an isoflavone (20) and a flavan-3-ol (21). Formononetin (20) is a new type of flavonoid isolated from the genus Dioscorea. The presence of formononetin (20) could be used for D. collettii identification. In addition to the family Dioscoreaceae, to the best of our knowledge, formononetin (20) has been previously reported only in the family Leguminosae (Ji et al., 2016). The occurrence of formononetin (20) suggests that there may be some similarities in the biosynthetic pathways in these two families. (þ)-Catechin (21) has been previously isolated from D. bulbifera (Gao et al., 2003) and D. antaly (Rakotobe et al., 2010). Sterols (22e24), especially b-sitosterol (22) and daucosterol (23), occurr extensively in species of Dioscorea, but they seem to be of little chemotaxonomic value. This study has further enriched our knowledge of D. collettii chemistry. Compounds 8e13, 18e20, and 25e29 were isolated from the genus Dioscorea for the first time and could be used as potential chemotaxonomic markers for species of Dioscorea. The chemical profile of D. collettii was generally consistent with the other species of sect. Stenophora Uline, further supporting the taxonomic assignment of D. collettii to sect. Stenophora Uline. From a phytochemical taxonomic viewpoint, many species of Dioscorea, especially D. nipponica, have close chemotaxonomic relationships with D. collettii. Acknowledgements This research was financially supported by the National Natural Science Foundation of China (Nos. 81373904 and 81673535). Appendix A. 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