Original Papers
Meroterpenes from Psoralea corylifolia against Pyricularia oryzae
Authors
Youwu Huang 1*, Xiaoyu Liu 2*, Yingchun Wu 1, Yiming Li 1, Fujiang Guo 1
Affiliations
1 2
Key words " Psoralea corylifolia l " Fabaceae l " meroterpenes l " antifungal l " Pyricularia oryzae l
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China Department of Biological Chemistry, Second Military Medicinal University, Shanghai, P. R. China
Abstract !
Six new meroterpenes, namely, 13-methoxyisobakuchiol (1), 13-ethoxyisobakuchiol (2), 12,13dihydro-13-hydroxybakuchiol (3), Δ10-12,13-dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5), and 15-demetyl-12,13-dihydro-13-ketobakuchiol (6), together with four known ones, namely, Δ3,2-hydroxybakuchiol (7), Δ1,3-hydroxybaku-
Introduction ! received revised accepted
March 12, 2014 July 10, 2014 July 21, 2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1382995 Published online August 15, 2014 Planta Med 2014; 80: 1298–1303 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Correspondence Fujiang Guo School of Pharmacy Shanghai University of Traditional Chinese Medicine 1200 Cailun Road Shanghai, 201203 P. R. China Phone: + 86 21 51 32 21 91 Fax: + 86 21 51 32 21 93 [email protected] Correspondence Yiming Li School of Pharmacy Shanghai University of Traditional Chinese Medicine 1200 Cailun Road Shanghai, 201203 P. R. China Phone: + 86 21 51 32 21 91 Fax: + 86 21 51 32 21 93 [email protected]
The seeds of Psoralea corylifolia L. [Cullen corylifolia (L.) Medik, Fabaceae], which are called “Bu-GuZhi” in China, have been used as traditional Chinese medicine to treat bone fractures, osteomalacia, osteoporosis, enuresis, and gynecological bleeding [1]. A number of studies have shown that its extracts exhibited various biological activities such as antioxidant [2], antibacterial [3], osteoblastic proliferation stimulating [4–6], DNA polymerase and topoisomerase II inhibitory [7], estrogenic, and α-glycosidase inhibitory activities [8, 9]. Phytochemical investigations of the seeds of P. corylifolia have resulted in the isolation and identification of chemical constituents including prenylflavones, coumarins, and several meroterpenes [1–3, 10–15]. Many researchers have reported the major meroterpenene bakuchiol and its analogues because of their bioactive activities. Bakuchiol showed estrogenic activity in vitro and could prevent bone loss, which may be related to the higher estrogen receptor-binding affinity [8]. It also inhibited protein tyrosine phosphatase 1B activity and reduced blood glucose levels in a dose-dependent manner in db/db mice, in which the hypoglycemic effect was not observed [16]. Moreover, in the fat-fed, streptozotocin-treated
* These authors contributed equally to this paper.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
chiol (8), bakuchiol (9), and Δ1,3-bakuchiol (10), were isolated from the seeds of Psoralea corylifolia. Their structures were identified based on spectral data, including those obtained via 1D and 2D NMR, and MS spectral analyses. Antifungal screening results indicated that all compounds showed moderate inhibitory activities against Pyricularia oryzae.
rat model, bakuchiol significantly lowered plasma glucose and triglyceride levels [17]. Other studies have shown that bakuchiol has selective cytotoxic activity on the human lung adenocarcinoma A549 cell line but has hardly any cytotoxicity in several other nontumorous cell lines [18]. Δ3,2-Hydroxy bakuchiol protects dopaminergic neurons from 1-methyl-4-phenylpyridinium injury and prevents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced behavioral and histological lesions in a Parkinsonʼs disease model [19]. Previous studies have also shown that bakuchiol has antimycobacterial and antifungal activities [20– 22]. In another study [23], it has been observed that bakuchiol showed bactericidal effects against all bacteria tested including Streptococcus mutans, Streptococcus sanguis, Streptococcus salivarius, Streptococcus sobrinus, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Actinomyces viscosus, and Porphyromonas gingivalis, with MICs [minimum inhibitory concentration (s)] ranging from 1 to 4 µg/mL. As such, it was believed to be a useful antibacterial agent against oral pathogens. A series of derivatives of bakuchiol were synthesized, and their HIF-1, NF-κB inhibitory [14], immunosuppressive [24], and antimicrobial [25] activities were investigated. Moreover, the relationships between their structure and activity were also determined. As part of the search for bioactive natural products against the
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1298
Original Papers
Table 1
1
H NMR data of compounds 1–6a (δ in ppm, J in Hz).
Position 1 2, 6 3, 5 4 7 8 9 10 11 12 13 14 15 1′ 2′ 3′a 3′b OCH3 OCH2CH3
a
Structures of compounds 1–10.
1b
2b
3c
4b
5b
6b
7.18 (d, 8.6) 6.71 (d, 8.6)
7.20 (d, 8.6) 6.72 (d, 8.6)
7.23 (d, 8.5) 6.76 (d, 8.5)
7.19 (d, 8.5) 6.72 (d, 8.5)
7.18 (d, 8.5) 6.70 (d, 8.5)
7.19 (d, 8.6) 6.71 (d, 8.6)
6.24 (d, 16.3) 6.04 (d, 16.3)
6.25 (d, 16.3) 6.06 (d, 16.3)
6.24 (d, 16.2) 6.04 (d, 16.2)
6.22 (d, 16.3) 6.05 (d, 16.3)
6.22 (d, 16.3) 6.05 (d, 16.3)
6.24 (d, 16.3) 6.02 (d, 16.3)
2.25 (d, 7.2) 5.59 (dt, 7.2, 15.8) 5.42 (d, 15.8)
2.27 (dt, 1.3, 7.2) 5.59 (dt, 7.2, 15.8) 5.46 (d, 15.8)
1.46d 1.33d 1.45d
1.24 (s) 1.24 (s) 1.21 (s) 5.95 (dd, 17.4, 10.8) 5.03 (dd, 1.3, 10.8) 5.06 (dd, 1.3, 17.4)
1.20 (s) 1.20 (s) 1.18 (s) 5.87 (dd, 17.4, 10.7) 5.00 (dd, 1.2, 17.4) 5.03 (dd, 1.2, 10.7)
5.05 d 5.00d 3.97 (dd, 7.7, 13.0) 1.82 (m) 1.70 (s) 1.61 (s) 1.21 (s) 5.96 (dd, 9.8, 16.3) 4.96d 4.96d 3.13 (s)
1.45d 1.54d 2.47 (t, 7.0)
1.22 (s) 1.22 (s) 1.18 (s) 5.93 (dd, 17.4, 10.8) 5.02 (dd, 1.3, 17.4) 5.04 (dd, 1.3, 10.8) 3.10 (s)
5.05d 5.00d 3.97 (dd, 7.7, 13.0) 1.82 (m) 1.72 (s) 1.64 (s) 1.23 (s) 5.96 (dd, 9.8, 16.3) 4.96d 4.96d 3.14 (s)
2.11 (s) 1.18 (s) 5.89 (dd, 17.3, 10.9) 5.01 (dd, 1.2, 17.3) 5.02 (dd, 1.2, 10.9)
3.33d 1.04 (t, 7.0)
The assignments were based on DEPT, HMQC and HMBC experiments; b measured at 400 MHz, in CD3OD; c measured at 400 MHz, in CDCl3; d overlapping signals
fungus Pyricularia oryzae (Magnaporthaceae), the meroterpene derivatives in the seeds of P. corylifolia and their antifungal activities were investigated. P. oryzae can cause rice blast and bring serious yield losses of rice, which is one of the most important cereals in the world. Controlling this disease is therefore one of the main goals of rice growers because when left untreated, the economic loss is significantly high [26, 27]. In addition, the deformation of mycelia of P. oryzae was also utilized as a screening assay for compounds that interfere with microtubule function [28]. The current study presents the isolation and structure elucidation of six new meroterpenes, namely, 13-methoxyisobakuchiol (1), 13-ethoxyisobakuchiol (2), 12,13-dihydro-13-hydroxybakuchiol (3), Δ10-12,13-dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5), and 15-demetyl-12,13-dihydro-13-ketobakuchiol (6), together with four known ones, namely, Δ3,2-hydroxybakuchiol
(7), Δ1,3-hydroxybakuchiol (8), bakuchiol (9), and Δ1,3-bakuchiol " Fig. 1). All the compounds showed moderate antifungal (10) (l activities against P. oryzae with 100% inhibition at MIC levels of 7.8 µg/mL to 31.2 µg/mL. However, the biological feature of the deformation of mycelia was not observed during the experiment.
Results and Discussion !
Compound 1 was obtained as a colorless oil with a molecular formula of C19H26O2 according to HR‑EI‑MS at m/z 286.1939 [M]+. Its 1 H NMR spectrum indicated typical signals of a phenolic mono" Table 1): AAʼXX′-type aromatic proton signals at δ terpene (l H 7.18 (d, J = 8.6 Hz, 2H, H-2, 6) and 6.71 (d, J = 8.6 Hz, 2H, H-3, 5); vinyl group signals at δH 5.02 (dd, J = 1.3, 17.4 Hz, 1H, H-3′a), Huang Y et al. Meroterpenes from Psoralea …
Planta Med 2014; 80: 1298–1303
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Fig. 1
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1300
Original Papers
a
13
C NMR data of compound 1–6 (δ in ppm)a.
Position
1b
2b
3c
4b
5b
6b
1 2, 6 3, 5 4 7 8 9 10 11 12 13 14 15 1′ 2′ 3′ OCH3 O‑CH2CH3
130.7 128.2 116.3 157.8 128.5 135.3 43.6 45.4 128.1 138.9 76.5 26.3 26.3 24.1 147.1 112.5 50.6
130.7 128.2 116.3 157.9 128.6 135.3 43.7 45.4 127.5 139.5 76.3 27.0 26.9 24.1 147.2 112.4
130.1 126.9 115.0 154.6 126.1 135.3 42.1 41.4 18.8 44.1 70.9 28.8 28.8 23.0 145.6 111.5
130.9 128.2 116.3 157.8 127.9 135.5 43.0 127.7 127.8 136.6 76.4 26.0 18.6 24.7 147.9 111.9 55.3
130.9 128.2 116.3 157.8 127.9 135.9 43.0 127.7 127.8 136.6 76.4 26.0 18.6 24.7 147.3 111.9 55.3
130.8 128.2 116.3 157.8 128.4 135.5 43.4 41.8 20.0 44.7 212.0 29.8 23.9 147.3 112.3
59.0 16.2
The assignments were based on DEPT, HMQC and HMBC experiments; b measured at 100 MHz, in CD3OD; c measured at 100 MHz, in CDCl3
5.04 (dd, J = 1.3, 10.8 Hz, 1H, H-3′b), and 5.93 (dd, J = 17.4, 10.8 Hz, 1H, H-2′); two trans double bonds at δH 6.24 (d, J = 16.3 Hz, 1H, H7) and 6.04 (d, J = 16.3 Hz, 1H, H-8); δH 5.59 (m, 1H, H-11) and 5.42 (d, J = 15.8 Hz, 1H, H-12); three methyl signals at δH 1.22 (s, 6H, H-14, 15) and 1.18 (s, 3H, H-1′); and one methylene at δH 2.25 (d, J = 7.2 Hz, 2H, H-10). Comparison of 1H and 13C NMR spectra " Table 1 and 2) with those of a known phenolic monoterdata (l pene, Δ3,2-hydroxybakuchiol (7) [19], which was obtained in the current study, showed that the only difference was that methoxylation (δH 3.10, s, 3H, -OCH3) occurred at a hydroxyl linked to C13. In the mass spectra, 1 showed 14 mass units more than 7, which supports the abovementioned assumption. This conclusion was further confirmed by the correlation between δH 3.10 (s, 3H, -OCH3) and C-13 (δC 76.5) in the HMBC spectrum. The stereochemistry of the stereogenic center at C-9 could be assumed based on biogenetic consideration because only 9S-bakuchiol is naturally occurring [14]. Thus, compound 1 was deter" Fig. 1. mined as 13-methoxyisobakuchiol, as shown in l Compound 2 was obtained as a colorless oil with a molecular formula of C20H28O2 established by HR‑EI‑MS at m/z 300.2090 [M]+. " Table 1 and 2) Comparison of 1H and 13C NMR spectra data (l with those of 7 showed that the only difference was that an ethyoxyl group substituted the hydroxyl linked to C-13 of 7. Thus, compound 2 was determined as 13-ethoxyisobakuchiol. Compound 3 was obtained as a colorless oil. The HR‑EI‑MS at m/z 274.1936 [M]+ confirmed the molecular formula of C18H26 O2. The 1H and 13C NMR spectra data of 3 were comparable with those of compound 7, which indicated that 3 was also a modified Δ3,2-hydroxybakuchiol (7) and a meroterpene. The absence of the proton signals of olefinic methine (H-11 and H-12) of Δ3,2hydroxybakuchiol (7) and the presence of two methylene proton signals at 1.33 (overlapped, 2H, H-11) and 1.45 (overlapped, 2H, H-12) in the 1H NMR led to the inference that an addition reaction occurred at the C-11 and C-12 double bonds of Δ3,2-hydroxybakuchiol (7). Compound 3 was therefore determined as 12,13-dihydro-13-hydroxybakuchiol, which was confirmed by HMQC and HMBC NMR analyses.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
A mixture of compounds 4 and 5 was obtained as a colorless oil and could not be separated via column chromatography on silica gel or HPLC. The 1H and 13C NMR spectra data of the mixture showed the presence of two compounds, and they possessed a similar molecular formula of C19H26O2 based on the HR‑EI‑MS results at m/z 286.1934 [M]+. The 1H NMR spectrum exhibited two sets of signals, and each set indicated the presence of one set of AA′XX′-type aromatic protons, two trans double bonds, one set of a vinyl group, three methyls, one oxymethine proton, one methine proton, and one methyloxy group. The abovementioned information implied that they were isomers. The 1H and 13C NMR spectra data were comparable with those of bakuchiol (9), which indicated that the mixture was also a modified bakuchiol. The HMBC spectrum, in which correlations were observed from the methyloxy signals to C-12 (δC 136.6), indicated that the methyloxy group was bound to C-12. The signals at δH 5.05 (2H, H-10), 5.00 (2H, H-11) in the 1H NMR spectrum and δC at 127.7 and 127.8 (C-10, 11) in the 13C NMR spectrum indicated that a dehydrogenation occurred at C-10 and C-11 of bakuchiol (9). Thus, 4 and 5 were determined as a mixture of Δ10-12,13-dihydro-12" Fig. 1. (R,S)-methoxyisobakuchiol, as shown in l Compound 6 was obtained as a colorless oil. Its molecular formula was assigned as C17H22O2 based on the HR‑EI‑MS peak at m/z 258.1619 [M]+. The 1H NMR spectra data of 6 indicated typical " Table 1): AA′XX′-type prosignals of a phenolic monoterpene (l ton signals at δH 7.19 (d, J = 8.6 Hz, 2H, H-2, 6) and 6.71 (d, J = 8.6 Hz, 2H, H-3, 5); one trans double bond signal at δH 6.24 (d, J = 16.3 Hz, 1H, H-7) and 6.02 (d, J = 16.3 Hz, 1H, H-8); one vinyl group signal at δH 5.01 (dd, J = 1.3, 17.3 Hz, 1H, H-3′a), 5.02 (dd, J = 1.3, 10.9 Hz, 1H, H-3′b), and 5.89 (dd, J = 17.3, 10.9 Hz, 1H, H2′); two methyls at δH 1.18 (s, 3H, H-1′,) and 2.11 (s, 3H, H-14); and three methylenes at δH 1.45 (H-10), 1.54 (H-11) and 2.47 (t, J = 3.0 Hz, H-12). The 13C NMR spectra data of 6 showed the signals of 17 carbon atoms including two methyls, three methylenes in the aliphatic region and one vinyl methylene, seven methines, and four quaternary carbons with one normal ketone at δC 212.0 (s, C-13) inside, which were identified via DEPT 135 experiments. By comparing the 1H and 13C NMR spectra data of 3 with those of
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Table 2
Original Papers
1301
Table 3 MIC values (µg/mL) of compounds 1–10 on P. oryzae with 100 % inhibition. Ketoco-
pounds
nazole
MIC value
7.8
1
2
3
4, 5
6
7
8
9
10
7.8
15.6
31.2
15.6
7.8
15.6
3.9
15.6
31.2
6, compound 6 was suggested to be a modified 11,12-tetrahydroΔ3,2- hydroxybakuchiol with the absence of one methyl group and the presence of one ketone carbon. In the HMBC spectrum, the correlations between 1.54 (m, H-11)/2.11 (s, H-14)/2.47 (t, J = 7.0, H-12) and δC 212.0 (s, C-13) confirmed the placement of the normal ketone carbon. Detailed analyses of HMBC correlations clearly identified the structure of 6 as 15-demetyl-12,13-dihydro-13-ketobakuchiol. Four known phenolic monoterpenes that were previously reported from this plant, namely, Δ3,2-hydroxybakuchiol (7) [19], Δ1,3-hydroxybakuchiol (8) [29], bakuchiol (9) [21], and Δ1,3-bakuchiol (10) [29], were also obtained. Furthermore, the antifungal activities of compounds 1–10 were evaluated via the P. oryzae inhibition test. Studies showed that abnormal features of P. oryzae conidia or hyphae (curling, expansion, too much hyphal branching, or moniliform, etc.) were related to antifungal or antitumor activities. Based on the P. oryzae bioassay, many antifungal and antineoplastic agents were identified from fungus metabolites [28] and extraction of the plant " Ta[30]. MIC values with 100 % inhibition of 1–10 are shown in l ble 3. All of the compounds showed moderate antifungal activities against P. oryzae at MIC levels of 7.8 µg/mL to 31.2 µg/mL. However, the abnormal shape of conidia was not observed during the experiment, suggesting these compounds have no potential antitumor activities.
Materials and Methods !
Plant materials The seeds of P. corylifolia were purchased from a local herbal medicine market in Shanghai (manufactured by Kangqiao Pharmaceuticals Company), and were authenticated by Dr. Yingchun Wu (School of Pharmacy, Shanghai University of Traditional Chinese Medicine). Voucher specimens (20120930) were deposited in the Natural Products Chemistry Laboratory of the School of Pharmacy, Shanghai University of Traditional Chinese Medicine.
General experimental procedures The IR spectra were obtained using a Nicolet-Magna-750-FTIR spectrometer (KBr pellets) (ThermoFisher). Optical rotations were recorded using a Perkin-Elmer 341 polarimeter. 1H, 13C, and 2D NMR spectra were obtained using a Bruker AV-400 instrument (1H: 400 MHz and 13C: 100 MHz). The EI‑MS and HR‑EI‑MS data were obtained using a Finnigan MAT-95 mass spectrometer (m/z). Silica gel (200–300 mesh) for column chromatography was purchased from Qingdao Haiyang Chemical Company. Sephadex LH-20 for column chromatography was purchased from GE Biosciences. ODS for column chromatography was purchased from Fuji Silica Chemical Company. TLC plates were obtained Yantai Jiangyou Company.
Extraction and isolation The dried seeds of P. corylifolia (9.5 kg) were extracted three times at reflux conditions in 95% ethanol (7.0 L and 2 h each at 80 °C). The combined extract was evaporated at reduced pressure to yield a crude extract (1.5 kg) in vacuo at 60 °C. The crude extract was suspended in water (3.0 L) and then successively partitioned with petroleum ether (PE) (3.0 L × 3) and ethyl acetate (EtOAc) (3.0 L × 3). The combined EtOAc part (400 g) was subjected to silica gel column chromatography (CC, 15 cm × 100 cm, 5.0 kg, mesh 100 to 200) and eluted with PE-EtOAc mixtures of increasing polarity (PE : PE-EtOAc = 15 : 1, 12 : 1, 9 : 1, 6 : 1, 3 : 1, 1 : 1, 1 : 3, 1 : 6, 1 : 9, and EtOAc, each 2 L, the volume of all samples was 500 mL) to yield 17 fractions (Fr. 1 to 17) according to the thin-layer chromatography (TLC) monitor. Fr. 9 (10 g) was subjected to silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-acetone (PE, PE-acetone = 7 : 1 to 1 : 1, 250 mL each sample) to obtain 11 subfractions (Fr. 9.1 to Fr. 9.11). Fr. 9.6 (1 g) was further separated via silica gel chromatography (CC, 35 cm × 4 cm, 150 g, mesh 300 to 400) eluted with CH2Cl2-MeOH (400 : 1, 200 : 1, 100 : 1, and 40 mL each sample) to obtain 8 (400 mg, 97.2 %). Fr. 9.5 (1.77 g) was purified via C18 chromatography (CC, 25 cm × 3 cm, 110 g) with 60% → 80 % MeOH (30 mL each sample) to obtain 6 (12 mg, 97.5 %) and 10 (13 mg, 97.6 %). Fr. 10 (12 g) was further separated via silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-acetone (10 : 1, 9 : 1, 8 : 1, 6 : 1, 4 : 1, 3 : 1, and 1 : 1, 250 mL each sample) to obtain 20 subfractions (Fr. 10.1 to Fr. 10.20). Fr. 10.4 (53 mg) was subjected to Sephadex LH-20 (CC, 51 cm × 2 cm) with MeOH and followed by C18 chromatography (CC, 24 cm × 2 cm, 50 g) with 70 %→85 % MeOH resp. (10 mL each sample resp.) to yield 4 and 5 (7 mg, 97.5 %) and 2 (23 mg, 98.4 %). Fr. 10.3 (63 mg) was purified by Sephadex LH-20 (CC, 51 cm × 2 cm) eluted with MeOH (10 mL each sample) to obtain 1 (47 mg, 98.2 %). Fr. 12 (35 g) was further separated via silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with CH2Cl2-MeOH (CH2Cl2-MeOH = 80 : 1, 70 : 1, 50 : 1, 250 mL each sample) to obtain 9 subfractions (Fr. 12.1 – Fr. 12.9). Fr. 12.2 (1.0 g) was repurified via silica gel chromatography (CC, 35 cm × 4 cm, 150 g, mesh 300 to 400) eluted with PE-EtOAc (PE, PEEtOAc = 5 : 1, 4 : 1, 3 : 1, EtOAC, 40 mL of each sample) to obtain 7 (148 mg, 98.6 %). Fr. 12.3 (55 mg) was chromatographed via C18 chromatography (CC, 20 cm × 2 cm, 30 g) with 65% → 80 % MeOH (5 mL each sample) to obtain 3 (20 mg, 98.1 %). Fr. 13 (22 g) was subjected to silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-EtOAc (PE, PE-EtOAc = 4 : 1, 3 : 1, 2 : 1 and EtOAc, 250 mL each sample) to obtain 14 fractions (Fr. 13.1 to Fr. 13.14). Fr. 13.3 (220 mg) was further purified via C18 chromatography (CC, 24 cm × 2 cm, 50 g) with 70% → 85 % MeOH (10 mL each sample) to obtain 9 (43 mg, 98.3 %). 13-Methoxyisobakuchiol (1): brown oil. [α]25 D + 7.3 (c 1.0, MeOH); 1 " Table 1 and 2. HMBC correlations H-2, H and 13C NMR data, see l 6/C‑3, 4, 5; H-3, 5/C‑2, 4, 6; H-7/C-8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/ C-8, 9, 11, 12, 1′, 2′; H-11/C-10, 13; H-12/C-10, 11, 13, 14, 15; H14, 15/C- 12, 13; H-1′/C‑8, 9, 10, 2′; H-2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV
Huang Y et al. Meroterpenes from Psoralea …
Planta Med 2014; 80: 1298–1303
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Com-
Original Papers
λmax (CH3OH) nm (log ε): 265 (3.63), 206 (3.88); IR (KBr) νmax 3296, 2974, 2931, 1676, 1608, 1514, 1450, 1412, 1366, 1236, 1170, 1157, 1101, 1059, 998, 973, 916, 848, 813 cm−1; EI‑MS: m/ z 286, 258, 241, 223, 205, 185, 173 (100 %), 158, 149, 145. HR‑EI‑MS: m/z 286.1939 [M]+ (calcd. for C19H26O2: 286.1933). 13-Ethoxyisobakuchiol (2): colorless oil. [α]25 D + 1.0 (c 1.0, MeOH); 1 " Table 1 and 2. HMBC correlations H-2, H and 13C NMR data, see l 6/C‑4; H-3, 5/C‑1, 4; H-7/C-2, 6, 8, 9; H-8/C-1, 7, 9, 10, 1′, 2′; H-10/ C-8, 9, 11, 12, 1′, 2′; H-11/C-10, 13; H-12/C-10, 11, 13, 14, 15; H14/C-12, 13; H-15/C-12, 13; H-16/C-13, 17; H-17/C-16; H-1′/C‑8, 9, 10, 2′; H-2′/C‑8, 9, 10, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.76), 206 (4.02); IR (KBr) νmax 3351, 2974, 2929, 1727, 1610, 1589, 1514, 1442, 1363, 1267, 1235, 1170, 1157, 1102, 1060, 973, 916, 847, 812 cm−1; EI‑MS: m/z 300, 254, 239, 223, 205, 187, 173 (100 %), 158, 149, 145. HR‑EI‑MS m/z 300.2090 [M]+ (calcd. for C20H28O2: 300.2089). 12,13-Dihydro-13-hydroxybakuchiol (3): colorless oil. [α]25 D + 33.1 " Table 1 and 2. HMBC (c 1.0, MeOH); 1H and 13C NMR data, see l correlations H-2, 6/C‑4, 7; H-3, 5/C‑1, 4; H-7/C-1, 6, 8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/C-8, 11, 13, 1′, 2′; H-11/C-13; H-12/C-11, 13, 14, 15; H-14, 15/C‑12, 13; H-1′/C‑8, 9, 2′; H-2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.63), 207 (3.79); IR (KBr) νmax 3379, 2969, 1705, 1677, 1610, 1514, 1453, 1371, 1241, 1171, 1102, 1001, 971, 912, 815 cm−1; EI‑MS: m/z 274, 256, 241, 223, 185, 173 (100 %), 158, 145. HR‑EI‑MS m/z 274.1936 [M]+ (calcd. for C18H26O2: 274.1933). Δ10-12,13-Dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5): color1 13 " Taless oil. [α]25 C NMR data, see l D − 0.7 (c 1.0, MeOH); H and ble 1 and 2. HMBC correlations H-2, 6/C‑4; H-3, 5/C‑1, 4; H-7/C-2, 6, 8, 9; H-8/C-1, 7, 9, 10, 1′, 2′; H-10/C-9, 2′; H-11/C-9, 2′; H-12/C8, 9, OCH3; H-14/C-11, 13; H-15/C-11, 13; H-1′/C‑8, 9, 2′; H-3′/ C‑9, 2′. UV λmax (CH3OH) nm (log ε): 263 (3.08), 206 (3.92); IR (KBr) νmax 3384, 2928, 1673, 1609, 1514, 1448, 1376, 1267, 1170, 1078, 971, 916, 838 cm−1; EI‑MS: m/z 286, 271, 254, 239, 204, 189, 173 (100 %), 158, 145. HR‑EI‑MS m/z 286.1934 [M]+ (calcd. for C19H26O2: 286.1933). 15-Demetyl-12,13-dihydro-13-ketobakuchiol (6): colorless oil. 1 13 " Table 1 and C NMR data, see l [α]25 D + 6.3 (c 1.0, MeOH); H and 2. HMBC correlations H-2, 6/C‑3, 4, 5, 7; H-3, 5/C‑1, 2, 4, 6; H-7/C1, 2, 6, 8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/C-8, 9, 11, 1′, 2′; H-11/C-10, 12, 13; H-12/C-10, 11, 13; H-14/C-12, 13; H-1′/C‑8, 9, 10, 2′, 3′; H2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.56), 206 (3.89); IR (KBr) νmax 3367, 2959, 1702, 1635, 1609, 1589, 1514, 1439, 1411, 1367, 1265, 1224, 1171, 972, 915, 816 cm−1; EI‑MS: m/z 258, 241, 223, 205, 185, 173, 163 (100 %), 149. HR‑EI‑MS m/z 258.1619 [M]+ (calcd. for C17H22O2: 258.1620).
Pyricularia oryzae inhibition test The P. oryzae inhibition test was performed to screen the antifungal activities of all compounds. P. oryzae was incubated at 37 °C for ten days and the spores were then collected in 10 mL of sterile water. Each well of the 96-well microplate contained 50 µL of the spore liquid. The compounds were dissolved in MeOH/H2O (10%) and added to the first line of a 96-well microplate. A serial twofold dilution of the compounds was made from 1 mg/mL. The 96well microplate was cultured at 37 °C for 16 h. The maximum activity dilution was defined as the maximum concentration of antimicrobial agents that completely inhibited the visible growth of the spores. Ketoconazole (98 %, Sigma) was used as the positive control sample. MeOH/H2O (10%) was used as the negative control sample.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
Acknowledgements !
This research program was supported by the Natural Science Foundation of Shanghai (13ZR1441700), “Xing-lin” scholar of SHUTCM, and Eastern Scholar Program.
Conflict of Interest !
All authors contributed to and have approved the final manuscript. The authors declare no conflict of interest.
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24 Chen HL, Du XL, Tang W, Zhou Y, Zuo JP, Feng HJ, Li YC. Synthesis and structure-immunosuppressive activity relationships of bakuchiol and its derivatives. Bioorg Med Chem 2008; 16: 2403–2411 25 Reddy MV, Thota N, Sangwan PL, Malhotra P, Ali F, Khan IA, Chimni SS, Koul S. Novel bisstyryl derivatives of bakuchiol: targeting oral cavity pathogens. Eur J Med Chem 2010; 45: 3125–3134 26 Ghazanfar MU, Habib A, Sahi ST. Screening of rice germplasm against Pyricularia oryzae, the cause of rice blast disease. Pak J Phytopathol 2009; 21: 41–44 27 Castejon-Munoz M, Lara-Alvarez I, Aguilar M. Resistance of rice cultivars to Pyricularia oryzae in Southern Spain. Span J Agric Res 2007; 5: 59–66 28 Kobayashi H, Sunaga R, Furihata K, Morisaki N, Iwasaki S. Isolation and structures of an antifungal antibiotic, fusarielin A, and related compounds produced by a Fusarium sp. J Antibiot 1995; 48: 42–52 29 Shah CC, Bhalla VK, Dev S. Meroterpenoids-V: Psoralea corylifolia Linn. – 4.2,3-epoxybakuchiol, Δ1,3-hydroxybakuchiol, and Δ3,2-hydroxybakuchiol. J Indian Chem Soc 1997; 74: 970–973 30 Hu K, Kobayashi H, Dong A, Jing Y, Iwasaki S, Yao X. Antineoplastic agents. III: Steroidal glycosides from Solanum nigrum. Planta Med 1999; 65: 35–38
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Original Papers
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Meroterpenes from Psoralea corylifolia against Pyricularia oryzae
Authors
Youwu Huang 1*, Xiaoyu Liu 2*, Yingchun Wu 1, Yiming Li 1, Fujiang Guo 1
Affiliations
1 2
Key words " Psoralea corylifolia l " Fabaceae l " meroterpenes l " antifungal l " Pyricularia oryzae l
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China Department of Biological Chemistry, Second Military Medicinal University, Shanghai, P. R. China
Abstract !
Six new meroterpenes, namely, 13-methoxyisobakuchiol (1), 13-ethoxyisobakuchiol (2), 12,13dihydro-13-hydroxybakuchiol (3), Δ10-12,13-dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5), and 15-demetyl-12,13-dihydro-13-ketobakuchiol (6), together with four known ones, namely, Δ3,2-hydroxybakuchiol (7), Δ1,3-hydroxybaku-
Introduction ! received revised accepted
March 12, 2014 July 10, 2014 July 21, 2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1382995 Published online August 15, 2014 Planta Med 2014; 80: 1298–1303 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Correspondence Fujiang Guo School of Pharmacy Shanghai University of Traditional Chinese Medicine 1200 Cailun Road Shanghai, 201203 P. R. China Phone: + 86 21 51 32 21 91 Fax: + 86 21 51 32 21 93 [email protected] Correspondence Yiming Li School of Pharmacy Shanghai University of Traditional Chinese Medicine 1200 Cailun Road Shanghai, 201203 P. R. China Phone: + 86 21 51 32 21 91 Fax: + 86 21 51 32 21 93 [email protected]
The seeds of Psoralea corylifolia L. [Cullen corylifolia (L.) Medik, Fabaceae], which are called “Bu-GuZhi” in China, have been used as traditional Chinese medicine to treat bone fractures, osteomalacia, osteoporosis, enuresis, and gynecological bleeding [1]. A number of studies have shown that its extracts exhibited various biological activities such as antioxidant [2], antibacterial [3], osteoblastic proliferation stimulating [4–6], DNA polymerase and topoisomerase II inhibitory [7], estrogenic, and α-glycosidase inhibitory activities [8, 9]. Phytochemical investigations of the seeds of P. corylifolia have resulted in the isolation and identification of chemical constituents including prenylflavones, coumarins, and several meroterpenes [1–3, 10–15]. Many researchers have reported the major meroterpenene bakuchiol and its analogues because of their bioactive activities. Bakuchiol showed estrogenic activity in vitro and could prevent bone loss, which may be related to the higher estrogen receptor-binding affinity [8]. It also inhibited protein tyrosine phosphatase 1B activity and reduced blood glucose levels in a dose-dependent manner in db/db mice, in which the hypoglycemic effect was not observed [16]. Moreover, in the fat-fed, streptozotocin-treated
* These authors contributed equally to this paper.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
chiol (8), bakuchiol (9), and Δ1,3-bakuchiol (10), were isolated from the seeds of Psoralea corylifolia. Their structures were identified based on spectral data, including those obtained via 1D and 2D NMR, and MS spectral analyses. Antifungal screening results indicated that all compounds showed moderate inhibitory activities against Pyricularia oryzae.
rat model, bakuchiol significantly lowered plasma glucose and triglyceride levels [17]. Other studies have shown that bakuchiol has selective cytotoxic activity on the human lung adenocarcinoma A549 cell line but has hardly any cytotoxicity in several other nontumorous cell lines [18]. Δ3,2-Hydroxy bakuchiol protects dopaminergic neurons from 1-methyl-4-phenylpyridinium injury and prevents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced behavioral and histological lesions in a Parkinsonʼs disease model [19]. Previous studies have also shown that bakuchiol has antimycobacterial and antifungal activities [20– 22]. In another study [23], it has been observed that bakuchiol showed bactericidal effects against all bacteria tested including Streptococcus mutans, Streptococcus sanguis, Streptococcus salivarius, Streptococcus sobrinus, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Actinomyces viscosus, and Porphyromonas gingivalis, with MICs [minimum inhibitory concentration (s)] ranging from 1 to 4 µg/mL. As such, it was believed to be a useful antibacterial agent against oral pathogens. A series of derivatives of bakuchiol were synthesized, and their HIF-1, NF-κB inhibitory [14], immunosuppressive [24], and antimicrobial [25] activities were investigated. Moreover, the relationships between their structure and activity were also determined. As part of the search for bioactive natural products against the
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Original Papers
Table 1
1
H NMR data of compounds 1–6a (δ in ppm, J in Hz).
Position 1 2, 6 3, 5 4 7 8 9 10 11 12 13 14 15 1′ 2′ 3′a 3′b OCH3 OCH2CH3
a
Structures of compounds 1–10.
1b
2b
3c
4b
5b
6b
7.18 (d, 8.6) 6.71 (d, 8.6)
7.20 (d, 8.6) 6.72 (d, 8.6)
7.23 (d, 8.5) 6.76 (d, 8.5)
7.19 (d, 8.5) 6.72 (d, 8.5)
7.18 (d, 8.5) 6.70 (d, 8.5)
7.19 (d, 8.6) 6.71 (d, 8.6)
6.24 (d, 16.3) 6.04 (d, 16.3)
6.25 (d, 16.3) 6.06 (d, 16.3)
6.24 (d, 16.2) 6.04 (d, 16.2)
6.22 (d, 16.3) 6.05 (d, 16.3)
6.22 (d, 16.3) 6.05 (d, 16.3)
6.24 (d, 16.3) 6.02 (d, 16.3)
2.25 (d, 7.2) 5.59 (dt, 7.2, 15.8) 5.42 (d, 15.8)
2.27 (dt, 1.3, 7.2) 5.59 (dt, 7.2, 15.8) 5.46 (d, 15.8)
1.46d 1.33d 1.45d
1.24 (s) 1.24 (s) 1.21 (s) 5.95 (dd, 17.4, 10.8) 5.03 (dd, 1.3, 10.8) 5.06 (dd, 1.3, 17.4)
1.20 (s) 1.20 (s) 1.18 (s) 5.87 (dd, 17.4, 10.7) 5.00 (dd, 1.2, 17.4) 5.03 (dd, 1.2, 10.7)
5.05 d 5.00d 3.97 (dd, 7.7, 13.0) 1.82 (m) 1.70 (s) 1.61 (s) 1.21 (s) 5.96 (dd, 9.8, 16.3) 4.96d 4.96d 3.13 (s)
1.45d 1.54d 2.47 (t, 7.0)
1.22 (s) 1.22 (s) 1.18 (s) 5.93 (dd, 17.4, 10.8) 5.02 (dd, 1.3, 17.4) 5.04 (dd, 1.3, 10.8) 3.10 (s)
5.05d 5.00d 3.97 (dd, 7.7, 13.0) 1.82 (m) 1.72 (s) 1.64 (s) 1.23 (s) 5.96 (dd, 9.8, 16.3) 4.96d 4.96d 3.14 (s)
2.11 (s) 1.18 (s) 5.89 (dd, 17.3, 10.9) 5.01 (dd, 1.2, 17.3) 5.02 (dd, 1.2, 10.9)
3.33d 1.04 (t, 7.0)
The assignments were based on DEPT, HMQC and HMBC experiments; b measured at 400 MHz, in CD3OD; c measured at 400 MHz, in CDCl3; d overlapping signals
fungus Pyricularia oryzae (Magnaporthaceae), the meroterpene derivatives in the seeds of P. corylifolia and their antifungal activities were investigated. P. oryzae can cause rice blast and bring serious yield losses of rice, which is one of the most important cereals in the world. Controlling this disease is therefore one of the main goals of rice growers because when left untreated, the economic loss is significantly high [26, 27]. In addition, the deformation of mycelia of P. oryzae was also utilized as a screening assay for compounds that interfere with microtubule function [28]. The current study presents the isolation and structure elucidation of six new meroterpenes, namely, 13-methoxyisobakuchiol (1), 13-ethoxyisobakuchiol (2), 12,13-dihydro-13-hydroxybakuchiol (3), Δ10-12,13-dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5), and 15-demetyl-12,13-dihydro-13-ketobakuchiol (6), together with four known ones, namely, Δ3,2-hydroxybakuchiol
(7), Δ1,3-hydroxybakuchiol (8), bakuchiol (9), and Δ1,3-bakuchiol " Fig. 1). All the compounds showed moderate antifungal (10) (l activities against P. oryzae with 100% inhibition at MIC levels of 7.8 µg/mL to 31.2 µg/mL. However, the biological feature of the deformation of mycelia was not observed during the experiment.
Results and Discussion !
Compound 1 was obtained as a colorless oil with a molecular formula of C19H26O2 according to HR‑EI‑MS at m/z 286.1939 [M]+. Its 1 H NMR spectrum indicated typical signals of a phenolic mono" Table 1): AAʼXX′-type aromatic proton signals at δ terpene (l H 7.18 (d, J = 8.6 Hz, 2H, H-2, 6) and 6.71 (d, J = 8.6 Hz, 2H, H-3, 5); vinyl group signals at δH 5.02 (dd, J = 1.3, 17.4 Hz, 1H, H-3′a), Huang Y et al. Meroterpenes from Psoralea …
Planta Med 2014; 80: 1298–1303
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Fig. 1
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a
13
C NMR data of compound 1–6 (δ in ppm)a.
Position
1b
2b
3c
4b
5b
6b
1 2, 6 3, 5 4 7 8 9 10 11 12 13 14 15 1′ 2′ 3′ OCH3 O‑CH2CH3
130.7 128.2 116.3 157.8 128.5 135.3 43.6 45.4 128.1 138.9 76.5 26.3 26.3 24.1 147.1 112.5 50.6
130.7 128.2 116.3 157.9 128.6 135.3 43.7 45.4 127.5 139.5 76.3 27.0 26.9 24.1 147.2 112.4
130.1 126.9 115.0 154.6 126.1 135.3 42.1 41.4 18.8 44.1 70.9 28.8 28.8 23.0 145.6 111.5
130.9 128.2 116.3 157.8 127.9 135.5 43.0 127.7 127.8 136.6 76.4 26.0 18.6 24.7 147.9 111.9 55.3
130.9 128.2 116.3 157.8 127.9 135.9 43.0 127.7 127.8 136.6 76.4 26.0 18.6 24.7 147.3 111.9 55.3
130.8 128.2 116.3 157.8 128.4 135.5 43.4 41.8 20.0 44.7 212.0 29.8 23.9 147.3 112.3
59.0 16.2
The assignments were based on DEPT, HMQC and HMBC experiments; b measured at 100 MHz, in CD3OD; c measured at 100 MHz, in CDCl3
5.04 (dd, J = 1.3, 10.8 Hz, 1H, H-3′b), and 5.93 (dd, J = 17.4, 10.8 Hz, 1H, H-2′); two trans double bonds at δH 6.24 (d, J = 16.3 Hz, 1H, H7) and 6.04 (d, J = 16.3 Hz, 1H, H-8); δH 5.59 (m, 1H, H-11) and 5.42 (d, J = 15.8 Hz, 1H, H-12); three methyl signals at δH 1.22 (s, 6H, H-14, 15) and 1.18 (s, 3H, H-1′); and one methylene at δH 2.25 (d, J = 7.2 Hz, 2H, H-10). Comparison of 1H and 13C NMR spectra " Table 1 and 2) with those of a known phenolic monoterdata (l pene, Δ3,2-hydroxybakuchiol (7) [19], which was obtained in the current study, showed that the only difference was that methoxylation (δH 3.10, s, 3H, -OCH3) occurred at a hydroxyl linked to C13. In the mass spectra, 1 showed 14 mass units more than 7, which supports the abovementioned assumption. This conclusion was further confirmed by the correlation between δH 3.10 (s, 3H, -OCH3) and C-13 (δC 76.5) in the HMBC spectrum. The stereochemistry of the stereogenic center at C-9 could be assumed based on biogenetic consideration because only 9S-bakuchiol is naturally occurring [14]. Thus, compound 1 was deter" Fig. 1. mined as 13-methoxyisobakuchiol, as shown in l Compound 2 was obtained as a colorless oil with a molecular formula of C20H28O2 established by HR‑EI‑MS at m/z 300.2090 [M]+. " Table 1 and 2) Comparison of 1H and 13C NMR spectra data (l with those of 7 showed that the only difference was that an ethyoxyl group substituted the hydroxyl linked to C-13 of 7. Thus, compound 2 was determined as 13-ethoxyisobakuchiol. Compound 3 was obtained as a colorless oil. The HR‑EI‑MS at m/z 274.1936 [M]+ confirmed the molecular formula of C18H26 O2. The 1H and 13C NMR spectra data of 3 were comparable with those of compound 7, which indicated that 3 was also a modified Δ3,2-hydroxybakuchiol (7) and a meroterpene. The absence of the proton signals of olefinic methine (H-11 and H-12) of Δ3,2hydroxybakuchiol (7) and the presence of two methylene proton signals at 1.33 (overlapped, 2H, H-11) and 1.45 (overlapped, 2H, H-12) in the 1H NMR led to the inference that an addition reaction occurred at the C-11 and C-12 double bonds of Δ3,2-hydroxybakuchiol (7). Compound 3 was therefore determined as 12,13-dihydro-13-hydroxybakuchiol, which was confirmed by HMQC and HMBC NMR analyses.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
A mixture of compounds 4 and 5 was obtained as a colorless oil and could not be separated via column chromatography on silica gel or HPLC. The 1H and 13C NMR spectra data of the mixture showed the presence of two compounds, and they possessed a similar molecular formula of C19H26O2 based on the HR‑EI‑MS results at m/z 286.1934 [M]+. The 1H NMR spectrum exhibited two sets of signals, and each set indicated the presence of one set of AA′XX′-type aromatic protons, two trans double bonds, one set of a vinyl group, three methyls, one oxymethine proton, one methine proton, and one methyloxy group. The abovementioned information implied that they were isomers. The 1H and 13C NMR spectra data were comparable with those of bakuchiol (9), which indicated that the mixture was also a modified bakuchiol. The HMBC spectrum, in which correlations were observed from the methyloxy signals to C-12 (δC 136.6), indicated that the methyloxy group was bound to C-12. The signals at δH 5.05 (2H, H-10), 5.00 (2H, H-11) in the 1H NMR spectrum and δC at 127.7 and 127.8 (C-10, 11) in the 13C NMR spectrum indicated that a dehydrogenation occurred at C-10 and C-11 of bakuchiol (9). Thus, 4 and 5 were determined as a mixture of Δ10-12,13-dihydro-12" Fig. 1. (R,S)-methoxyisobakuchiol, as shown in l Compound 6 was obtained as a colorless oil. Its molecular formula was assigned as C17H22O2 based on the HR‑EI‑MS peak at m/z 258.1619 [M]+. The 1H NMR spectra data of 6 indicated typical " Table 1): AA′XX′-type prosignals of a phenolic monoterpene (l ton signals at δH 7.19 (d, J = 8.6 Hz, 2H, H-2, 6) and 6.71 (d, J = 8.6 Hz, 2H, H-3, 5); one trans double bond signal at δH 6.24 (d, J = 16.3 Hz, 1H, H-7) and 6.02 (d, J = 16.3 Hz, 1H, H-8); one vinyl group signal at δH 5.01 (dd, J = 1.3, 17.3 Hz, 1H, H-3′a), 5.02 (dd, J = 1.3, 10.9 Hz, 1H, H-3′b), and 5.89 (dd, J = 17.3, 10.9 Hz, 1H, H2′); two methyls at δH 1.18 (s, 3H, H-1′,) and 2.11 (s, 3H, H-14); and three methylenes at δH 1.45 (H-10), 1.54 (H-11) and 2.47 (t, J = 3.0 Hz, H-12). The 13C NMR spectra data of 6 showed the signals of 17 carbon atoms including two methyls, three methylenes in the aliphatic region and one vinyl methylene, seven methines, and four quaternary carbons with one normal ketone at δC 212.0 (s, C-13) inside, which were identified via DEPT 135 experiments. By comparing the 1H and 13C NMR spectra data of 3 with those of
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Table 2
Original Papers
1301
Table 3 MIC values (µg/mL) of compounds 1–10 on P. oryzae with 100 % inhibition. Ketoco-
pounds
nazole
MIC value
7.8
1
2
3
4, 5
6
7
8
9
10
7.8
15.6
31.2
15.6
7.8
15.6
3.9
15.6
31.2
6, compound 6 was suggested to be a modified 11,12-tetrahydroΔ3,2- hydroxybakuchiol with the absence of one methyl group and the presence of one ketone carbon. In the HMBC spectrum, the correlations between 1.54 (m, H-11)/2.11 (s, H-14)/2.47 (t, J = 7.0, H-12) and δC 212.0 (s, C-13) confirmed the placement of the normal ketone carbon. Detailed analyses of HMBC correlations clearly identified the structure of 6 as 15-demetyl-12,13-dihydro-13-ketobakuchiol. Four known phenolic monoterpenes that were previously reported from this plant, namely, Δ3,2-hydroxybakuchiol (7) [19], Δ1,3-hydroxybakuchiol (8) [29], bakuchiol (9) [21], and Δ1,3-bakuchiol (10) [29], were also obtained. Furthermore, the antifungal activities of compounds 1–10 were evaluated via the P. oryzae inhibition test. Studies showed that abnormal features of P. oryzae conidia or hyphae (curling, expansion, too much hyphal branching, or moniliform, etc.) were related to antifungal or antitumor activities. Based on the P. oryzae bioassay, many antifungal and antineoplastic agents were identified from fungus metabolites [28] and extraction of the plant " Ta[30]. MIC values with 100 % inhibition of 1–10 are shown in l ble 3. All of the compounds showed moderate antifungal activities against P. oryzae at MIC levels of 7.8 µg/mL to 31.2 µg/mL. However, the abnormal shape of conidia was not observed during the experiment, suggesting these compounds have no potential antitumor activities.
Materials and Methods !
Plant materials The seeds of P. corylifolia were purchased from a local herbal medicine market in Shanghai (manufactured by Kangqiao Pharmaceuticals Company), and were authenticated by Dr. Yingchun Wu (School of Pharmacy, Shanghai University of Traditional Chinese Medicine). Voucher specimens (20120930) were deposited in the Natural Products Chemistry Laboratory of the School of Pharmacy, Shanghai University of Traditional Chinese Medicine.
General experimental procedures The IR spectra were obtained using a Nicolet-Magna-750-FTIR spectrometer (KBr pellets) (ThermoFisher). Optical rotations were recorded using a Perkin-Elmer 341 polarimeter. 1H, 13C, and 2D NMR spectra were obtained using a Bruker AV-400 instrument (1H: 400 MHz and 13C: 100 MHz). The EI‑MS and HR‑EI‑MS data were obtained using a Finnigan MAT-95 mass spectrometer (m/z). Silica gel (200–300 mesh) for column chromatography was purchased from Qingdao Haiyang Chemical Company. Sephadex LH-20 for column chromatography was purchased from GE Biosciences. ODS for column chromatography was purchased from Fuji Silica Chemical Company. TLC plates were obtained Yantai Jiangyou Company.
Extraction and isolation The dried seeds of P. corylifolia (9.5 kg) were extracted three times at reflux conditions in 95% ethanol (7.0 L and 2 h each at 80 °C). The combined extract was evaporated at reduced pressure to yield a crude extract (1.5 kg) in vacuo at 60 °C. The crude extract was suspended in water (3.0 L) and then successively partitioned with petroleum ether (PE) (3.0 L × 3) and ethyl acetate (EtOAc) (3.0 L × 3). The combined EtOAc part (400 g) was subjected to silica gel column chromatography (CC, 15 cm × 100 cm, 5.0 kg, mesh 100 to 200) and eluted with PE-EtOAc mixtures of increasing polarity (PE : PE-EtOAc = 15 : 1, 12 : 1, 9 : 1, 6 : 1, 3 : 1, 1 : 1, 1 : 3, 1 : 6, 1 : 9, and EtOAc, each 2 L, the volume of all samples was 500 mL) to yield 17 fractions (Fr. 1 to 17) according to the thin-layer chromatography (TLC) monitor. Fr. 9 (10 g) was subjected to silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-acetone (PE, PE-acetone = 7 : 1 to 1 : 1, 250 mL each sample) to obtain 11 subfractions (Fr. 9.1 to Fr. 9.11). Fr. 9.6 (1 g) was further separated via silica gel chromatography (CC, 35 cm × 4 cm, 150 g, mesh 300 to 400) eluted with CH2Cl2-MeOH (400 : 1, 200 : 1, 100 : 1, and 40 mL each sample) to obtain 8 (400 mg, 97.2 %). Fr. 9.5 (1.77 g) was purified via C18 chromatography (CC, 25 cm × 3 cm, 110 g) with 60% → 80 % MeOH (30 mL each sample) to obtain 6 (12 mg, 97.5 %) and 10 (13 mg, 97.6 %). Fr. 10 (12 g) was further separated via silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-acetone (10 : 1, 9 : 1, 8 : 1, 6 : 1, 4 : 1, 3 : 1, and 1 : 1, 250 mL each sample) to obtain 20 subfractions (Fr. 10.1 to Fr. 10.20). Fr. 10.4 (53 mg) was subjected to Sephadex LH-20 (CC, 51 cm × 2 cm) with MeOH and followed by C18 chromatography (CC, 24 cm × 2 cm, 50 g) with 70 %→85 % MeOH resp. (10 mL each sample resp.) to yield 4 and 5 (7 mg, 97.5 %) and 2 (23 mg, 98.4 %). Fr. 10.3 (63 mg) was purified by Sephadex LH-20 (CC, 51 cm × 2 cm) eluted with MeOH (10 mL each sample) to obtain 1 (47 mg, 98.2 %). Fr. 12 (35 g) was further separated via silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with CH2Cl2-MeOH (CH2Cl2-MeOH = 80 : 1, 70 : 1, 50 : 1, 250 mL each sample) to obtain 9 subfractions (Fr. 12.1 – Fr. 12.9). Fr. 12.2 (1.0 g) was repurified via silica gel chromatography (CC, 35 cm × 4 cm, 150 g, mesh 300 to 400) eluted with PE-EtOAc (PE, PEEtOAc = 5 : 1, 4 : 1, 3 : 1, EtOAC, 40 mL of each sample) to obtain 7 (148 mg, 98.6 %). Fr. 12.3 (55 mg) was chromatographed via C18 chromatography (CC, 20 cm × 2 cm, 30 g) with 65% → 80 % MeOH (5 mL each sample) to obtain 3 (20 mg, 98.1 %). Fr. 13 (22 g) was subjected to silica gel chromatography (CC, 70 cm × 10 cm, 2.0 kg, mesh 300 to 400) eluted with PE-EtOAc (PE, PE-EtOAc = 4 : 1, 3 : 1, 2 : 1 and EtOAc, 250 mL each sample) to obtain 14 fractions (Fr. 13.1 to Fr. 13.14). Fr. 13.3 (220 mg) was further purified via C18 chromatography (CC, 24 cm × 2 cm, 50 g) with 70% → 85 % MeOH (10 mL each sample) to obtain 9 (43 mg, 98.3 %). 13-Methoxyisobakuchiol (1): brown oil. [α]25 D + 7.3 (c 1.0, MeOH); 1 " Table 1 and 2. HMBC correlations H-2, H and 13C NMR data, see l 6/C‑3, 4, 5; H-3, 5/C‑2, 4, 6; H-7/C-8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/ C-8, 9, 11, 12, 1′, 2′; H-11/C-10, 13; H-12/C-10, 11, 13, 14, 15; H14, 15/C- 12, 13; H-1′/C‑8, 9, 10, 2′; H-2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV
Huang Y et al. Meroterpenes from Psoralea …
Planta Med 2014; 80: 1298–1303
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Com-
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λmax (CH3OH) nm (log ε): 265 (3.63), 206 (3.88); IR (KBr) νmax 3296, 2974, 2931, 1676, 1608, 1514, 1450, 1412, 1366, 1236, 1170, 1157, 1101, 1059, 998, 973, 916, 848, 813 cm−1; EI‑MS: m/ z 286, 258, 241, 223, 205, 185, 173 (100 %), 158, 149, 145. HR‑EI‑MS: m/z 286.1939 [M]+ (calcd. for C19H26O2: 286.1933). 13-Ethoxyisobakuchiol (2): colorless oil. [α]25 D + 1.0 (c 1.0, MeOH); 1 " Table 1 and 2. HMBC correlations H-2, H and 13C NMR data, see l 6/C‑4; H-3, 5/C‑1, 4; H-7/C-2, 6, 8, 9; H-8/C-1, 7, 9, 10, 1′, 2′; H-10/ C-8, 9, 11, 12, 1′, 2′; H-11/C-10, 13; H-12/C-10, 11, 13, 14, 15; H14/C-12, 13; H-15/C-12, 13; H-16/C-13, 17; H-17/C-16; H-1′/C‑8, 9, 10, 2′; H-2′/C‑8, 9, 10, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.76), 206 (4.02); IR (KBr) νmax 3351, 2974, 2929, 1727, 1610, 1589, 1514, 1442, 1363, 1267, 1235, 1170, 1157, 1102, 1060, 973, 916, 847, 812 cm−1; EI‑MS: m/z 300, 254, 239, 223, 205, 187, 173 (100 %), 158, 149, 145. HR‑EI‑MS m/z 300.2090 [M]+ (calcd. for C20H28O2: 300.2089). 12,13-Dihydro-13-hydroxybakuchiol (3): colorless oil. [α]25 D + 33.1 " Table 1 and 2. HMBC (c 1.0, MeOH); 1H and 13C NMR data, see l correlations H-2, 6/C‑4, 7; H-3, 5/C‑1, 4; H-7/C-1, 6, 8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/C-8, 11, 13, 1′, 2′; H-11/C-13; H-12/C-11, 13, 14, 15; H-14, 15/C‑12, 13; H-1′/C‑8, 9, 2′; H-2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.63), 207 (3.79); IR (KBr) νmax 3379, 2969, 1705, 1677, 1610, 1514, 1453, 1371, 1241, 1171, 1102, 1001, 971, 912, 815 cm−1; EI‑MS: m/z 274, 256, 241, 223, 185, 173 (100 %), 158, 145. HR‑EI‑MS m/z 274.1936 [M]+ (calcd. for C18H26O2: 274.1933). Δ10-12,13-Dihydro-12-(R,S)-methoxyisobakuchiol (4 and 5): color1 13 " Taless oil. [α]25 C NMR data, see l D − 0.7 (c 1.0, MeOH); H and ble 1 and 2. HMBC correlations H-2, 6/C‑4; H-3, 5/C‑1, 4; H-7/C-2, 6, 8, 9; H-8/C-1, 7, 9, 10, 1′, 2′; H-10/C-9, 2′; H-11/C-9, 2′; H-12/C8, 9, OCH3; H-14/C-11, 13; H-15/C-11, 13; H-1′/C‑8, 9, 2′; H-3′/ C‑9, 2′. UV λmax (CH3OH) nm (log ε): 263 (3.08), 206 (3.92); IR (KBr) νmax 3384, 2928, 1673, 1609, 1514, 1448, 1376, 1267, 1170, 1078, 971, 916, 838 cm−1; EI‑MS: m/z 286, 271, 254, 239, 204, 189, 173 (100 %), 158, 145. HR‑EI‑MS m/z 286.1934 [M]+ (calcd. for C19H26O2: 286.1933). 15-Demetyl-12,13-dihydro-13-ketobakuchiol (6): colorless oil. 1 13 " Table 1 and C NMR data, see l [α]25 D + 6.3 (c 1.0, MeOH); H and 2. HMBC correlations H-2, 6/C‑3, 4, 5, 7; H-3, 5/C‑1, 2, 4, 6; H-7/C1, 2, 6, 8, 9; H-8/C-1, 7, 9, 1′, 2′; H-10/C-8, 9, 11, 1′, 2′; H-11/C-10, 12, 13; H-12/C-10, 11, 13; H-14/C-12, 13; H-1′/C‑8, 9, 10, 2′, 3′; H2′/C‑8, 9, 1′; H-3′/C‑9, 2′. UV λmax (CH3OH) nm (log ε): 262 (3.56), 206 (3.89); IR (KBr) νmax 3367, 2959, 1702, 1635, 1609, 1589, 1514, 1439, 1411, 1367, 1265, 1224, 1171, 972, 915, 816 cm−1; EI‑MS: m/z 258, 241, 223, 205, 185, 173, 163 (100 %), 149. HR‑EI‑MS m/z 258.1619 [M]+ (calcd. for C17H22O2: 258.1620).
Pyricularia oryzae inhibition test The P. oryzae inhibition test was performed to screen the antifungal activities of all compounds. P. oryzae was incubated at 37 °C for ten days and the spores were then collected in 10 mL of sterile water. Each well of the 96-well microplate contained 50 µL of the spore liquid. The compounds were dissolved in MeOH/H2O (10%) and added to the first line of a 96-well microplate. A serial twofold dilution of the compounds was made from 1 mg/mL. The 96well microplate was cultured at 37 °C for 16 h. The maximum activity dilution was defined as the maximum concentration of antimicrobial agents that completely inhibited the visible growth of the spores. Ketoconazole (98 %, Sigma) was used as the positive control sample. MeOH/H2O (10%) was used as the negative control sample.
Huang Y et al. Meroterpenes from Psoralea … Planta Med 2014; 80: 1298–1303
Acknowledgements !
This research program was supported by the Natural Science Foundation of Shanghai (13ZR1441700), “Xing-lin” scholar of SHUTCM, and Eastern Scholar Program.
Conflict of Interest !
All authors contributed to and have approved the final manuscript. The authors declare no conflict of interest.
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