Note Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
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Euphorhelipanes A and B, Triglyceride-Lowering Euphorbia Diterpenoids with a Bicyclo[4.3.0]nonane Core from Euphorbia helioscopia Wei Li,† Ya-Qi Tang,† Shi-Xin Chen,‡ Gui-Hua Tang,† Li-She Gan,‡ Chan Li,† Yong Rao,† Zhi-Shu Huang,† and Sheng Yin*,† †
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, People’s Republic of China College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China
‡
J. Nat. Prod. Downloaded from pubs.acs.org by TULANE UNIV on 02/06/19. For personal use only.
S Supporting Information *
ABSTRACT: Euphorhelipanes A (1) and B (2), two Euphorbia diterpenoids with a new 4-(5,5-dimethylheptan-2-yl)-2,7dimethylbicyclo[4.3.0]nonane skeleton, were isolated from a 95% ethanol extract of the whole plants of Euphorbia helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 represent the first examples of Euphorbia diterpenoids with a 5/6 fused carbon ring system, and their plausible biosynthetic pathways originating from jatrophanes are proposed. Compounds 1 and 2 showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells at concentrations of 1−50 μM. Euphorbia diterpenoids refer to a group of structurally intriguing and biologically significant diterpenoids from the plants of the genus Euphorbia (Euphorbiaceae). So far, more than 700 Euphorbia diterpenoids, representing ca. 30 skeletal types, have been isolated from Euphorbia plants.1,2 The great structural diversity arising from highly functionalized macrocyclic and polycyclic skeletons confers a wide range of biological activities and has made this compound class a research hot-spot in the related scientific communities over the past decades.2 For example, ingenol 3-angelate (5/7/7/3 ring system) from E. peplus was approved by the FDA in 2012 for the treatment of actinic keratosis.3 Resiniferatoxin (5/7/6 ring system) from E. resinifera is an ultrapotent vanilloid receptor agonist currently under phase II and III clinical evaluation for the treatment of bladder hyperreflexia, diabetic neuropathy, and cancer pain.4 Prostratin (5/7/6/3 ring system) from E. cornigera is considered as a promising therapeutic agent in HIV treatment due to its unique ability to activate latent viral reservoirs and protect healthy cells from infection.5 Euphorbia helioscopia L. is an annual herb widely distributed in China. Its aerial parts are used as a traditional Chinese medicine for treatment of warts, bacillary dysentery, and tumors.6 Previous chemical investigations of this species revealed that abietane, lathyrane, and jatrophane diterpenoids © XXXX American Chemical Society and American Society of Pharmacognosy
were the main metabolites, and some of them possessed fascinating structures and intriguing activities.7−10 For instance, heliosterpenoid A and heliojatrone B, possessing a new 5/6/4/6 ring system and an unprecedented transbicyclo[8.3.0]tridecane core, respectively, were identified as potent ATP binding cassette transporter B1 (ABCB1) inhibitors.7,8 Secoheliosphane B, possessing an unusual 7,8seco-jatrophane skeleton, showed modest activity against HSV1.9 In our continuing efforts toward discovering structurally interesting and biologically significant diterpenoids from Euphorbiaceae plants,11−13 two new diterpenoids with an unusual bicyclo[4.3.0]nonane core were isolated from the aqueous ethanol extract of the whole plants of E. helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 dose-dependently reduce the triglyceride (TG) level in oleic acid (OA)-stimulated HuH7 cells. Herein, the isolation, structural elucidation, biosynthetic considerations, and TG-lowering effects of 1 and 2 are discussed. Received: September 13, 2018
A
DOI: 10.1021/acs.jnatprod.8b00780 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Construction of the 2D structure for 1 was accomplished by interpretation of 2D NMR data (Figure 1). Three spin
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RESULTS AND DISCUSSION Euphorhelipane A (1) was obtained as colorless needles. The molecular formula C 20 H 30 O 4 was determined by the HRESIMS ion at m/z 335.2213 [M + H]+ (calcd for 335.2217) and 13C NMR data, corresponding to six indices of hydrogen deficiency (IHDs). The IR absorption bands revealed the presence of hydroxy (3451 cm−1) and carbonyl (1707 cm−1) groups. The 1H NMR data (Table 1) displayed
Figure 1. Key 1H−1H COSY (bold lines) and HMBC (blue →) correlations of 1 (left). Single-crystal X-ray structure of 1 (right).
systems, H-3/H-4, H-11/H-12/H-13/H3-20, and H3-16/H-2/ H-1/H-5/H-6/H-7 (H3-17), were first established by the 1 H−1H COSY correlations. The connectivities of these fragments, the ketocarbonyls, the oxygenated sp3 tertiary carbon, and the quaternary carbon were done by analysis of the key HMBC correlations. The HMBC correlations of H-3/C-1, C-2, and C-16 and H-4/C-1 and C-5 connected the Δ3(4) double bond to C-2 and C-5 to generate a five-membered Aring. A ketocarbonyl (C-15) and an oxymethine (C-7) were attached to an oxygenated sp3 tertiary carbon (C-14) by HMBC correlations of HO-14/C-7, C-14, and C-15. The HMBC correlation from H-1 to C-15 linked C-1 to C-15 to form a six-membered B-ring. Thus, the bicyclo[4.3.0]nonane core of 1 was established. The HMBC correlations from H3-18 and H3-19 to C-9, C-10, and C-11 and from H3-8 to the other ketocarbonyl (C-9) defined a 3,3-dimethylhept-4-en-2-one side chain. The C9 side chain was connected to C-14 of the bicyclic carbon core via C-13 by HMBC correlations of H-7/C-13 and H3-20/C-14, which generated a 4-(5,5-dimethylheptan-2-yl)2,7-dimethylbicyclo[4.3.0]nonane skeleton. The relative configuration of 1 was established by analysis of the NOESY data (Figure 2) and 1H−1H coupling constants.
Table 1. 1H NMR (500 MHz) and 13C NMR (125 MHz) Spectroscopic Data of 1 and 2 in CDCl3 (J in Hz, δ in ppm) 1
2
no.
δH, mult. (J in Hz)
δC
δH, mult. (J in Hz)
δC
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 14-OH
2.43, dd (12.7, 10.2) 2.90, m 5.64, ddd (5.7, 2.6, 1.4) 5.76, ddd (5.7, 1.9, 1.9) 2.90, m 2.09, m 4.04, d (2.2) 2.05, s
62.7 37.5 137.6 130.4 52.9 37.0 78.4 25.3 211.0 50.2 135.5 129.3 41.8 83.3 210.4 18.5 15.2 23.6 24.5 15.6
2.47, dd (12.1, 10.4) 2.94, m 5.66, br d (5.7) 5.76, br d (5.7) 2.93, m 2.08, m 3.89, br s 2.10, s
62.3 37.4 137.6 130.5 53.1 36.6 78.9 25.4 211.1 50.4 135.5 129.3 42.5 83.5 210.6 18.3 15.1 23.9 23.9 15.0
5.49, d (15.8) 5.29, dd (15.8, 9.2) 2.73, m
1.02, 1.21, 1.15, 1.12, 1.11, 4.18,
d (6.8) d (6.8) s s d (6.8) br s
5.60, d (15.9) 5.58, dd (15.9, 9.2) 2.76, m
1.09, 1.16, 1.22, 1.23, 0.79, 4.19,
d (6.5) d (6.8) s s d (6.8) br s
signals for six methyl groups [δH 1.02 (d, J = 6.8 Hz), 1.11 (d, J = 6.8 Hz), 1.12 (s), 1.15 (s), 1.21 (d, J = 6.8 Hz), and 2.05 (s)], two trans-olefinic protons [δH 5.29 (1H, dd, J = 15.8, 9.2 Hz) and 5.49 (1H, d, J = 15.8 Hz)], two cis-olefinic protons [δH 5.64 (1H, ddd, J = 5.7, 2.6, 1.4 Hz) and 5.76 (1H, ddd, J = 5.7, 1.9, 1.9 Hz)], an oxymethine proton [δH 4.04 (1H, d, J = 2.2 Hz)], an exchangeable proton [δH 4.18 (1H, br s)], and a series of aliphatic multiplets. The 13C NMR spectrum, combined with DEPT experiments, resolved 20 carbon resonances attributable to two ketocarbonyls (δC 211.0 and 210.4), two disubstituted double bonds (δC 137.6, 135.5, 130.4, and 129.3), six methyls, six sp3 methines (one oxygenated), an oxygenated sp3 tertiary carbon, and an sp3 quaternary carbon. As four of the six IHDs were accounted for by two ketocarbonyls and two double bonds, the remaining two IHDs required that 1 was bicyclic.
Figure 2. Key NOE (blue dashed arrows) correlations of 1 and 2.
The strong NOE interactions of H-6/H-1 and H-13 and H-1/ H-13 indicated that H-6, H-1, and the C9 side chain occupied the axial positions of the B-ring (chair conformation) and were arbitrarily assigned α-orientations. Thus, the NOE correlations of H-1/H3-16, H-2/H-5, and H-6/H-7 assigned H-2, H-5, and 7-OH as β-oriented. The trans-relationships of H-2/H-1/H-5 and cis-relationship of H-6/H-7 were supported by the large coupling constants of H-1 (dd, J = 12.7, 10.2 Hz) and small coupling constants of H-7 (d, J = 2.2 Hz), respectively. The geometry of the Δ11(12) double bond was assigned as E by NOE correlations of H-13/H-11 and H-12/H3-19, as well as by the coupling constant of H-11/H-12 (J = 15.8 Hz). B
DOI: 10.1021/acs.jnatprod.8b00780 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Me-20 in 2. This assignment was consistent with the preferred conformations of (13S*)-1 and also explained the different variation tendencies of the 1H chemical shifts for Me-20 and H-12 in these two compounds, as the anisotropic effect of the 15-ketocarbonyl could induce a shielding effect on the protons facing toward it,14 leading to the upfield-shifted 1H chemical shifts for H-12 and Me-20 in 1 and 2, respectively. The absolute configuration of 2 was assigned as (1R,2S,5S,6S,7S,13S,14S) by using the same ECD data protocol described for 1 (Figure 4). Compounds 1 and 2 possessed an unprecedented scaffold that is hard to correlate with the known diterpenoid types. Inspired by the presence of the 3,3-dimethylhept-4-en-2-one side chain, which is a fragment commonly observed in the 12membered macrocycle of jatrophanes, a putative biosynthetic pathway of 1 and 2 is proposed from the accompanying major jatrophanes, euphoscopin A (3) and epieuphoscopin A (4)15 (Scheme 1). Briefly, 3 and 4 are susceptible to an enzyme-
Although the side chain in 1 could rotate about the C-13−C14 bond in solution, the strong NOE correlations of H-13/H-1 and H-6 and H3-20/H-7 suggested the presence of a stable conformation in which the Me-20 and H-13 adopted β and α orientations, respectively. This was supported by quantum chemical calculation of the preferred conformations of (13S*)and (13R*)-1 in solution (Figure S2a and b, Supporting Information). As shown in Figure 3, in all three preferred
Figure 3. Preferred conformation analysis of (13R*)- and (13S*)-1 in solution. (A) Three overlapped preferred conformers of (13R*)-1. (B) Six overlapped preferred conformers of (13S*)-1.
Scheme 1. Proposed Biosynthetic Pathway for Compounds 1 and 2
conformers of (13R*)-1, Me-20 and H-13 adopted β and α orientations, respectively, meeting the requirements of the observed NOE correlations, while in all six preferred conformers of (13S*)-1 the orientations of Me-20 were inversed, unable to generate the NOE correlation of Me-20/H7. The absolute configuration of 1 was determined by comparison of its experimental and simulated electronic circular dichroism (ECD) spectra using the quantum chemical time-dependent density functional theory (TDDFT) method (Supporting Information). As shown in Figure 4, the
catalyzed retro-aldol reaction followed by selective hydrolysis of the acetyl esters to generate the 7,8-seco-jatrophane-type intermediate i.9 The cleavage of the C-4−C-15 bond of i accompanied by the formations of the Δ3(4) double bond and the 15-ketocarbonyl by Grob fragmentaion 16 afforded intermediate ii. Michael addition between C-1 and the α,βunsatured formyl followed by aldol condensation between C14 and C-7 would afford 1 and 2. Compounds 1 and 2 were screened for their triglyceridelowering effect in an OA-stimulated HuH7 cell model, and the clinic lipid-lowering drug rosiglitazone was used as the positive control. As shown in Figure 5A, the stimulation of OA led to a significant increase of the TG level in HuH7 cells, while the treatments of 1 and 2 dose-dependently decreased the TG level in the range of 1−50 μM, being comparable to those of rosiglitazone. This was confirmed by the Oil Red O staining experiment (Figure 5B), in which the treatment with 1 and 2 effectively inhibited the formation of lipid droplets. As the TGlowering effects of 1 and 2 may arise from their intrinsic cytotoxicity, the lactate dehydrogenase (LDH)-releasing assay was also carried out. As shown in Figure 5C, the treatment with 1 and 2 at 0.1−50 μM did not alter the LDH-releasing level, suggesting tolerance of these compounds in cells. Bicyclic diterpenoids with a 5/6 fused carbon ring system are rare in nature.17−19 Compounds 1 and 2 represent the first examples of this diterpenoid class found in the genus
Figure 4. Experimental and calculated ECD spectra of 1 (left) and 2 (right) in MeCN.
experimental ECD spectrum of 1 showed Cotton effects around 312 (+), 281 (−), 213 (−), and 190 (+) nm, respectively, which matched well with those calculated for the (1R,2S,5S,6S,7S,13R,14S)-isomer, indicating that 1 possessed the same absolute configuration. This assignment was confirmed by single-crystal X-ray diffraction using Cu Kα radiation [Flack parameter at −0.03(8)] (Figure 1). Euphorhelipane B (2), a colorless oil, had the same molecular formula, C20H30O4, as 1, indicating that it was an isomer of 1. The 1H and 13C NMR spectra of 2 were similar to those of 1, with the major differences being the 1H chemical shifts around C-13 (H3-20: δH 0.79 in 2, 1.11 in 1; H-12: δH 5.58 in 2; 5.29 in 1), implying that 2 was a 13-epimer of 1. This was supported by comparison of the NOE data of 2 with those of 1 (Figure 2), in which the only difference was the replacement of the correlation of H-7/H3-20 in 1 by the correlation of H-1/H3-20 in 2, suggesting the α-orientation of C
DOI: 10.1021/acs.jnatprod.8b00780 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Figure 5. TG-lowering effects of 1 and 2 in OA-stimulated HuH7 cells. (A) TG level determination by TG assay. (B) Oil Red O staining of lipid droplets. (C) LDH-releasing level determination. *p < 0.05, **p < 0.01, ***p < 0.001, compared with blank group; #p < 0.05, ##p < 0.01, ###p < 0.001, compared with OA-stimulated cells. n = 4 independent experiments. Biosciences) were used for column chromatography (CC). All solvents (analytical grade) used were obtained from Guangzhou Chemical Reagents Company, Ltd. Plant Material. The whole plants of Euphorbia helioscopia were collected in Hanzhong, Shanxi Province, P. R. China, in April 2017. The plant was identified by Dr. You-Kai Xu, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, and voucher specimens (YEHL201704) are stored at the School of Pharmaceutical Sciences, Sun Yat-sen University. Extraction and Isolation. The air-dried powder of whole E. helioscopia plants (25 kg) was extracted using 95% EtOH (3 × 60 L) at room temperature. After evaporating the solvent, the residue (2.2 kg) was suspended in H2O and extracted with EtOAc (3 × 4 L). The EtOAc portion (800 g) was chromatographed over MCI gel CC (MeOH/H2O, 30 → 100%) to give four subfractions (I−IV). Fr. III (130 g) was chromatographed over C18 reversed-phase (RP-18) silica gel eluted with MeOH/H2O (60 → 100%) to obtain three fractions (Fr. IIIa−Fr. IIIc). Fraction IIIc (35 g) was separated by silica gel CC (petroleum ether/EtOAc, 15:1 → 1:2), followed by a Sephadex LH20 column (MeOH) to afford four fractions (Fr. IIIc1−Fr. IIIc4). Fr. IIIc2 was purified by RP-HPLC equipped with a YMC-pack ODS-A column (MeCN/H2O, 55:45, 3 mL/min) to give 1 (8.2 mg, tR 30.3 min) and 2 (6.3 mg, tR 32.4 min). Fr. IV (30g) was subjected to silica gel CC (petroleum ether/EtOAc, 50:1 → 0:1) to afford fractions IVa−IVd. Fr. IVd (1.2 g) was loaded onto a Sephadex LH-20 column eluted with MeOH to yield fractions IVd1−IVd3. Fr. IVd3 (600 mg) was separated by RP-HPLC with a YMC-pack ODS-A column (MeCN/H2O, 70:30, 3 mL/min) to afford 3 (260.3 mg, tR 13.2 min) and 4 (45.0 mg, tR 15.3 min). Euphorhelipane A (1): colorless crystals (petroleum ether/EtOAc, 5:1), mp 115−116 °C; [α]20D −10 (c 0.3, MeCN); UV (MeCN) λmax (log ε) 198 (3.92) nm; ECD (c 1.5 × 10−3 M, MeCN) λmax (Δε) 312
Euphorbia. Their unique biosynthetic pathways, involving a series of ring openings and reconstructions of the jatrophane backbone, rendered them a new scaffold containing seven consecutive stereogenic centers. Especially, the skeletal reconstruction of five-membered ring A in jatrophane diterpenoids is reported for the first time, supporting that the jatrophanes might be precursors of skeletally diverse Euphorbia diterpenoids in the Euphorbiaceae family.7−9 The decent TG-lowering effect and tolerance of 1 and 2 may also make them appealing template molecules in future hypolipidemic drug development.
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EXPERIMENTAL SECTION
General Experimental Procedures. Melting points were measured on an X-4 melting instrument and are uncorrected. Optical rotations were determined on a Rudolph Autopol I automatic polarimeter. ECD spectra were obtained on an Applied Photophysics Chirascan spectrometer, and UV spectra on a Shimadzu UV-2450 spectrophotometer. IR spectra were determined in KBr disks on a Bruker Tensor 37 infrared spectrophotometer. NMR spectra were measured on a Bruker AM-500 spectrometer at 25 °C. ESIMS and HRESIMS were performed on a Waters Micromass Q-TOF spectrometer (Waters, Milford, MA, USA). X-ray data were collected using an Agilent Xcalibur Nova X-ray diffractometer. Semipreparative HPLC was performed with a Shimadzu LC-20 AT equipped with an SPD-M20A PDA detector. Purification by HPLC was performed on a YMC-pack ODS-A column (250 × 10 mm, S-5 μm, 12 nm). Silica gel (100−200 and 300−400 mesh, Qingdao Haiyang Chemical Co., Ltd.), MCI gel (CHP20P, 75−150 μm, Mitsubishi Chemical Industries Ltd.), reversed-phase C18 (RP-C18) silica gel (12 nm, S50 μm, YMC Co., Ltd.), and Sephadex LH-20 gel (Amersham D
DOI: 10.1021/acs.jnatprod.8b00780 J. Nat. Prod. XXXX, XXX, XXX−XXX
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(+0.21), 281 (−0.84), 213 (−1.19), 190 (+3.80) nm; IR (KBr) νmax 3451, 2968, 2934, 2878, 1707, 1457, 1355, 1123, 981, 707 cm−1; 1H and 13C NMR data, see Table 1 and Table S1; ESIMS m/z 335.3 [M + H]+; HRESIMS m/z 335.2213 [M + H]+ (calcd for C20H31O4, 335.2217). Euphorhelipane B (2): colorless oil, [α]20D −17 (c 0.2, MeCN); UV (MeCN) λmax (log ε) 201 (3.98) nm; ECD (c 6.0 × 10−4 M, MeCN) λmax (Δε) 284 (−2.05), 224 (−0.57), 207 (+3.83) nm; IR (KBr) νmax 3456, 2963, 2931, 2875, 1708, 1457, 1354, 1123, 982, 707 cm−1; 1H and 13C NMR data, see Table 1 and Table S1; ESIMS m/z 335.2 [M + H]+; HRESIMS m/z 335.2218 [M + H]+ (calcd for C20H31O4, 335.2217). Crystallographic Data. Compound 1 was recrystallized from petroleum ether/EtOAc (5:1) to afford colorless needles. 4(C20H30O4) (M = 1337.75 g/mol): orthorhombic, space group P212121 (no. 19), a = 10.93590(10) Å, b = 24.4434(3) Å, c = 28.6271(3) Å, V = 7652.33(14) Å3, Z = 4, T = 100 K, μ(Cu Kα) = 0.634 mm−1, Dcalc = 1.161 g/cm3, 73 765 reflections measured (4.754° ≤ 2θ ≤ 144.248°), 15 071 unique (Rint = 0.0686, Rsigma = 0.0438), which were used in all calculations. The final R1 was 0.0806 (I > 2σ(I)) and wR2 was 0.2324 (all data). Flack parameter = −0.03(8). Crystallographic data for the structure of 1 have been deposited in the Cambridge Crystallographic Data Centre (deposition number: CCDC 1857260). Cell Culture. Hepatoma cell line HuH7 was cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin under a condition of 5% CO2 at 37 °C. Oleic Acid Induction. HuH7 cells were exposed to oleic acid to induce lipid accumulation in HuH7 cells as previously reported.20 Briefly, OA was coupled with fatty-acid-free bovine serum albumin, and then HuH7 cells were exposed to the mixture (the final concentration of OA is 0.5 mM) for 24 h in the presence of compound treatment at indicated concentrations. Triglyceride Level Determination and Oil Red O Staining Assay. Cells were fixed by 4% paraformaldehyde for 1 h at room temperature and then subject to Oil Red O staining as reported. Cellular triglycerides were extracted as recently described21 and determined using the commercial Peridochrom TG GPO-PAP kit (Jiancheng Bio, China) following the manufacturer’s instructions. Lactate Dehydrogenase Releasing Assay. Cells plated at low density (5000 cells/well) in 96-well plate were cultured with compounds at indicated concentrations. After 24 h of incubation, the level of LDH in the culture medium was determined by a commercial LDH kit (Jiangsu, China, Beyotime) according to the manufacturer’s instructions to assess cell viability. The LDH-releasing level in Ctrl group cells was viewed as 100%, and the relative releasing level of LDH in compound-treated cells was calculated. Statistical Analysis. Results are expressed as the mean ± SEM. Data between two groups were analyzed by Student’s t test using Graphpad Prism (Graphpad Software Inc., CA, USA). A p value of ≤0.05 was considered statistically significant.
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Zhi-Shu Huang: 0000-0002-6211-5482 Sheng Yin: 0000-0002-5678-6634 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank the Natural Science Foundation of China (81722042 and 81573302) and the Science and Technology Planning Project of Guangdong Province, China (2015A020211007), for providing financial support for this work.
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REFERENCES
(1) Shi, Q. W.; Su, X. H.; Kiyota, H. Chem. Rev. 2008, 108, 4295− 4327. (2) Vasas, A.; Hohmann, J. Chem. Rev. 2014, 114, 8579−8612. (3) Gupta, A. K.; Paquet, M. J. Cutaneous Med. Surg. 2013, 17, 173− 179. (4) Kissin, I.; Szallasi, A. Curr. Top. Med. Chem. 2011, 11, 2159− 2170. (5) Miana, G. A.; Riaz, M.; Shahzad-ul-Hussan, S.; Paracha, R. Z.; Paracha, U. Z. Mini-Rev. Med. Chem. 2015, 15, 1122−1130. (6) Flora of China Editorial Committee. Flora of China; Science Press: Beijing, 1997; Vol. 44, p 71. (7) Mai, Z. P.; Ni, G.; Liu, Y. F.; Li, L.; Shi, G. R.; Wang, X.; Li, J. Y.; Yu, D. Q. Sci. Rep. 2017, 7, 4922−4929. (8) Mai, Z. P.; Ni, G.; Liu, Y. F.; Li, L.; Li, J. Y.; Yu, D. Q. Org. Lett. 2018, 20, 3124−3127. (9) Mai, Z. P.; Ni, G.; Liu, Y. F.; Li, Y. H.; Li, L.; Li, J. Y.; Yu, D. Q. J. Org. Chem. 2018, 83, 167−173. (10) Wang, W. P.; Jiang, K.; Zhang, P.; Shen, K. K.; Qu, S. J.; Yu, X. P.; Tan, C. H. Phytochemistry 2018, 145, 93−102. (11) Zhu, J. Y.; Wang, R. M.; Lou, L. L.; Li, W.; Tang, G. H.; Bu, X. Z.; Yin, S. J. Med. Chem. 2016, 59, 6353−6369. (12) Zhang, J. S.; Tang, Y. Q.; Huang, J. L.; Li, W.; Zou, Y. H.; Tang, G. H.; Liu, B.; Yin, S. Phytochemistry 2017, 144, 151−158. (13) Zhang, J. S.; Zhang, Y.; Li, S.; Ahmed, A.; Tang, G. H.; Yin, S. Bioorg. Chem. 2018, 80, 511−518. (14) Karabatsos, G. J.; Sonnichsen, G. C.; Hsi, N.; Fenoglio, D. J. J. Am. Chem. Soc. 1967, 89, 5067−5068. (15) Yamamura, S.; Shizuri, Y.; Kosemura, S.; Ohtsuka, J.; Tayama, T.; Ohba, S.; Ito, M.; Saito, Y.; Terada, Y. Phytochemistry 1989, 28, 3421−3436. (16) Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741−3766. (17) Hanson, J. R. Nat. Prod. Rep. 1992, 9, 1−16. (18) Peters, R. J. Nat. Prod. Rep. 2010, 27, 1521−1530. (19) Li, R.; Morris-Natschke, S. L.; Lee, K. H. Nat. Prod. Rep. 2016, 33, 1166−1226. (20) Rao, Y.; Liu, H.; Gao, L.; Yu, H.; Ou, T. M.; Tan, J. H.; Huang, S. L.; Wang, H. G.; Li, D.; Gu, L. Q. J. Med. Chem. 2015, 58, 9395− 9413. (21) Rao, Y.; Yu, H.; Gao, L.; Lu, Y. T.; Xu, Z.; Liu, H.; Gu, L. Q.; Ye, J. M.; Huang, Z. S. Br. J. Pharmacol. 2017, 174, 2457−2470.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00780. MS, IR, 1D and 2D NMR spectra for 1 and 2, and ECD calculations of 1 (PDF)
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AUTHOR INFORMATION
Corresponding Author
*(S. Yin) Tel: +86-20-39943090. Fax: +86-20-39943090. Email:
[email protected]. ORCID
Gui-Hua Tang: 0000-0002-8831-7154 E
DOI: 10.1021/acs.jnatprod.8b00780 J. Nat. Prod. XXXX, XXX, XXX−XXX
