Diterpene Alkaloids with an Aza-ent-kaurane Skeleton from Isodon

Article pubs.acs.org/jnp

Diterpene Alkaloids with an Aza-ent-kaurane Skeleton from Isodon rubescens Xu Liu,†,‡,⊥ Jing Yang,†,§,⊥ Wei-Guang Wang,† Yan Li,† Ji-Zhou Wu,‡ Jian-Xin Pu,*,† and Han-Dong Sun*,† †

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, People’s Republic of China ‡ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People’s Republic of China § Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China S Supporting Information *

ABSTRACT: Two compounds belonging to a new group of diterpene alkaloids, kaurines A and B (1 and 2), and an alkaloid bearing a succinimide moiety (3) were obtained from Isodon rubescens. Their structures and absolute configurations were determined by spectroscopy and quantum-chemical computational 13C NMR and ECD data analysis. These alkaloids differ from known diterpene alkaloids and diterpenoids and are presumably biosynthesized from entkaurane diterpenoids.

T

erpenoids play an important role in natural product chemistry and biology.1 Their dazzling structural diversity arises from their synthesis via cascade-like multistep cyclizations and framework rearrangements2 and from the subsequent incorporation of oxygen, nitrogen, sulfur, and halogen functionalities.3−5 Owing to their broad and prominent bioactivity,11−13 diterpene alkaloids (DAs) attract more extensive attention than other natural nitrogen-containing terpenoids, as far as total synthesis,6 biosynthesis,7 medicinal chemistry,8 and phytochemistry are concerned.9,10 Molecules within this class can be classified as either typical or atypical DAs.10 The latter group features unusual skeletons, unpredictable occurrence, and incidental biogenesis. In contrast, typical DAs are exclusively isolated from the genera Aconitum, Consolida, Delphinium, and Spiraea10 and are presumably biosynthesized from ent-atisanoids or ent-kauranoids.14 Somewhat surprisingly, DAs are rarely isolated from the Isodon genus, a rich source of ent-kauranoids.15,16 Three new DAs, kaurines A−C (1−3), along with three known diterpenoids (4−6) were isolated from Isodon rubescens (Hemsl.) H. Hara. Compounds 1 and 2 feature a unique 7,20-aza-ent-kaurane skeleton, while 3 contains a rare succinimide moiety. Herein, the isolation, structure elucidation, and cytotoxic evaluation of these compounds are described.

with its 13C NMR spectrum, suggested a molecular formula of C20H27NO5 (calcd 362.1967) with eight indices of hydrogen deficiency. The NMR spectrum showed resonances (Tables 1 and 2 and details in Supporting Information) attributed to an α,β-unsaturated ester moiety (δC 165.6, C-15; δC 141.1, C-16; δC 127.9, C-17), which was defined by the HMBC correlations of H2-17 (δH 6.52, s; δH 5.42, s) to C-15 and C-16 (Figure 1). Analysis of the 1H−1H COSY and HSQC spectra starting from

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RESULTS AND DISCUSSION Kaurine A (1) was isolated as an amorphous powder. An [M + H]+ ion peak at m/z 362.1972 in its HRESIMS data, together © XXXX American Chemical Society and American Society of Pharmacognosy

Received: August 1, 2014

A

DOI: 10.1021/np5006136 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Table 1. 1H NMR Data of Compounds 1−4 (Pyridine-d5, δ in ppm, J in Hz)

Table 2. 13C NMR Data of Compounds 1−4 (Pyridine-d5, δ in ppm)

δH (type, J) no.

a

1

1β

3.90 (br s)

2α

1.98 (overlap)

2β

2.01 (overlap)

3α

5β

1.34 (dt, 14.0, 4.0) 1.26 (td, 14.0, 3.2) 1.60 (s)

6α

4.01 (s)

8β 9β

3.47 (br dt, 9.8, 9.6) 2.85 (d, 9.6)

11α

5.67 (s)

3β

11β

2

a

b

3

4

3.77 (overlap) 1.89 (overlap) 2.04 (overlap) 1.31 (overlap) 1.30 (overlap) 1.33 (overlap) 3.75 (overlap)

3.63 (br s)

3.62 (br t, 5.6)

1.88 (overlap)

2.42 (m)

1.88 (overlap)

1.81 (m)

1.38 (overlap)

1.40 (m)

1.36 (overlap)

1.35 (m)

1.43 (d, 6.0)

1.46 (d, 6.4)

4.18 (dd, 11.2, 6.0)

4.24 (dd, 10.4, 6.4)

1.89 (overlap) 1.91 (overlap) 2.06 (overlap) 2.26 (m) 1.45 (m)

1.84 (overlap)

1.91 (overlap)

2.51 (m)

2.46 (m)

1.77 (m)

1.95 (overlap)

2.09 (m) 1.92 (dd, 13.2, 6.5) 2.79 (t, 9.0) 5.40 (s)

1.81 (m) 1.56 (m)

12α 12β

1.89 (d, 13.9) 2.05 (overlap)

13α 14α

2.78 (br s) 2.29 (overlap) 2.27 (overlap)

3.12 (d, 9.7) 4.83 (s)

16α 17a

6.52 (s)

6.28 (s)

17b

5.42 (s)

5.47 (s)

18 19 20a 20b 21 HO-1 HO-6

1.03 (s) 0.68 (s) 8.85 (s)

1.19 (s) 0.72 (s) 8.80 (s)

6.89 (d, 3.4) 6.95 (s)

6.64 (d, 4.3) 7.00 (d, 10.9) 9.27 (s) 7.34 (s)

HO-7 HO-14 a

a

4.08 (m) 4.30 (dd, 13.8, 5.4) 3.95 (dd, 13.8, 9.0) 1.25 (s) 1.12 (s) 4.73 (d, 10.2) 4.40 (d, 10.2) 2.62 (s) 6.08 (d, 4.8) 6.36 (d, 11.2) 8.68 (s) 7.86 (s)

1a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

70.2 30.9 39.1 33.7 62.5 74.1 94.9 33.2 50.0 49.0 78.6 28.5 33.0 32.5 165.6 141.1 127.9 30.8 24.6 168.9

2a d t t s d d s d d s d t d t s s t q q d

71.2 31.8 39.5 33.6 57.2 75.3 94.0 63.6 55.5 48.4 24.2 31.2 44.0 73.4 210.8 153.6 119.7 31.0 23.7 169.3

3b d t t s d d s s d s t t d d s s t q q d

73.0 30.9 39.7 34.5 61.9 75.0 98.4 63.1 54.5 41.8 19.8 21.6 37.9 74.2 223.0 50.7 35.9 33.5 22.2 64.6 29.1 178.1

4c d t t s d d s s d s t t d d s d t q q t t s

75.3 31.0 39.9 34.5 61.1 74.0 98.9 63.5 54.7 42.2 20.9 31.4 44.4 73.6 209.7 153.9 119.5 33.8 22.7 64.5

d t t s d d s s d s t t d d s s t q q t

a

Recorded at 100 MHz. bRecorded at 150 MHz. cRecorded at 125 MHz.

3.18 (br d, 9.6) 5.32 (br s)

was defined by the HMBC correlations of H-5, H-8, and H-14 to C-7, of H-1 to C-9, of H-8 and H-9 to C-10, and of H-9 to C-20. One oxygen atom thus remains to be assigned, and the data indicate that either this oxygen or the nitrogen must be sp2 hybridized and paired with the sp2 C-20 at δC 168.9. Furthermore, the intense 3J HMBC correlation of H-20/C-7 established a C-7 (δC 94.9) hemiaminal group in order to account for the residual index of hydrogen deficiency. Finally, the two fragments of 1 were integrated to form the gross structure of an 8,15-seco-ent-kaurane or abietane. Given that 1 is an ent-kaurane, similar to diterpenoids isolated from I. rubescens, significant ROESY correlations of H-8 to H-5β, H-9β, and H-14β showed that the B-/C-rings of 1 were cis-fused, unlike the trans-fusion in abietanes. Additionally, the ROESY correlations of H-1/H-5β/H-9β, H-6/H3-19/H-20, and H-11/H-9β/H-12α/H-20 indicated that H-1, H-6, and H11 were β-, α-, and α-oriented, respectively. Consequently, compound 1 represents a rare 8,15-seco-ent-kaurane backbone with a lactone moiety bridging C-11 and C-13 similar to rubescesin T (7).17 Kaurine B (2) indicated the same formula as compound 1, according to 13C NMR data and an [M + H]+ ion peak at m/z 362.1966 in the HRESIMS data. Its 1H and 13C NMR data (Tables 1 and 2) closely resembled those of oridonin (4),18 except for the presence of an iminium carbon at δC 169.3 instead of an oxymethylene group. In the HMBC data (Figure 2), H-1/H-9 and C-7/C-10 correlated with the carbon and proton of the imine moiety, respectively, suggesting the presence of a 7,20-hemiaminal moiety, similar to compound 1. The residual structure was corroborated by detailed analysis of the HMBC. The relative configuration of 2 was deduced based on its ROESY correlations being the same as those of 4. Thus, 2 was the hemiaminal analogue of hemiacetal 4.

6.26 (br s) 5.49 (br s) 1.29 1.12 4.77 4.39

no.

(s) (s) (d, 9.6) (d, 9.6)

5.92 (br s) 6.92 (d, 10.4) 9.14 (s) 7.38 (s)

Recorded at 600 MHz. bRecorded at 800 MHz.

H-11 (δH 5.67, s), combined with the HMBC correlations of H9 (δH 2.85, d, J = 9.6 Hz) with C-11 and C-12, suggested that fragment 1a includes a kaurane-type C-ring moiety. In addition, the HMBC correlations of H-11 with C-15 and of H-13 (δH 2.78, s) with C-15 and C-17 indicated that the C-ring is bridged by a lactone linking C-11 and C-16, thus defining unit 1a as shown. The 1H−1H COSY and HSQC data for fragment 1b indicate the presence of two spin systems (Figure 1), HO-1/CH-1/ CH 2 -2/CH 2 -3 and CH-5/CH-6/HO-6. In the HMBC spectrum, the protons of the two methyl groups correlated with the methyl carbons and also with C-3, C-4, and C-5, suggesting the presence of a C-3/C-4/C-5 chain with geminal methyl groups (C-18 and C-19) attached to C-4. The HMBC correlations of HO-1, H-5, and H-20 (δH 8.85, s) with C-10, and of H-1 and H-5 with C-20, established the presence of a kaurane-type A-ring moiety. In addition, a kaurane-type B-ring B

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Figure 1. Key HMBC (H→C), 1H−1H COSY (bold −), and ROESY (H↔H) correlations of compound 1.

Figure 2. Key HMBC (H→C), 1H−1H COSY (bold −), and ROESY (H↔H) correlations of compound 2.

Figure 3. Key HMBC (H→C), 1H−1H COSY (bold −), and ROESY (H↔H) correlations of compound 3.

Figure 4. Deviation plots afforded by subtracting calculated δC from experimental δC for the pair of C-16 epimers of 3.

with C-15 evidenced the presence of the CH-16/CH2-17 group in 3 instead of the olefinic moiety in 4. Besides the C20H29O6 ent-kaurane fragment, a symmetrical succinimide unit accounted for the extra C4H4NO2 moiety, which showed two two-carbon peaks at δC 29.1 and 178.1 and a four-proton singlet at δH 2.62. The weaker deshielding effect of the succinimide moiety on C-17 (δC 35.9 in 4 vs δC 63.4 in 619), as well as the HMBC correlation of H2-17/C-22, facilitated linkage of the two substructures.

The molecular formula of kaurine C (3) was established as C24H33NO8 based on 13C NMR data, an ESIMS peak at m/z 486 ([M + Na]+), and an HREIMS peak at m/z 463.2216 ([M]+, calcd 463.2206), indicating nine indices of hydrogen deficiency. However, the 13C NMR and DEPT spectra of 3 contained only 22 peaks, two of which (at δC 29.1 and 178.1) were of substantially higher intensity than the others. The other 20 carbon signals and HMBC correlations resembled those of 4 (Table 2 and Figure 3). HMBC correlations of H-13 and H-16 with C-17, of H-14 with C-15 and C-16, and of H-16 and H2-17 C

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Figure 5. ECD spectra (a−c) of 1−3: Experimental (blue) and calculated (red) ECD spectra in MeOH.

Scheme 1. Plausible Biosynthesis Relationships between New DAs (1−3) and Their Analogous Diterpenoids (4−7)

electronic circular dichroism (ECD) was taken to define the absolute configurations of compounds 1−3.20 Optimized geometries of preferred conformations within a 10 kcal/mol energy window were obtained, and their ECD spectra were calculated at the B3LYP/6-31G(d,p) level, using the PCM model to simulate the effect of dissolution in MeOH (Supporting Information, Tables S1−S8 and Figures S1−S6). As shown in Figure 5, the calculated curves for compounds 1− 3 with the indicated absolute configurations were in good agreement with the experimental curves, confirming that these compounds possess ent-kaurane structural frameworks. The typical DAs can be divided into C20, C19, C18, and dimeric subgroups. C20-DAs are thought to be formed by the amination of ent-kaurane or ent-atisane diterpenoids; the other subgroups are then formed by cleavage, rearrangement, and dimerization.14 Some studies have validated aspects of this hypothesis, particularly those relating to the incorporation of nitrogen.7,21 Hemiaminal condensation and subsequent Schiff

The NOEs of H-1/H-9β, H-6/H3-19, and H-14/H2-20 indicated that 3 was a 1α,6β,14β-trihydroxy-ent-kaurane (Figure 3). The three protons of the CH-16/CH2-17 fragment correlated to H-12β in the ROESY spectrum. To determine the relative configuration of C-16, quantum-chemical calculations were performed to predict the 13C NMR data for the two possible C-16 epimers of 3. The predictions for the (16S*) epimer matched the experimental data more closely than those for the (16R*) epimer (Figure 4, details in Supporting Information Tables S9 and S10). In particular, the predicted chemical shifts for C-12, C-16, and C-17 of the (16S*) epimer deviated from the experimental values by −1.53, −2.29, and −3.51 ppm, respectively, whereas the corresponding deviations for the (16R*) epimer were much larger (−10.76, −6.52, −9.66 ppm, respectively). Compound 3 was therefore assigned a (16S*) configuration. Crystals suitable for X-ray diffraction analysis could not be obtained. Thus, recourse to experimental and calculated D

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grade and obtained from Sinopharm Chemical Reagent Co. Ltd., China. All solvents were distilled before use. Plant Material. The aerial parts of Isodon rubescens (Hemsl.) Hara. were collected in Jianshi County, Hubei Province, P. R. China, in September 2010, and identified by Prof. Ying-Ming Wang. A voucher specimen (No. IP20081006) has been deposited in Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji School of Pharmacy, Huazhong University of Science and Technology. Extraction and Isolation. The air-dried and powdered aerial parts of I. rubescens (10 kg) were incubated with 95% aqueous EtOH (4 × 40 L) at room temperature to yield an extract (910 g), which was dissolved in H2O and mixed with EtOAc. The EtOAc fraction (550 g) was subjected to silica gel CC, eluting with CHCl3/acetone (1:0−0:1 gradient system), to give fractions A−F. Fraction E (52 g) was decolored with an MCI gel column (90% MeOH/H2O) and subjected to silica gel CC. Elution with CHCl3/acetone (20:1 to 1:1) produced nine subfractions (E1−E9). The E9 subfraction (5 g) was further fractionated into subfractions E9/1−E9/4 by means of RP-18 CC (30−90% MeOH/H2O). Separation of the E9/2 subfraction (500 mg) by preparative HPLC (30−60% MeOH/H2O) yielded several subfractions and a pure sample of compound 6 (200 mg). Compounds 2 (10 mg) and 3 (12 mg) were isolated by semipreparative HPLC separation of the original HPLC subfractions, and compound 1 (1.8 mg) was isolated after two successive semipreparative HPLC separations of subfraction E9/3 (380 mg). Fraction C (120 g) was decolored like fraction E and subjected to silica gel CC (PE/acetone, 20:1 to 1:1) to give C1−5. C4 (12 g) was resubjected to silica gel CC, eluted with CHCl3/acetone (40:1, 20:1, 10:1), to give C4/1−C4/8. Compounds 4 (160 mg) and 5 (200 mg) were obtained by separation of C4/4 (2.5 g) using silica gel CC (PE/EtOAc, 20:1 to 5:1). Kaurine A (1): white, amorphous powder; [α]26D +9 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 208 (2.78) nm; IR (KBr) νmax 3431, 2951, 2930, 2870, 1701, 1624, 1373, 1300, 1248, 1168, 1072, 993, 534 cm−1; positive ESIMS m/z 384 [M + Na]+; positive HRESIMS [M + H]+ m/z 362.1972 (calcd for C20H28NO5, 362.1967); 1 H NMR data see Table 1; 13C NMR data, see Table 2. Kaurine B (2): white, amorphous powder; [α]25D −78 (c 0.04, MeOH); UV (MeOH) λmax (log ε) 237 (2.93), 203 (2.8) nm; IR (KBr) νmax 3441, 2927, 2870, 1710, 1640, 1452, 1272, 1168, 1091, 1057, 581 cm−1; positive ESIMS m/z 362 [M + H]+; positive HRESIMS [M + H]+ m/z 362.1966 (calcd for C20H28NO5, 362.1967); 1 H NMR data see Table 1; 13C NMR data, see Table 2. Kaurine C (3): white, amorphous powder; [α]26D −29 (c 0.1, MeOH); UV (MeOH) λmax (log ε) nm 204 (2.98); IR (KBr) νmax cm−1 3420, 2927, 1698, 1634, 1407, 1384, 1172, 1061; positive HREIMS m/z 463.2216 ([M]+, calcd for C24H33NO8, 463.2206); 1H NMR data see Table 1; 13C NMR data, see Table 2. Cytotoxicity Assay. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays were performed to evaluate the cytotoxicity of compounds 1, 2, and 4−6. The HL-60 (human promyelocytic leukemia), SMMC-7721 (liver cancer), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer) cell lines were seeded in a 96-well plate at a density of 5000 to 10 000 cells per well in 100 μL of medium, treated with 5 μL solutions of the studied compounds at different concentrations, and cultivated for 48 h at 37 °C. Then, 20 μL of an MTT solution in medium was added to each well, and the plates were incubated at 37 C under 5% CO2 for 4 h. The medium was then removed, and SDS (10%, 200 μL) was added to each well to dissolve the dark blue crystalline precipitate that had formed. The absorbance of the resulting solutions was measured at a test wavelength of 595 nm, and the extent of cell growth inhibition was calculated for each treatment. IC50 values were determined by the Reed and Muench method, and cisplatin was used as a positive control. All concentrations of each tested compound were assayed in triplicate.

base formation is responsible for the formation of the CN bonds in all typical DAs. Interestingly, compounds 1−3 are homologous to the known diterpenoids 7, 4, and 6, respectively. These similarities suggest that 1 and 2 may be derived from hebeirubescensin (5)22 and 4, respectively, via two steps of hemiaminal condensations. On the other hand, 3 may be derived from 4 by the formal Michael addition of ammonia to the α,β-unsaturated carbonyl moiety followed by diacylation with succinic acid, suggesting that the biosynthesis of 3 differs greatly from that of 1 and 2. In contrast, the nitrogenous moieties of 1 and 2 appear to have been appended to the carbon skeleton via some more complex mechanism. The carbon skeletons of the kaurine-type DAs are similar (and in some cases, identical) to those of certain typical DAs. However, whereas the “aza-bridge” of typical DAs links C-19 and C-20 of the A-ring, that of the kaurines crosses the B-ring by linking C-7 and C-20. This minor difference aside, the kaurine-DAs can be regarded as the “twins” of typical DAs given the similarities of their precursors, backbones, and biosynthetic pathways. The kaurine-DAs (1 and 2) were therefore identified as the first members of a new DA family (albeit one whose diversity is currently much lower than that of the typical DA family), whereas 3 can be regarded as a new atypical DA because of its unconventional biogenesis. The wide range of ent-kauranoid derivatives that could potentially be formed by the selective decoration of the carbon skeleton with nitrogen is conspicuous. It is possible that the DAs reported herein are just the tip of the iceberg and many other “kaurines” may be identified in the future. The in vitro cytotoxicity of compounds 1, 2, 4, 5, and 6 toward the A-549, MCF-7, SMMC-7721, SW-480, and HL-60 cancer cell lines was investigated by means of the MTT assay,23 using cisplatin as the positive control. Only 4 exhibited any activity, yielding modest IC50 values in the range 7.2−18.9 μM. Its hemiaminal analogue 2 was not cytotoxic (IC50 > 40 μM) despite bearing the exomethylene cyclopentanone moiety that has been identified as a key pharmacophore.16 In keeping with previous reports, compound 7 was also active,17 but in this assay its hemiaminal analogue 1 was not. Further chemical and pharmacological investigations will be required to elucidate the potential bioactivity of these molecules and related compounds.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured in MeOH with Horiba SEPA-300 and JASCO P-1020 polarimeters. UV spectra were obtained using a Shimadzu UV-2401A spectrophotometer. ECD spectra were measured on an Applied Photophysics Chirascan spectrophotometer. Scanning IR spectroscopy was performed using a Bruker Tensor-27 spectrophotometer with KBr pellets. NMR spectra were recorded on Bruker AM-400, DRX-500, Avance III-600, and Avance III-800 spectrometers. ESIMS, HRESIMS, and HREIMS experiments were performed on a Bruker HCT/Esquire spectrometer and a Waters AutoSpec Premier P776 spectrometer. Column chromatography (CC) was performed with silica gel (100− 200 mesh, Qingdao Marine Chemical, Inc., Qingdao, People’s Republic of China), Lichroprep RP-18 gel (40−63 μm, Merck, Darmstadt, Germany), and MCI gel (75−150 μm, Mitsubishi Chemical Corporation, Tokyo, Japan). Preparative HPLC and semipreparative HPLC were performed on an Agilent 1100 liquid chromatograph with a Zorbax SB-C18 (9.4 mm × 25 cm) column and on a Shimadzu LC-8A preparative liquid chromatograph with a Shimadzu PRC-ODS (K) column, respectively. Fractions were monitored by TLC, and spots were visualized by heating silica gel plates sprayed with 5% H2SO4 in EtOH. Petroleum ether (PE, 60−90 °C), EtOAc, CHCl3, acetone, MeOH, and EtOH were of analytical E

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(21) Hao, X. J.; Nie, J. J.; Sun, H. Acta Bot. Yunnan. 1997, 19, 297− 303. (22) Huang, S. X.; Zhou, Y.; Pu, J. X.; Li, R. T.; Li, X.; Xiao, W. L.; Lou, L. G.; Han, Q. B.; Ding, L. S.; Peng, S. L.; Sun, H. D. Tetrahedron 2006, 62, 4941−4947. (23) Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey, M. L.; Czerwinski, M. J.; Fine, D. L.; Abbott, B. J.; Mayo, J. G.; Shoemaker, R. H.; Boyd, M. R. Cancer Res. 1988, 48, 589−601.

ASSOCIATED CONTENT

S Supporting Information *

1D and 2D NMR, MS, UV, and IR spectra of compounds 1−3, CD spectra of 1−4, and detailed procedures of quantumchemical computational 13C NMR and ECD. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions ⊥

X. Liu and J. Yang contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project was supported financially by the NSFC-Joint Foundation of Yunnan Province (Grant U1302223), the National Natural Science Foundation of China (Grants 21322204 and 81172939), the Reservation-Talent Project of Yunnan Province (Grant 2011CI043), and the West Light Foundation of the Chinese Academy of Sciences (J.-X.P.).

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DOI: 10.1021/np5006136 J. Nat. Prod. XXXX, XXX, XXX−XXX