Article Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
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Dimeric Pyranonaphthoquinone Glycosides with Anti-HIV and Cytotoxic Activities from a Soil-Derived Streptomyces Xin He,†,‡,⊥ Yongjiang Wang,†,⊥ Rong-Hua Luo,§,⊥ Liu-Meng Yang,§ Li Wang,† Dale Guo,‡ Jing Yang,† Yun Deng,‡ Yong-Tang Zheng,§ and Sheng-Xiong Huang*,†
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†
State Key Laboratory of Phytochemistry and Plant Resources in West China, CAS Center for Excellence in Molecular Plant Sciences, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, People’s Republic of China ‡ Key Laboratory of Standardization of Chinese Herbal Medicine, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People’s Republic of China § Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, People’s Republic of China S Supporting Information *
ABSTRACT: Eight new sulfur-bridged pyranonaphthoquinone (PNQ) dimers, naquihexcins C−J (1−8), a new PNQ monomer, naquihexcin K (10), and three known analogues (9, 11, and 12) were isolated from Streptomyces sp. KIB3133. The new structures were elucidated by interpretation of spectroscopic data. Dimer 4 was synthesized via a cascade SN2 reactions between two monomers and sodium sulfide, an approach motivated by the proposed biosynthetic pathway of dimeric pyranonaphthoquinones. Naquihexcin E (3) exhibited moderate HIV-1 inhibitory activity. Naquihexcins C (1), E (3), and I (7) showed inhibitory effects against two tumor cell lines (HL-60 and MCF-7) with IC50 values ranging from 1.4 to 16.1 μM.
N
synthesis of dimer 4 using the isolated monomers are presented below.
atural pyranonaphthoquinone antibiotics are widespread in bacteria and fungi and exhibit antitumor, antibacterial (mainly Gram-positive bacteria), antiviral, and antiprotozoan activities.1−4 The biosynthesis of the naphtho[2,3-c]pyran5,10-dione moiety typically uses acetate/malonate units condensed via the type II polyketide synthase pathways.5,6 Some natural pyranonaphthoquinone monomer units can produce symmetrical or asymmetrical dimers through a C−C bond,1−4 an oxygen bridge,7−10 or a sulfur bridge.11−14 Soil-dwelling Streptomyces are a prolific source of bioactive compounds.6 In our continuous efforts to discover novel bioactive natural products,15−17 Streptomyces sp. KIB3133, a strain isolated from the rhizospheric soil of tea (Camellia sinensis), caught our attention since its extract showed potent cytotoxicity against several cancer cell lines. Its 16S rRNA gene sequence (GenBank No. MK182942) shows 99.5% identity to Streptomyces hebeiensis NBRC 101006 (GenBank No. NR112601.1). High-performance liquid chromatography (HPLC) analysis showed that Streptomyces sp. KIB3133 is a prolific secondary metabolite producer. Subsequently, 12 compounds including nine sulfur-bridged dimers (1−9) and three monomers, were isolated and identified. Among the isolates, three types of sugar moieties (glucuronic acid, methyl glucuronate, and unsaturated hexuronic acid) were found to be attached at different positions on the pyranonaphthoquinone core. Details of the isolation, structure elucidation, and bioactivity of these metabolites as well as the biomimetic © XXXX American Chemical Society and American Society of Pharmacognosy
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RESULTS AND DISCUSSION Compounds were isolated from the fermentation extract of Streptomyces sp. KIB3133 by various chromatographic methods. Among them, compounds 1−8 are new dimeric pyranonaphthoquinones, and compound 10 is a new monomer, which may serve as a precursor of the dimer. The others were confirmed as known pyranonaphthoquinones, naquihexcin A (9),11 OM-173αE (11),18 and nanaomycin βE (12),19 respectively. Naquihexcin C (1) was obtained as a yellow oil, and a molecular formula of C40H42O20S was determined by its HRESIMS data requiring 20 degrees of unsaturation. Comprehensive analysis of the 1H/13C (Tables 1 and S1, Supporting Information) and DEPT NMR data (Figure S3, Supporting Information) indicated the presence of four methyls, four methylenes, 15 methines, and 17 additional carbons. The NMR data of 1 were similar to those of naquihexcin A,11 with obvious differences as follows: a carbonyl group at C-13′ in 1 instead of a methylene present in naquihexcin A, confirmed by the HMBC correlations from Received: January 9, 2019
A
DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products Table 1.
13
Article
C NMR Spectroscopic Data of Compounds 1−8 in DMSO-d6 at 150 MHz
no.
1
2
3
4
5
6
7
8
1 3 4 4a 5 5a 6 7 8 9 9a 10 10a 11 12 13 14 1′ 3′ 4′ 4a′ 5′ 5a′ 6′ 7′ 8′ 9′ 9a′ 10′ 10a′ 11′ 12′ 13′ 14′ 1″ 2″ 3″ 4″ 5″ 6″ 7″
72.7 61.9 27.5 61.5 189.8 133.1 119.5 137.4 124.1 160.4 114.2 197.1 75.9 14.8 39.4 170.4 51.4 72.7 62.5 27.6 61.6 189.8 133.0 119.6 137.3 124.1 160.4 114.2 197.1 76.0 14.5 39.7 168.9
72.7 61.9 27.5 61.6 189.8 133.0 119.5 137.3 124.2 160.4 114.1 197.1 76.0 14.8 39.3 170.4 51.4 72.7 62.5 27.5 61.6 189.8 133.0 119.6 137.3 124.1 160.4 114.2 197.0 76.1 14.6 39.6 168.9
72.8 61.8 27.5 61.7 189.9 133.0 119.6 137.4 124.3 160.4 114.1 197.2 76.0 14.7 39.1 170.4 51.4 72.7 62.5 27.6 61.7 189.8 132.9 119.6 137.3 124.2 160.4 114.2 197.2 76.0 14.8 39.6 168.9 92.4 69.5 66.5 113.1 140.8 162.9
72.8 62.5 27.3 61.5 189.8 133.1 119.8 137.3 124.0 160.4 114.2 197.0 75.8 14.8 39.7 170.5 51.5 72.8 62.8 27.5 61.2 189.3 125.7 120.4 120.2 150.5 150.3 115.0 196.7 75.9 14.8 39.7 170.3 51.5 100.0 72.8 75.8 71.5 75.2 170.3
72.7 62.4 27.5 61.6 189.8 133.2 119.1 137.5 124.0 160.4 114.3 197.0 76.0 14.8 39.7 170.4 51.4 72.5 62.6 28.3 61.7 190.0 133.0 119.6 137.3 124.1 160.4 114.2 197.3 76.1 15.0 34.4 66.0
94.1 72.2 75.9 71.4 76.0 170.1
72.8 62.4 27.5 61.5 189.9 133.1 119.7 137.3 124.1 160.5 114.2 197.1 75.9 14.9 39.7 170.5 51.3 73.4 62.6 27.4 61.4 190.3 134.5 121.2 135.4 121.3 156.9 119.3 189.3 76.5 15.0 39.7 170.4 51.4 99.6 72.9 75.8 71.3 75.2 169.3 52.0
72.7 62.4 27.4 61.5 189.8 133.2 119.1 137.3 124.0 160.5 114.3 197.0 75.9 14.9 39.7 170.4 51.4 72.5 62.5 28.3 61.7 190.0 133.0 119.6 137.3 124.1 160.5 114.2 197.2 76.1 14.8 34.4 66.0
94.1 72.2 75.6 71.3 75.9 169.0 52.1
72.8 62.4 27.5 61.5 189.9 133.1 119.7 137.3 124.1 160.5 114.2 197.1 75.9 15.0 39.8 170.5 51.4 73.4 62.6 27.4 61.4 190.3 134.5 121.2 135.4 121.5 156.9 119.5 189.4 76.5 15.0 39.8 170.4 51.4 99.8 72.9 76.1 71.3 75.4 170.1
103.2 73.2 76.0 71.6 75.5 169.7 51.8
103.0 73.3 76.2 71.7 75.6 170.8
H-1″ (δH 5.49) to C-13′ (δC 168.9) and from H-12′ (δH 2.45) to C-13′. An unsaturated hexuronic unit found in naquihexcin A was replaced by a methyl glucoronate group in 1, which was confirmed by 1H−1H COSY correlations of H-1″ (δH 5.49)/ H-2″ (δH 3.25)/H-3″ (δH 3.35)/H-4″ (δH 3.42)/H-5″ (δH 3.96), together with the HMBC correlations from H-5″ to C1″ (δC 94.1) and C-6″ (δC 169.0) and from H-7″ (δH 3.68) to C-6″ (δC 169.0) (Figure 1). The relative configuration of 1 was established by ROESY NMR data. The ROESY correlations of H-11 (H-11′) and H-3 (H-3′) suggested these protons were on the same side and were assigned to be β-oriented (Figure 1). Similarly, the ROESY correlations of H-1/10a-OH/H-4 and H-1′/10′a-OH/ H-4′ indicated that these protons were α-oriented. The ROESY correlations of H-1″/H-3″/H-5″ and H-2″/H-4″ and the large coupling constant (8.2 Hz) of H-1″ and H-2″ indicated that the sugar was β-methyl glucuronate with a relative configuration of 1″R*, 2″S*, 3″R*, 4″R*, 5″R*.
The absolute configuration of 1 was deduced by the optical rotation of the hydrolyzed sugar and circular dichroism (CD) data. The optical rotation value {[α]26.9 D +16.0 (c 0.05, H2O)} of the hydrolyzed sugar of 1 was consistent with that of the +12.9 (c 0.09, H2O)},20 standard D-glucuronic acid {[α]]26.5 D and the sugar moiety of 1 was designated as β-D-methyl glucuronate. On the basis of similar CD spectra between 1 and naquihexcin A (Figure S9), the absolute configuration of 1 was established as 1S, 3S, 4aS, 10aR, 1′S, 3′S, 4a′S, 10′aR, 1″R, 2″S, 3″R, 4″R, 5″R. Therefore, the structure of 1 was determined as shown and named naquihexcin C. Naquihexcin D (2) has a molecular formula of C39H40O20S as deduced from the HRESIMS data. The NMR data of compounds 2 and 1 demonstrated similarities, with the only difference being a methoxy at C-7″ was absent in 2. It can be inferred that the sugar moiety in 2 was glucuronic acid, instead of a methyl glucuronate in 1. This inference can balance the molecular weight variation (Δ14) between 1 and 2. As in the B
DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Figure 1. Key 2D NMR correlations of 1.
2) from H-5″ to C-1″ (δC 99.8) and C-6″ (δC 170.1). Finally, the planar structure of 4 was elucidated as a glucuronic acid connecting to the sulfur-bridged dimer aglycone at C-9′ based on the HMBC correlation from H-1″ to C-9′ (δC 156.9). Considering the shared biosynthetic pathway, the absolute configuration of 4 was assumed to be identical with that of 1− 3. Accordingly, the absolute configuration of 4 was established as 1S, 3S, 4aS, 10aR, 1′S, 3′S, 4a′S, 10a′R, 1″R, 2″S, 3″R, 4″R, 5″R. Naquihexcin G (5) possessed the molecular formula C41H44O20S as determined by HRESIMS experiment. By comparing their NMR data, 5 was found to closely resemble 4 (Tables 1 and S1, Supporting Information). The difference was that the glucuronic acid in 4 was replaced by a methyl glucuronate in 5. This assignment was further confirmed by the HMBC correlation from H-7″ (δH 3.68) to C-6″ (δC 169.3). Therefore, the structure of 5 was defined. Naquihexcin H (6) was obtained as a yellow oil, and its HRESIMS data released a negative peak at m/z 889.1878 ([M − H]−, calcd for 899.1867), consistent with the molecular formula C40H42O21S. NMR data of 6 revealed it was similar to 4 (Tables 1 and S1, Supporting Information). In contrast to 4, the appearance of the 13C NMR signals at δC 150.5 and δC 150.3 showed the existence of an additional oxygen substitution in the benzene ring. The detection of two mutually coupled proton signals at H-6′ (δH 7.58, d, J = 8.4 Hz) and H-7′ (δH 7.56, d, J = 8.4 Hz) and HMBC correlations from H-6′ to C-8′ (δC 150.5) showed C-8′ was an oxygenbearing carbon. A key HMBC correlation from H-1″ (δH 5.19) to C-8′ suggested the glucuronic acid was linked to C-8′. Thus, the structure assigned to 6 was as shown. Naquihexcins I (7) and J (8) were obtained as yellow oils. Their molecular formulas were determined to be C40H44O19S and C39H42O19S, respectively, based on their HRESIMS data. Compounds 7 and 8 had the same skeleton as 1 according to their 1D NMR data (Tables 1 and S1, Supporting Information). Comparison of the spectroscopic data of 7 with those of 1 revealed that they were quite similar except for a methylene (δC 66.0) in 7 replaced by a carbonyl (δC 168.9)
case of 1, the stereochemistry of 2 was determined by a ROESY experiment and CD data. Naquihexcin E (3) has a molecular formula of C39H38O19S, as deduced from the HRESIMS. Comparison of 1H and 13C NMR data (Tables 1 and S1, Supporting Information) of 3 with those of naquihexcin A11 indicated that a methylene group at C-13′ in naquihexcin A was replaced by a carbonyl group in 3. This hypothesis was supported by the key HMBC correlations from H-1″ (δH 6.02) to C-13′ (δC 168.9) and from H-12′ (δH 2.48) to C-13′. The absolute configuration of 3 was deduced to be the same as that of naquihexcin A, based on the similar CD spectra between naquihexcin A and 3 (Figure S27, Supporting Information). Accordingly, the structure of 3 was elucidated as shown. Naquihexcin F (4) was obtained as a yellow oil. The HRESIMS gave a pseudomolecular ion peak at m/z 897.1867 [M + Na]+ (calcd for C40H42O20SNa, 897.1882), implying 20 degrees of hydrogen deficiency. The 1H and 13C NMR spectroscopic data (Tables 1 and S1, Supporting Information) of 4 closely resembled those of BE-52440A.11,12 The principal difference was the presence of glucuronic acid in 4, which was supported by the 1H−1H COSY correlations (Figure 2) of H1″ (δH 5.18)/H-2″ (δH 3.36)/H-3″ (δH 3.30)/H-4″ (δH 3.41)/H-5″ (δH 3.97) and the HMBC correlations (Figure
Figure 2. Key 1H−1H COSY (blue lines) and HMBC (red arrows) correlations of compounds 4 and 10. C
DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Figure 3. (A) Proposed biosynthetic pathway of dimeric PNQs. (B) Chemical synthesis of dimer 4 from its monomers 10 and 11.
Table 2. Cytotoxicity of Selected Compounds no.
1a
3a
7a
cisplatinb
paclitaxelb
HL-60 MCF-7
16.1 ± 0.7 3.4 ± 0.2
9.9 ± 0.3 1.4 ± 0.1
14.9 ± 0.6 3.4 ± 0.2
1.8 ± 0.04 12.0 ± 0.6
1000
9.6 2.8 ± 1.2 44.7 8.6 9.6 0.3
5.4 22.5 >2.2 4.2 5.9 >2907.0
chromatography triple quadrupole mass spectrometer. HRESIMS data were obtained using an Agilent 1290 UPLC/6540 Q-TOF mass instrument. Column chromatography (CC) was performed using silica gel (300−400 mesh, Qingdao Marine Chemical Inc., China), Sephadex LH-20 (25−100 μm, Pharmacia Biotech Ltd., Sweden), and MCI gel (75−150 μm, Mitsubishi Chemical Corporation, Tokyo, Japan). Semipreparative HPLC was conducted on a Hitachi Chromaster system equipped with a DAD detector, a YMC-Triart C18 column (250 × 10 mm i.d., 5 μm), and a flow rate of 3.0 mL/min. LC-MS was performed using an Agilent 1200 series HPLC system coupled to an Agilent q TOF 6540 mass spectrometer with a YMCTriart C18 column (250 × 4.6 mm i.d., 5 μm) using mobile phase C (H2O) and mobile phase D (methanol) at a flow rate of 1.0 mL/min. The method: 0−100% D (20 min); 100% D (3 min); 100%−10% D (2 min); 10% D (3 min). Microbiology. The strain Streptomyces sp. KIB3133 was isolated from the rhizospheric soil of tea (Camellia sinensis), which was collected in Puer City, Yunnan Province, China, in 2016. Its 16S rRNA gene sequence (GenBank No. MK182942) shows 99.5% identity to Streptomyces hebeiensis NBRC 101006 (GenBank No. NR112601.1). Fermentation, Extraction, and Isolation. Streptomyces sp. KIB3133 was grown on MS medium agar (soybean flour 20 g/L, mannitol 20 g/L, agar 20 g/L, pH 7.2) plates incubated for 5 days at 30 °C. The mycelium was inoculated into 250 mL baffle Erlenmeyer flasks containing 50 mL of sterile seed medium (tryptone soy broth, 30 g/L) and cultivated for 1 day at 30 °C on a rotary shaker (250 rpm). Aliquots (13 mL) of the culture were transferred into 1 L baffled Erlenmeyer flasks containing 300 mL of production media consisting of 1.5% glycerol, 0.3% beef extract, 0.3% corn steep liquor, 0.1% NaCl, 0.05% K2HPO4, and 0.05% MgSO4·7H2O (pH 7.2) and incubated on a rotary shaker (220 rpm) at 30 °C for 6 days. After fermentation, the culture (25 L) was centrifuged (4000 rpm, 15 min) to yield the supernatant and a mycelia cake. The supernatant was extracted with EtOAc three times. The EtOAc extract was evaporated under reduced pressure at temperatures within 45 °C to yield an oily crude extract (6.0 g). The mycelia were extracted with 3 L of methanol and then evaporated to dryness. This aqueous concentrate was finally extracted with EtOAc (1 L × 3) to give 2.0 g of an oily crude extract after removing the EtOAc. Both extracts revealed an identical set of metabolites based on HPLC analysis. Therefore, both extracts were combined for further purification. The combined extract (8.0 g) was subjected to silica gel (150 g, 300−400 mesh) by column chromatography with a successive elution of petroleum ether−EtOAc (1:0, 20:1, 10:1, 5:1, 2:1, 1:1, 0:1, v/v) and CH3OH, yielding eight fractions (F1−F8). Compound 11 (7.2 mg, tR = 12.0 min) was isolated from fraction F2 by semipreparative HPLC (CH3OH−H2O, 75:25). Compound 12 (15.9 mg, tR = 32.3 min) was obtained from fraction F5 by semipreparative HPLC (CH3OH−H2O, 55:45 → 60:40). F7 (2.1 g) was further fractionated via MCI MPLC eluting with a gradient MeOH−H2O system (from 20:80 → 100:0 v/v) to afford nine subfractions (F7-1−F7-9). Fraction F7-7/8 was further separated via Sephadex LH-20 (CH3OH−CHCl3, 1:1) column chromatography to yield six subfractions (H1−H7). Fraction H2 was further purified by semipreparative HPLC (CH3OH−H2O, 46:54 → 50:50) to afford compounds 4 (13.1 mg, tR = 21.5 min) and 5 (11.7 mg, tR = 27.5 min). Compounds 6 (2.3 mg, tR = 25.0 min), 7 (9.0 mg, tR = 50.0 min), and 8 (9.3 mg, tR = 40.3 min) were purified E
DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
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cm−1; HRESIMS m/z 507.1156 [M − H]− (calcd for C23H23O13, 507.1144); 1H NMR (600 MHz, DMSO-d6) δH 7.75 (t, J = 7.9 Hz, H-7), 7.58 (d, J = 8.9 Hz, H-8), 7.57 (d, J = 7.7 Hz, H-6), 5.24 (d, J = 7.5 Hz, H-1′), 4.46 (q, J = 6.7 Hz, H-1), 4.09 (m, H-3), 3.98 (d, J = 9.7 Hz, H-5′), 3.61 (s, Me-14), 3.42 (m, H-4′), 3.35 (m, H-2′), 3.30 (m, H-3′), 2.76 (dd, J = 15.0, 4.7 Hz, H-4a), 2.67 (dd, J = 15.8, 3.9 Hz, H-12a), 2.36 (dd, J = 15.8, 9.2 Hz, H-12b), 1.70 (dd, J = 15.0, 11.0 Hz, H-4b), 1.63 (d, J = 6.7 Hz, H-11); 13C NMR (150 MHz, DMSO-d6) δC 190.7 (C-5), 188.1 (C-10), 170.8 (C-13), 170.1 (C6′), 156.7 (C-9), 135.0 (C-7), 133.1 (C-5a), 120.9 (C-8), 120.2 (C9a), 119.9 (C-6), 99.3 (C-1′), 75.9 (C-3′), 75.4 (C-5′), 72.9 (C-2′), 71.3 (C-4′), 65.5 (C-1), 62.6 (C-4a), 62.4 (C-10a), 61.0 (C-3), 51.4 (C-14), 39.9 (C-12), 23.9 (C-4), 15.9 (C-11). Acid Hydrolysis of 1. Approximately 5 mg of 1 was hydrolyzed using 5% HCl (5 mL) at 60 °C for 6 h. The cold reaction mixture was extracted with EtOAc (3 × 10 mL). The aqueous phase, after removal of water, was eluted by reversed-phase column chromatography (RP18, MeOH−H2O, 10:90), giving D-glucuronic acid (0.5 mg). The optical rotation values were measured after 24 h of dissolution in +16.0 (c 0.05, H2O); H2O. The hydrolyzed sugar of 1: [α]26.9 D standard D-glucuronic acid: [α]26.5 D +12.9 (c 0.09, H2O). Chemical Synthesis of Compound 4. Naquihexcin K (10) (1.2 mg) and OM-173αE (11) (0.9 mg) were incubated with one molar equivalent of sodium sulfide in dry tetrahydrofuran at 25 °C for 40 min. The reaction was monitored by TLC. Then the solvent was evaporated in vacuo, and the residue was subjected to LC-MS analysis. Cytotoxicity Assay. Two human tumor cell lines, HL-60 (acute leukemia) and MCF-7 (breast cancer), were used in the cytotoxicity assays, which were obtained from ATCC. Cells were cultured in RPMI 1640 or DMEM medium supplemented with 10% fetal bovine serum. Cells (100 μL) were seeded into 96-well plates at a concentration of 5 × 103 cell/well. Following a 24 h incubation period, different concentrations of samples dissolved in DMSO were added to each well, respectively. Each experiment was performed in triplicate. Negative controls were treated with DMSO alone, and positive controls with paclitaxel and cisplatin. After being incubated for a further 72 h, MTS solution (20 μL) was added to each well and the cells were further incubated at 37 °C for 2 h. The optical density was measured at 492 nm using a MULTISKAN FC, and the IC50 value of each compound was calculated by the Reed and Muench method.23 Anti-HIV-1 Assay. The cellular toxicity against C8166 cells (CC50) was evaluated by the MTT method, and anti-HIV-1 activity was measured as previously described.24,25 Briefly, C8166 cells (4 × 105/mL) were infected with HIV-1IIIB at a multiplicity of infection of 0.06. Samples with different concentrations (100 μL) were added to each well, respectively, and each sample was measured by triplicate. Lamivudine (3TC) was used as positive control. After 72 h, the cytopathic effect was measured by computing the quantity of syncytia. The percentage inhibition of syncytial cell formation was calculated by the percentage of syncytial cells in the treated culture and that in the infected control culture, and 50% effective concentration (EC50) was calculated.
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AUTHOR INFORMATION
Corresponding Author
*Tel (S.-X. Huang): +86-871-6521-5112. E-mail: sxhuang@ mail.kib.ac.cn. ORCID
Sheng-Xiong Huang: 0000-0002-3616-8556 Author Contributions ⊥
X. He, Y. Wang, and R.-H. Luo contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was financially supported by the National Natural Science Foundation of China to S.-X.H. (Nos. U1702285 and 81522044), the Strategic Priority Research Program of the CAS (No. XDB27020205), Key Research Program of Frontier Sciences, CAS (No. QYZDB-SSWSMC051), Science and Technology Talents Program of Yunnan Province (No. 2013HA022), the 13th Five-Year Key Scientific and Technological Program of China (No. 2017ZX09101004-014-007), and Yunnan Innovative Research Team for Discovery and Biosynthesis of Bioactive Natural Products (2018HC012).
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REFERENCES
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.9b00022. Anti-HIV-1 activities of compounds, NMR data of compounds 9, 11, and 12, LC-MS analysis of the reaction, and HRESIMS, IR, CD, and NMR spectra of compounds 1−8 and 10 (PDF) F
DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.jnatprod.9b00022 J. Nat. Prod. XXXX, XXX, XXX−XXX
