Medermycin-Type Naphthoquinones from the Marine-Derived

4 hours ago - Four new medermycin-type naphthoquinones, strepoxepinmycins A–D (1–4), and one known compound, medermycin (5), were identified from ...
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Medermycin-Type Naphthoquinones from the Marine-Derived Streptomyces sp. XMA39 Yong-Jun Jiang,† Da-Shan Zhang,† Hao-Jian Zhang,† Jia-Qi Li,† Wan-Jing Ding,† Cheng-Dong Xu,† and Zhong-Jun Ma*,†,‡ †

Institute of Marine Biology, Ocean College, Zhejiang University, Zhoushan 316021, People’s Republic of China Ocean Academy, Zhejiang University, Zhoushan 316021, People’s Republic of China

‡

J. Nat. Prod. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/13/18. For personal use only.

S Supporting Information *

ABSTRACT: Four new medermycin-type naphthoquinones, strepoxepinmycins A−D (1−4), and one known compound, medermycin (5), were identified from Streptomyces sp. XMA39. Their structures were elucidated by analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and ECD calculations. Among these compounds, strepoxepinmycin A (1) represents a rare 5,10-oxepindione ring system typically formed by a Baeyer−Villiger oxidation, and strepoxepinmycin B (2) is an isolation artifact derived from 1. Bioactivity evaluations of these compounds showed that compounds 3 and 4 exhibited cytotoxicity against HCT-116 and PC-3 cancer cell lines and 4 exhibited moderate inhibition of ROCK 2 protein kinase. In addition, all of the new compounds showed antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus and antifungal activity against Candida albicans.

M

signals including a tetrasubstituted aromatic ring [δC 119.2, 123.2, 131.1, 131.6, 134.2, and 151.9], an angolosamine ring [δC 17.9, 28.9, 36.7, 41.2, 65.8, 69.4, and 70.8], and three carbonyl carbons [δC 169.4, 173.5, and 174.9]. On the basis of the above data and previous studies of the known antibiotic medermycin, compound 1 was assigned as a medermycin-type analogue.2−8 Construction of the planar structure for 1 was accomplished mainly with the aid of 2D NMR spectra. The COSY spectrum of 1 exhibits four spin systems: a, H-1′/H-2′/H-3′/H-4′/ H-5′/H-6′, b, H-1/H-13, c, H-4/H-3/H-11, and d, H-6/H-7, as shown in Figure 1. The benzene ring was established by the HMBC correlations of H-6 with C-8 and C-9a and of H-7 with C-5a and C-9. According to the key HMBC correlations of H-1′ with C-8 and C-9 and H-7 with C-1′, the angolosamine unit was determined to be attached to C-8 of the benzene ring. Thus, fragment (i) was constructed. Then, the pyran ring of fragment (ii) was constructed by the HMBC correlations of H-1 with C-3 and C-4a, H-3 with C-1 and C-4a, and H-4 with C-4a and C-10a. A γ-lactone ring fused to the pyran ring was deduced from the HMBC correlations of H-11/C-3, H-12/ C-11, H-12/C-8, and H-7/C-17, and Me-13 was attached at C-1 as inferred from the HMBC correlations of Me-13 with C-1 and C-10a. The key HMBC correlation of H-1/C-10 indicated that fragment (i) was attached to fragment (ii) through a ketone carbonyl carbon (C-10). Moreover, the HMBC correlation of H-6/C-5 suggested that an ester carbonyl carbon was connected at C-5a. Finally, to satisfy the last degree of unsaturation, the ester oxygen was attached at C-4a to form a

edermycin-type antibiotics, belonging to the pyranonaphthoquinones (PNQs), have a typical angolosamine moiety on the naphthoquinone nucleus at C-8.1 Only 10 medermycin-type analogues have been reported since the first isolation of medermycin from Streptomyces K73 in 1976, some of which have been proved to possess antibacterial, antifungal, and cytotoxicity activities.2−8 In the course of our search for structurally new and bioactive natural products from marine-derived actinomycetes,15,16 a strain classified as Streptomyces sp. XMA39 was selected for its cytotoxic activity against the PC3 cell line (the EtOAc extract showed about 73% inhibition at 10 μg/mL). As a result, three new medermycin-type analogues and a related isolation artifact, strepoxepinmycins A−D (1−4), along with the known compound medermycin (5) were isolated from large culture of the strain. Strepoxepinmycins A and B are the first medermycintype naphthoquinones with a rare 5,10-oxepindione ring system framework. Herein, we describe the isolation, structure identification, and biological activities of the above compounds. Strepoxepinmycin A (1) possessed a molecular formula of C24H27NO9 with 12 degrees of unsaturation as established by HRESIMS analysis. Analysis of 1H NMR data of 1 revealed a characteristic 1,2,3,4-tetrasubstituted aromatic ring at δH 7.46 (1H, d, J = 8.0 Hz) and 7.92 (1H, d, J = 8.0 Hz), a typical angolosamine moiety [δH 1.32 (3H, d, J = 6.0 Hz), 1.87 (1H, m), 2.38 (1H, m), 2.72 (3H, s), 2.75 (3H, s), 3.41 (1H, dd, J = 15.6, 9.0 Hz), 3.57 (1H, overlap), 3.59 (1H, overlap), and 5.06 (1H, br d, J = 10.2 Hz)], one methyl group (δH 1.45 (1H, d, J = 6.8 Hz), one methylene [δH 3.26 (1H, dd, J = 17.8, 5.2 Hz), 2.55 (1H, d, J = 17.8 Hz)], and three oxygenated methines [δH 4.92 (1H, overlap), 4.94 (1H, overlap), and 5.30 (1H, d, J = 3.0 Hz)]. The 13C NMR data of 1 revealed 24 carbon © XXXX American Chemical Society and American Society of Pharmacognosy

Received: July 4, 2018

A

DOI: 10.1021/acs.jnatprod.8b00544 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Figure 1. Key COSY and HMBC correlations of compound 1.

5,10-oxepindione ring system, which was also confirmed by the deshielded chemical shift of C-4a (δC 153.6). Therefore, the planar structure of compound 1 was elucidated as shown. Among the natural medermycin-type derivatives known to date, the configuration of the angolosamine ring is absolutely conserved.2−8 Because the absolute configuration of the angolosamine ring of co-isolated medermycin (5) has been confirmed by total synthesis,9−11 the absolute configurations of the angolosamine ring of compounds 1−4 were assigned as 1′R, 3′R, 4′S, and 5′R based on their shared biosynthetic origin.12−14 This assignment was also supported by the significant NOESY correlations as shown in Figure 2. The observation of NOESY cross-peaks between Me-13 and H-3/H-4 confirmed the β-orientation of H-3, H-4, and Me-13 in 1 (Figure 2). In order to establish the absolute configuration of the C-1, C-3, and C-4 stereogenic carbons, electronic circular dichroism (ECD) calculations were carried out for (1R,3R,4S, 1′R,3′R,4′S,5′R)-1 or (1S,3S,4R,1′R,3′R,4′S,5′R)-1. The results showed that the calculated ECD curve of (1R,3R,4S,1′R,3′R,4′S,5′R)-1 revealed a good agreement with the measured spectrum (Figure 4), indicating the absolute configuration of 1 to be 1R, 3R, 4S, 1′R, 3′R, 4′S, 5′R. Furthermore, both 1 and co-purified medermycin (5) had positive specific rotations and similar experimental ECD curves (Figure 4), supporting the correctness of the absolute configuration of 1. Strepoxepinmycin B (2) was assigned the molecular formula C25H31NO10 on the basis of its HRESIMS data. The 1H and 13 C NMR data of compound 2 were very similar to those of compound 1, except that methanolysis of the lactone moiety in 1 had occurred. The structure was confirmed by 2D NMR

Figure 2. Key NOESY correlations (dashed arrows) of compounds 1−4.

Figure 3. Key COSY and HMBC correlations of compounds 2−4.

spectra (Figure 3). As MeOH was used in the process of early silica gel chromatography isolation, we speculate that compound 2 is an isolation artifact derived from 1. The similar experimental ECD curves between 2 and 1 suggested that the absolute configuration of 2 was 1R, 3R, 4S, 1′R, 3′R, 4′S, 5′R, in accordance with that of 1 (Figure 4, Figures S39−40, Supporting Information). Thus, the structure of 2 was determined as shown. Compound 3 was isolated as a yellowish oil. The HRESIMS analysis of 3 showed an [M + H]+ ion peak at m/z 508.2179, indicating a molecular formula of C25H33NO10, in agreement with 10 indices of hydrogen deficiency. Comparison of the 1D

Chart 1

B

DOI: 10.1021/acs.jnatprod.8b00544 J. Nat. Prod. XXXX, XXX, XXX−XXX

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These differences suggested that the Δ4a(10a) olefinic bond in G15-G was replaced by a vicinal diol system, as deduced from the HMBC cross-peaks of 4a-OH (δH 6.71, s) with C-4a and of 10a-OH (δH 6.52, s) with C-10a. The relative configuration of 3 was assigned based on the analysis of NOESY correlations (Figure 2). The clear NOESY correlations of Me-13/10a-OH and 10a-OH/H-3 showed 10a-OH being β-oriented. Furthermore, 4a-OH was α-oriented, as deduced through the NOESY cross-peaks of 4a-OH/H-1 and 4a-OH/H-11. In order to further confirm the absolute configuration of 3, we used the solution time-dependent density functional theory (TDDFT) ECD calculations. By comparing the experimental spectrum with the calculated ECD spectra, the calculated ECD curve of (1R,3S, 4aS,10aS,1′R,3′R,4′S,5′R)-3 revealed a good agreement with the measured spectrum (Figure 5 and Figures S41 and S42). Thus, the absolute structure of 3, named strepoxepinmycin C, was determined as shown. Compound 4 was assigned the molecular formula C25H29NO9 deduced from its HRESIMS data, implying 12 indices of hydrogen deficiency. The 1H and 13C NMR spectroscopic data (Table 1) were similar to those of 3. The main differences included the absence of four saturated carbons and the presence of two double bonds in 3. The structure was supported by HMBC correlations from H-13 to C-1 and C-10a and from H-11 to C-3 and C-4 and the COSY correlations of H-3/H-11 (Figure 3). ECD calculations failed to established

Figure 4. Experimental ECD spectra for 1, 2, and 5 and calculated ECD spectra of 1.

NMR data (Table 1) with related reference data revealed that 3 was an analogue of G15-G, a medermycin-type antibiotic isolated from Streptoverticillium thioluteum G15.6 The differences included the lack of a double bond present in G15-G and the occurrence of two oxygenated tetrahedral carbons in 3.

Table 1. 1H (600 MHz) and 13C (125 MHz) NMR Data of Compounds 1−4 (DMSO-d6) 1 no.

δC, type

1 3 4

66.3, CH 67.4, CH 72.1, CH

4a 5 5a 6 7 8 9 9a 10 10a 11

153.6, C 169.4, C 134.2, C 123.2, CH 131.6, CH 131.1, C 151.9, C 119.2, C 173.5, C 123.3, C 36.3, CH2

12 13 12-OMe 1′ 2′

174.9, C 17.3, CH3

3′ 4′ 5′ 6′ 7′ 8′ 4′-OH 9-OH 4a-OH 10a-OH

65.8, 69.4, 76.6, 17.9, 36.7, 41.2,

70.8, CH 28.9, CH2 CH CH CH CH3 CH3 CH3

2 δH, J in Hz

4.94, overlap 4.92, overlap 5.30, d (3.0)

7.46, d (8.0) 7.92, d (8.0)

3.26, dd (17.8, 5.2) 2.55, d (17.8) 1.45, d (6.8) 5.06, br d (10.2) 2.38, m 1.87, m 3.59, overlap 3.41, dd (15.6, 9.0) 3.57, overlap 1.32, d (6.0) 2.72, s 2.75, s 6.11, d (5.0) 11.35, s

δC, type 66.2, CH 68.0, CH 63.3, CH 160.2, C 169.6, C 133.9, C 122.9, CH 130.8, CH 131.2, C 151.6, C 119.0, C 174.0, C 120.5, C 35.3, CH2 171.0, C 16.7, CH3 51.5, CH3 70.5, CH 29.4, CH2 65.9, 69.3, 76.7, 18.0, 36.9, 41.3,

CH CH CH CH3 CH3 CH3

3 δH, J in Hz

4.80, q (6.5) 4.41, m 4.33, m

δC, type 62.6, CH 67.6, CH 28.1, CH2 76.7, C 194.2, C 131.9, C 117.8, CH 132.9, CH 135.1, C 155.9, C 115.8, C 202.9, C 76.2, C 37.2, CH2

7.41, d (8.0) 7.87, d (8.0)

2.78, overlap 2.66, overlap 1.37, d (6.5) 3.64, s 5.11, br d (10.6) 2.38, m 1.80, m 3.57, m 3.43, dd (15.6, 9.0) 3.54, m 1.32, d (6.0) 2.71, s 2.79, s 6.15, d (6.0) 11.32, s

171.7, C 15.5, CH3 51.3, CH3 70.2, CH 29.2, CH2 65.7, 69.4, 76.4, 18.0, 36.9, 41.0,

CH CH CH CH3 CH3 CH3

4 δH, J in Hz

4.27, 4.38, 2.38, 1.74,

q (6.3) m overlap d (17.4)

7.50, d (8.0) 7.84, d (8.0)

3.14, dd (15.2, 9.8) 2.60, dd (15.2, 5.0) 1.23, 3.60, 4.89, 2.35, 1.65, 3.58, 3.38, 3.50, 1.29, 2.69, 2.78, 6.10,

d (6.3) s br d (10.8) m m m overlap dd (8.9, 6.2) d (6.2) s s br s

δC, type 159.1, C 61.4, CH 159.5, C 116.4, C 178.4, C 134.8, C 118.6, CH 133.6, CH 135.9, C 158.7, C 117.0, C 186.6, C 116.1, C 39.7, CH2 170.2, C 13.8, CH3 51.6, CH3 70.1, CH 29.3, CH2 65.8, 69.4, 76.5, 17.9, 37.5, 40.8,

CH CH CH CH3 CH3 CH3

δH, J in Hz 5.64, t (6.2)

7.74, d (8.0) 7.90, d (8.0)

2.84, m

2.73, 3.61, 4.93, 2.34, 1.70, 3.60, 3.41, 3.51, 1.29, 2.72, 2.78,

s s br d (10.8) m m overlap overlap dd (8.9,6.2) d (6.2) s s

6.71, s 6.52, s C

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2.50 ppm for the 1H spectra and at 39.5 ppm for the 13C spectra. HRESIMS data were obtained using an Agilent 6230 TOF LC-MS tandem spectrometer. Silica gel (300−400 mesh, Qingdao Haiyang Chemical Company) and Sephadex LH-20 (Amersham Pharmacia Biotech) were used for column chromatography. A Shimadzu LC-20AP preparative HPLC system with an Agilent Pursuit C-18 column (10 μm, 21.2 × 250 mm) was used for sample purification. Artificial sea salt was bought from the Zhejiang Province Salt Industry Group Co., Ltd. Fermentation, Extraction, and Purification. Colonies of the strain growing on a Gause’s agar plate were directly inoculated into 500 mL Erlenmeyer flasks, containing 250 mL of Gause’s liquid medium (soluble starch 20.0 g, KNO3 1.0 g, KH2PO4 0.5 g, MgSO4 0.5 g, NaCl 0.5 g, FeSO4·7H2O 0.01 g, and sea salt 25.0 g dissolved in 1 L of H2O, pH = 7.0−7.2), and then incubated at 28 °C for 8 days on a rotary shaker (180 rpm). A total of 100 bottles were prepared for fermentation. The fermentation broths were extracted with EtOAc three times. The resulting EtOAc fraction was dried under vacuum and yielded an organic extract (1.5 g), which was subjected to silica gel CC (30 g, 60 cm × 5.0 cm) eluting with CH2Cl2−MeOH (50:1, 30:1, 20:1, 10:1, 5:1, 1:1, and 0:1 each 500 mL) to give nine fractions (A−I). Fraction E (200 mg) was first separated by Sephadex LH-20 (150 cm × 2.5 cm, MeOH) and further purified by preparative HPLC (10−100% MeOH and 0.05% trifluoroacetic acid in H2O, 40 min, flow rate 20 mL/min) to give 2 (5.2 mg, tR = 11.7 min), 1 (3.3 mg, tR = 13.8 min), 3 (3.5 mg, tR = 15.6 min), 5 (15 mg, tR = 18.7 min), and 4 (2.3 mg, tR = 23.5 min). Strepoxepinmycin A (1): yellowish oil; [α]20D +22 (c 0.15, MeOH); UV (MeOH) λmax (log ε) 228 (3.78), 256 (3.27), 283 (2.97), 312 (3.32) nm; ECD (c 1.1 × 10−3 M, MeOH), λmax (Δε) 211 (22.9), 251 (1.07), 280 (−0.28), 330 (−3.12) nm; IR νmax 3379, 1671, 1201, 1131, 838 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 474.1762 [M + H]+ (calcd for C24H28NO9, 474.1764), 496.1580 [M + Na]+ (calcd for C24H27NNaO9, 496.1584), and 512.1315 [M + K]+ (calcd for C24H27KNO9, 512.1323). Strepoxepinmycin B (2): yellowish oil; [α]20D +23 (c 0.18, MeOH); UV (MeOH) λmax (log ε) 228 (3.73), 256 (3.19), 281 (2.88), 311 (3.47) nm; ECD (c 0.9 × 10−3 M, MeOH), λmax (Δε) 211 (21.7), 251 (−1.5), 311 (2.60), 330 (−3.7) nm; IR νmax 3396, 1676, 1203, 1138, 1134, 802 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 506.2020 [M + H]+ (calcd for C25H32NO10, 506.2020) and 528.1838 [M + Na]+ (calcd for C25H31NNaO10, 528.1846). Strepoxepinmycin C (3): yellow oil; [α]20D +60 (c 0.5, MeOH); UV (MeOH) λmax (log ε) 236 (3.90), 346 (3.28) nm; ECD (c 0.9 × 10−3 M, MeOH), λmax (Δε) 228 (1.30), 241 (−1.92), 254 (8.21), 280 (12.48), 330 (0.91), 373 (−3.75) nm; IR νmax 3373, 1673, 1434, 1199, 1132, 1087, 1006, 801 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 508.2179 [M + H] + (calcd for C 25 H34NO 10 508.2183). Strepoxepinmycin D (4): yellow oil; [α]20D +95 (c 0.5, MeOH); UV (MeOH) λmax (log ε) 223 (3.84), 249 (3.88), 308 (3.16), 387 (3.26) nm; ECD (c 1 × 10−3 M, MeOH), λmax (Δε) 211 (6.91), 254 (−0.91), 280 (1.54), 400 (1.72) nm; IR νmax 3390, 1732, 1671, 1633, 1579, 1424, 1249, 1201, 1105, 1083, 801 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 488.1915 [M + H]+ (calcd for C25H30NO9, 488.1921).

Figure 5. Experimental ECD spectrum and calculated ECD spectra of 3.

the absolute configuration of C-3 in 4 due to the similarities of the calculated ECD curves for the C-3 epimers of 4 (Figure S43). However, considering that compound 4 shares the same biosynthesis pathway with co-isolated compounds 1−3 and medermycin (5), we speculate that the absolute configuration of C-3 should be R. The structure of 4 was named strepoxepinmycin D. All of the isolates were evaluated for cytotoxicity against the PC-3 and HCT-116 cancer cell lines, for protein kinase inhibition of ROCK2, and for antimicrobial activities against Escherichia coli (ATCC 25922), methicillin-resistant Staphylococcus aureus (ATCC 43300), and Candida albicans (Table 2). Among the test results, compounds 3 and 4 exhibited significant cytotoxicity against HCT116 cells with IC50 values of 4.4 ± 0.1 and 2.9 ± 0.1 μM, respectively. The ROCK2 protein kinase inhibition assay showed that compound 4 exhibited moderate inhibition of ROCK2 with an IC50 value of 9.0 ± 0.6 μM. In addition, all of the new compounds were active against E. coli with MICs of 4.0−10 μg/mL, S. aureus with MICs of 3.0−15 μg/mL, and C. albicans with MICs of 6.0−10 μg/mL.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on an AUTOPOL I digital polarimeter (Rudolph Research Analytical). UV and ECD spectra were measured on a Shimadzu UV-1800 and a JASCO J-1500-150ST spectrophotometer, respectively. IR spectra were acquired on a Thermo Scientific Nicolet iS10 FT-IR spectrometer. NMR data were recorded in DMSO-d6 using a Bruker AV III 600 MHz NMR spectrometer, and the solvent peak was set to

Table 2. Cytotoxicity, ROCK2 Protein Kinase Inhibition, and Antimicrobial Activities of Compounds 1−5 IC50 (μM)

MIC (μg/mL)

compound

PC-3

HCT-116

ROCK2

E. coli

MRSA

CA

1 2 3 4 5 polymyxin B vancomycin amphotericin B

>40 >40 16 ± 1 19 ± 1 0.015 ± 0.001

>40 >40 4.4 ± 0.1 2.9 ± 0.1 0.043 ± 0.001

>20 >20 >20 9.0 ± 0.6 0.011 ± 0.002

8.0 10 5.0 4.0 2.0 2.0

12 15 6.0 3.0 0.25

7.0 10 9.0 6.0 5.0

1.0 2.0 D

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Medermycin (5): yellow oil; [α]20D +170 (c 0.1, MeOH), lit.2 [α]22D +170 (c 1.0, MeOH); ECD (c 1.1 × 10−3 M, MeOH), λmax (Δε) 215 (19.5), 256 (2.84), 294(−2.94), 345 (4.82) nm. Cytotoxicity Assay. The sulforhodamine B (SRB) assay, performed as previously described,15−17 was used for testing the cytotoxicity of compounds 1−4 against the PC3 and HCT-116 human cancer cells. Medermycin was simultaneously tested as a positive control. Briefly, PC3 and HCT116 human cancer cells were seeded in 96-well plates for 24 h, followed by addition of the test compounds at different concentrations. After 72 h of incubation at 37 °C, 100 μL of 10% cold trichloroacetic acid solution was added to each well, further incubated for 2 h at 4 °C, and then washed with distilled H2O four times, and the cells were allowed to dry. A solution containing 0.4% SRB (80 μL) was added to dissolve the dried cells, which were then rinsed with 1% acetic acid solution four times. After drying, 10 mM Tris buffer (100 μL) was added to dissolve the dried cells. The OD value of each well was measured at a test wavelength of 515 nm using a microplate reader (BioTech). The IC50 values of the tested compounds were calculated using the method reported by Reed and Muench.18 ROCK2 Assay. The ROCK2 protein kinase inhibition assay was conducted as previously described,16 using the HTRF KinEASE kit protocol. Briefly, 4 μL of tested compound solutions at different concentrations was added to a 6 μL mixture (substrate, enzyme, and ATP, each 2 μL) and further incubated for 0.5 h at 37 °C, and then SA-XL665 and STK antibody−cryptate solutions (each 5 μL) were added. The mixture was incubated at room temperature for 1 h. The HTRF signal was measured by a SPARK 10M (TECAN) microplate reader. Medermycin (5) was used as a positive control. All of the tests were conducted in triplicate. Antimicrobial Assay. The antimicrobial tests against methicillinresistant E. coli (ATCC 25922), S. aureus (ATCC 43300), and C. albicans in vitro used the microdilution method. Polymyxin B, vancomycin, and amphotericin B were used as positive controls for E. coli, S. aureus, and C. albicans, respectively. Briefly, a 10 mg/mL stock solution of tested compounds (in DMSO) was diluted with microbial cell suspension to make a series of concentrations in sterile 96-well plates, and the final volume was 200 μL. The plates were incubated at 37 °C for 12 h, and the MIC was assigned as the lowest concentration that was completely clear against a black background. All tests were conducted in triplicate.

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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.8b00544. 1D, 2D NMR, HRESIMS, and IR spectra of new compounds, 1D NMR spectra for compound 5, and ECD calculations for compounds 1−4 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhong-Jun Ma: 0000-0002-5825-5095 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Fundamental Research Funds for the Central Universities (No. 2018QNA4043). REFERENCES

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