Secondary Metabolites Produced by Combined Culture of Penicillium

Jul 2, 2019 - UPLC-MS data and an analysis of structural features showed that ... Produced by Combined Culture of Penicillium crustosum and a Xylaria ...
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Secondary Metabolites Produced by Combined Culture of Penicillium crustosum and a Xylaria sp. Guihong Yu,† Zichao Sun,† Jixing Peng,§ Meilin Zhu,† Qian Che,† Guojian Zhang,†,‡ Tianjiao Zhu,†,‡ Qianqun Gu,† and Dehai Li*,†,‡

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†

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People’s Republic of China ‡ Laboratory for Marine Drugs and Bioproducts of Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, People’s Republic of China § Key Laboratory of Testing and Evaluation for Aquatic Product Safety and Quality, Ministry of Agriculture and Rural Affairs, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, People’s Republic of China S Supporting Information *

ABSTRACT: Four new alkyl aromatics, penixylarins A−D (1−4), along with the known biogenetically related 1,3dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6), were isolated from a mixed culture of the Antarctic deep-sea-derived fungus Penicillium crustosum PRB-2 and the mangrove-derived fungus Xylaria sp. HDN13-249. UPLC-MS data and an analysis of structural features showed that compounds 1 and 2 were produced by collaboration of the two fungi, while compounds 3−6 could be produced by Xylaria sp. HDN13-249 alone, but in noticeably increased quantities by cocultivation. Compounds 2, 3, 5, and 6 showed antibacterial activity against a panel of strains, and compound 3 possessed potential antituberculosis effects (MIC = 6.25 μM against Mycobacterium phlei).

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analysis. A follow-up examination of this cocultivation system resulted in the isolation of four new alkyl aromatics, named penixylarins A−D (1−4), along with the known biogenetically related 1,3-dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3-dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6). UPLC-MS data and structural features indicated that compounds 1 and 2 were produced by collaboration of the two fungi, while compounds 3−6 were produced by Xylaria sp. HDN13-249 alone, with the quantities increased dramatically by cocultivation. The antimicrobial activities of the compounds, with the exception of compound 4 (limited quantity and unstable), were evaluated, and compounds 2, 3, 5, and 6 showed activities against Mycobacterium phlei, Bacillus subtilis, or Vibrio parahemolyticus. Herein, we report details of the isolation, structure elucidation, and bioactivity evaluation of the compounds. The two strains P. crustosum PRB-2 and Xylaria sp. HDN13249 were cocultured in 15 cm Petri dishes containing 45 mL of fungal solid medium (ingredients see Experimental Section) for 30 days at 28 °C. Guided by UPLC-MS data, the EtOAc extract (5 g) of the mycelia and the solid medium (3 L) was fractionated by ODS MPLC and HPLC to yield compounds 1−6.

arine-derived fungi possessing various biosynthetic gene clusters have proven to be important sources for the production of novel chemical skeletons with a broad range of bioactivities.1,2 Due to the fact that most of the gene clusters encoding secondary metabolites are silent under laboratory conditions, many methods have been developed at the genome, transcriptome, proteome, or metabolome levels to exploit the biosynthetic potential stored inside fungal strains.1,3 Among them, microorganism coculture, which is inspired by natural microbe communities, is an effective method to trigger the production of novel secondary metabolites, via several possible mechanisms including (a) new products triggered by chemical signals or cell−cell contact; (b) the products of one organism further modified by another one.1,3−6 Interestingly, secondary metabolites induced by microorganism coculture often show significant activities, such as antibacterial, cytotoxic, and antifouling activities, partially due to triggering of a defense mechanism.7−13 In our previous work, the Antarctic deep-sea-derived fungus Penicillium crustosum PRB-2 has been shown to produce novel bioactive structures and harbor various secondary metabolites encoding genes.14,15 In order to tap into the chemical potential of PRB-2, a variety of strains isolated from diverse marine environments were cocultivated with PRB-2. During this process, we found that when P. crustosum PRB-2 was cocultured with the mangrove-derived fungus Xylaria sp. HDN13-249, new metabolites were detected by HPLC-UV © XXXX American Chemical Society and American Society of Pharmacognosy

Received: April 14, 2019

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DOI: 10.1021/acs.jnatprod.9b00345 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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Table 1. 1H (500 MHz) and 13C (125 MHz) NMR Data of Compounds 1 and 2 (DMSO-d6, δ ppm) 1 no.

Compound 1 was isolated as a pale yellow oil, with a molecular formula of C33H50O6 that was deduced from the HREIMS peak at m/z 541.3537 [M − H]−. The 1D NMR spectroscopic data (Table 1) of 1 indicated the presence of 10 nonprotonated carbons including one carbonyl (δC 203.3), three aromatic methines, one oxygenated methine, two aryllinked methylenes (δC 32.9, δH 2.50; δC 17.8, δH 3.77), three methyls, and an alkyl side chain (δH 1.0−1.4), which had similar correlations to those observed in compound 5.16 The difference between compounds 1 and 5 was the replacement of the aromatic hydrogen (δH 6.01) in 5 by an acetophenone moiety in 1, which was further supported by 2D NMR spectra. The existence of the acetophenone moiety was supported by the HMBC correlations between H-1′ and C-2′/C-3′/C-7′, between 3′-OH and C-2′/C-3′/C-4′, between H-5′ and C-3′/ C-6′/C-8′, between H3-9′ and C-4′/C-8′, and between H3-10′ and C-5′/C-6′/C-7′. The acetophenone moiety was further linked to C-6 evidenced by the HMBC correlations from H-1′ to C-1/C-5/C-6 (Figure 1). The absolute configuration of C12″ was determined by making MPA esters of 1,17 and the proton signals around C-12″ of both derivatives were assigned by 1D and 2D NMR data (Table S1 and Figure S1). The ΔδRS values between 1a and 1b (R- and S-MPA esters of 1 on 12″OH, respectively) were positive for H-10′′/11′′ and negative for H-13′′/14′′/15′′/16′′/17′′ (Figure 2), indicating a 12″S configuration. Compound 2 was isolated as a pale yellow oil with the molecular formula C33H50O9S according to the HRESIMS ions detected at m/z 621.3109 [M − H]−. Considering the highly similar 1H and 13C NMR data (Table 1) and molecular formulas of compounds 1 and 2, compound 2 was deduced to be the 12″-OH sulfonated derivative of 1, which was further confirmed by the chemical shifts of C-11″, C-12′′, C-13′′ (δC 34.3, 76.2, 34.2 in 2 vs δC37.6, 70.0, 37.7 in 1) and H-12″ (δH 3.98 in 2 vs δH 3.31 in 1), as well as the 2D NMR data (Figure S2). Similar to compounds 5 and 6,16 compound 2 can also transform to compound 1 by losing the SO3 group (Figure S3), which suggested the absolute configuration of C-12″ in compound 2 was the same as 1. Compounds 3 and 4 were both isolated as pale yellow oils, with molecular formulas C24H40O5 and C24H40O8S established by the HRESIMS data, respectively. The 1D NMR data of 3 were similar to those of 5. The differences between them were the lack of an aromatic methine (δH 6.01, δC 106.3) and the presence of an additional aromatic quaternary carbon (δC 106.0) and a carbonyl (δC 173.1) in 3.16 Further interpretation

δC, type

δH (J in Hz)

1 2 3 4 5 6 1′ 2′ 3′ 4′ 5′ 6′ 7′ 8′ 9′ 10′ 1″ 2″

154.8, C 100.3, CH 156.5, C 109.1, CH 144.8, C 114.8, C 17.8, CH2 113.9, C 160.7, C 112.2, C 131.2, CH 116.6, C 162.0, C 203.3, C 26.5, CH3 16.3, CH3 32.9, CH2 32.1, CH2

3″

29.7,a CH2 29.7,a CH2 29.5,a CH2 29.5,a CH2 29.5,a CH2 29.5,a CH2 29.5,a CH2 25.4,b CH2 37.6,c CH2 1.18−1.32, overlap 70.0, CH 3.31, overlap 37.7,c CH2 1.18−1.32, overlap 25.7,b 1.21, 1.32, overlap CH2 31.9, CH2 1.05−1.24, overlap 22.6, CH2 1.24, overlap 14.4, CH3 0.83, t (6.9) 9.01, s 13.43, s 4.17, d (5.4)

4″ 5″ 6″ 7″ 8″ 9″ 10″ 11″ 12″ 13″ 14″ 15″ 16″ 17″ 3-OH 3′-OH 12″-OH

6.19, d (2.4) 6.05, d (2.4)

3.77, s

7.52, s

2.50, s 2.03, s 2.50, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.05−1.31, overlap 1.32, overlap

2 δC, type 154.5, C 100.2, CH 156.6, C 109.2, CH 144.8, C 114.5, C 17.7, CH2 113.9, C 160.6, C 112.5, C 131.3, CH 116.4, C 161.3, C 203.6, C 26.6, CH3 16.3, CH3 32.9, CH2 31.9, CH2

δH (J in Hz) 6.20, s 6.06, s

3.78, s

7.54, s

34.3,f CH2

2.51, s 2.04, s 2.50, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.05−1.25, overlap 1.18−1.29, overlap 1.41, overlap

76.2, CH 34.2,f CH2

3.98, t (5.9) 1.41, overlap

29.7,d CH2 29.6,d CH2 29.6,d CH2 29.5,d CH2 29.5,d CH2 29.5,d CH2 29.3,d CH2 24.7,e CH2

25.0,e CH2 1.18−1.29, overlap 31.9, CH2 1.05−1.25, overlap 22.6, CH2 1.23, overlap 14.4, CH3 0.83, t (6.5) 13.40, s

a−f

Interchangeable.

of the 2D NMR spectra confirmed that one of the aromatic hydrogens in 5 was replaced by a carboxylic acid group (Figure 1). The 1D NMR data of compounds 3 and 4 were also similar, and the major differences were the chemical shifts of C-11″, C-12′′, C-13′′ (δC 34.3, 76.2, 34.3 in 4 vs δC 37.6, 70.0, 37.6 in 3) and H-12″ (δH 3.99 in 4 vs δH 3.31 in 3), suggesting the replacement of the 12″-OH in 3 by a sulfate group in 4, which was supported by the 2D NMR data. The 12″S absolute configurations of compounds 3 and 4 were deduced to be the B

DOI: 10.1021/acs.jnatprod.9b00345 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

Scheme 1. Plausible Route of Formation for 1 and 2

Figure 1. Key HMBC correlations of 1 and 3.

quantity and unstable), were also tested against seven other microorganisms by the microdilution method, including Mycobacterium phlei, Bacillus subtilis, Vibrio parahemolyticus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Proteus vulgaris. Compounds 2, 3, 5, and 6 showed activities against M. phlei, B. subtilis, or V. parahemolyticus, with MIC values ranging from 6.25 to 100 μM (Table 3). Among them, compound 3 showed promising activity against M. phlei, which indicated the antituberculosis potential. In summary, four new alkylaromatics, namely, penixylarins A−D (1−4), along with the biogenetically related 1,3dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6), were isolated from a mixed culture of P. crustosum PRB-2 and Xylaria sp. HDN13-249. UPLC-MS data and an analysis of structural features suggested that compounds 1 and 2 were generated by a nonenzymatic Michael addition between an ortho-quinone methide intermediate and compounds 5 and 6, which were produced by PRB-2 and HDN13-249, respectively, while compounds 3−6 can be produced by Xylaria sp. HDN13-249 alone, but with the quantities increased obviously by cocultivation. Compounds 2, 3, 5, and 6 showed inhibitory activities against M. phlei, B. subtilis, or V. parahemolyticus. This result was a typical example for microorganism cocultivation that produced new compounds by a nonenzymatic coupling of precursors and demonstrated that microorganism cocultivation is an effective method to trigger the production of bioactive secondary metabolites.

Figure 2. ΔδRS values of 1a and 1b.

same as those of 1 and 2 according to their common biogenetic origin and the negative optical rotations. The planar structures of compounds 5 and 6 were determined to be the same as 1,3-dihydroxy-5-(12hydroxyheptadecyl)benzene (5) and 1,3-dihydroxy-5-(12sulfoxyheptadecyl)benzene (6) based on the NMR data, respectively, and their absolute configurations were also deduced to be 12″S based on biogenetic consideration and the negative optical rotations.16 The formation process of compounds 1−6 was tentatively proposed based on the UPLC-MS analysis and the structure characteristics. The UPLC-MS profiles showed that compounds 1 and 2 were not produced by either of the two fungi when cultured alone under the same conditions, while compounds 3−6 could be detected from the fermentation broth of Xylaria sp. HDN13-249 when cultured alone. In addition, we also found that the quantities of compounds 3−6 obviously increased by cocultivation, especially 3 and 4 (Figures S4 and S5 in the Supporting Information). Based on the structures, compounds 1 and 2 contained a clavatol fragment (acetophenone moiety), which was derived from a chemically active ortho-quinone methide intermediate produced by P. crustosum PRB-2.14,15 Similar to the formation pathways of the previous isolated penilactones A and B,14,15 compounds 1 and 2 were proposed to be generated by a nonenzymatic Michael addition between the ortho-quinone methide intermediate and compounds 5 and 6, respectively (Scheme 1). The cytotoxicities of 1−6 were tested against 12 cell lines (HL-60, K562, BEL-7402, HCT-116, A549, HeLa, L-02, MGC-803, HO8910, SH-SY5Y, PC-3, MDA-MB-231) using the methylthiazoletrazolium (MTT) or sulforhodamine B (SRB) method, but no activity was detected (IC50 > 30 μM). To check the effects of the produced compounds on the cocultivated strains, the inhibitory activities of compounds 1− 6 against P. crustosum PRB-2 and Xylaria sp. HDN13-249 were performed by a disk diffusion test, but no compounds showed activity at 25 μg per disk. The antimicrobial activities of those compounds, with the exception of compound 4 (limited

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EXPERIMENTAL SECTION

General Experimental Procedures. Specific rotations were measured on a JASCO P-1020 digital polarimeter. UV spectra were recorded on a Beckman DU 640 spectrophotometer. NMR spectra were obtained on an Agilent 500 MHz DD2 spectrometer with tetramethylsilane as an internal standard. ESIMS spectra were obtained on a Thermo Scientific LTQ Orbitrap XL mass spectrometer (Thermo Fisher Scientific) or a Micromass Q-TOF ULTIMA GLOBAL GAA076 LC mass spectrometer (Waters Corporation). Semipreparative HPLC was performed on an ODS column (HPLC (YMC-Pack ODS-A, 10 × 250 mm, 5 μm, 3 mL/ min)) (YMC Co., Ltd.). Medium-pressure preparation liquid chromatography (MPLC) was performed on a Bona-Agela CHEETAHTM HP100 (Beijing Agela Technologies Co., Ltd.).18 Fungal Material. The fungal strain Xylaria sp. HDN13-249 was isolated from the root of Sonneratia caseolaris collected from the mangrove conservation area of Hainan, China. It was identified by ITS sequence, and the sequence data have been submitted to C

DOI: 10.1021/acs.jnatprod.9b00345 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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Table 2. 1H (500 MHz) and 13C (125 MHz) NMR Data of Compounds 3 and 4 (DMSO-d6, δ ppm) 3 no.

δC, type

1 2 3 4 5 6 1′ 1″ 2″ 3″

164.2, C 101.0, CH 161.8, C 110.2, CH 147.6, C 106.0, C 173.1, C 35.7, CH2 31.8, CH2 29.7,a CH2 29.6,a CH2 29.6,a CH2 29.5,a CH2 29.5,a CH2 29.5,a CH2 29.3,a CH2 25.7,b CH2 37.6, CH2 70.0, CH 37.6, CH2 25.3,b CH2 31.9, CH2 22.6, CH2 14.4, CH3

4″ 5″ 6″ 7″ 8″ 9″ 10″ 11″ 12″ 13″ 14″ 15″ 16″ 17″

δH (J in Hz)

4 δC, type

2.73, m 1.45, m 1.15−1.27, overlap

164.0, C 101.0, CH 162.0, C 110.5, CH 147.6, C 105.6, C 173.2, C 35.8, CH2 31.8, CH2 29.7,c CH2

1.15−1.27, overlap

29.6,c CH2

1.15−1.27, overlap

29.6,c CH2

1.15−1.27, overlap

29.5,c CH2

1.15−1.27, overlap

29.5,c CH2

1.15−1.27, overlap

29.5,c CH2

1.15−1.27, overlap

29.3,c CH2

1.31, overlap

25.0,d CH2 34.3, CH2 76.2, CH 34.3, CH2 24.7,d CH2 32.0, CH2 22.6, CH2 14.4, CH3

6.11, d (2.5) 6.08, d (2.4)

1.18−1.32, overlap 3.31, overlap 1.18−1.32, overlap 1.21, overlap1.32, overlap 1.21 overlap 1.24 overlap 0.83 t (6.9)

inoculated at the same time approximately 1 cm apart in the Petri dish. After 30 days of incubation, the mycelia and the solid medium (total 3 L) were extracted with EtOAc and concentrated under reduced pressure to give an extract (5.0 g). Purification. The EtOAc extract (5.0 g) was separated by MPLC using a gradient elution of MeOH−H2O (5−100%), yielding eight subfractions (fractions 1−8). Guided by the retention times and specific ion peaks of the UPLC-MS data, fractions 6 and 7 were selected. Fraction 6 was separated by semipreparative HPLC eluting with MeOH−H2O (50:50, with 2/1000 trifluoroacetic acid in water) to furnish compounds 6 (20.0 mg, tR 16.5 min) and 4 (4.0 mg, tR 18.5 min). Fraction 7 was fractionated by semipreparative HPLC with a gradient elution of MeOH−H2O (60−100%, with 2/1000 trifluoroacetic acid in water) to give compounds 2 (13.0 mg, tR 21.5 min), 3 (5.0 mg, tR 24.5 min), 5 (15.0 mg, tR 26.0 min), and 1 (10 mg, tR 29.5 min), respectively. Penixylarin A (1): pale yellow oil; [α]20D −4.7 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 218 (4.05), 283 (2.10), 329 (0.90) nm; 1H and 13 C NMR data, see Table 1; HRESIMS m/z 541.3537 [M − H]− (calcd for C33H49O6, 541.3535). Penixylarin B (2): pale yellow oil; [α]20D −7.8 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 218 (4.10), 283 (2.16), 330 (0.95) nm; 1H and 13 C NMR data, see Table 1; HRESIMS m/z 621.3109 [M − H]− (calcd for C33H49O9S, 621.3103). Penixylarin C (3): pale yellow oil; [α]20D −5.5 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 218 (4.02), 260 (2.21), 300 (1.05) nm; 1H and 13 C NMR data, see Table 2; HRESIMS m/z 407.2802 [M − H]− (calcd for C24H39O5, 407.2803). Penixylarin D (4): pale yellow oil; [α]20D −10.2 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 219 (4.00), 261 (2.56), 299 (1.25) nm; 1H and 13C NMR data, see Table 2; HRESIMS m/z 487.2372 [M − H]− (calcd for C24H39O8S, 487.2371). 1,3-Dihydroxy-5-(12-hydroxyheptadecyl)benzene (5): [α]20D −2.3 (c 0.1, MeOH). 1,3-Dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6): [α]20D −4.9 (c 0.1, MeOH). Assay of Cytotoxicity Inhibitory Activity. As previously reported.19−21 Assay of Antimicrobial Activity. As previously reported.22,23 Preparation of MPA Esters Derived from 1 (1a and 1b). The sample of compound 1 (2.0 mg each) was treated with (R)- or (S)MPA (9 mg) with N,N'-dicyclohexylcarbodiimide (10 mg) and 4dimethylaminopyridine (8 mg) in dry CDCl3 (0.5 mL). After stirring for 0.5 h at room temperature, the residue was evaporated under reduced pressure was purified by HPLC individually (MeOH−H2O = 50−100%, 3 mL/min) to obtain the (R)-MPA ester (1a) and (S)MPA ester (1b), respectively. (R)-MPA Ester (1a): pale yellow oil; 1H and 13C NMR data, Table S1; ESIMS m/z 689.4 [M − H]−. (S)-MPA Ester (1b): pale yellow oil; 1H and 13C NMR data, Table S1; ESIMS m/z 689.4 [M − H]−.

δH (J in Hz) 6.10, d (2.4) 6.15, d (2.5)

2.72, m 1.46, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.19−1.33, overlap 1.43, overlap 3.99, t (6.7) 1.43, overlap 1.19−1.33, overlap 1.22, overlap 1.24, overlap 0.84, t (6.7)

a−d

Interchangeable.

Table 3. Inhibitory Effects of Compounds 1−3, 5, and 6 on Three Kinds of Microorganisms compd

Mycobacterium phlei

Bacillus subtilis

Vibrio parahemolyticus

1 2 3 5 6 ciprofloxacin

>200 >200 6.25 25.0 12.5 1.56

>200 100 >200 >200 >200 1.56

>200 >200 12.5 >200 25.0 12.5

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GenBank (accession number: MK334345). The isolation and identification of Penicillium crustosum PRB-2 have been previously described.14 These two fungi were deposited at the Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People’s Republic of China. Fermentation and Extraction. P. crustosum PRB-2 and Xylaria sp. HDN13-249 were incubated on PDA medium for 5 days to prepare inocula, respectively. Then, the two fungi were cocultured under static fermentation in 15 cm Petri dishes containing 45 mL of solid medium [soluble starch (40 g/L), yeast extract (1 g/L), MgSO4 (0.3 g/L), monosodium glutamate (2 g/L), sucrose (40 g/L), KH2PO4 (0.5 g/L), maltose (30 g/L), bean flour (0.5 g/L), peptone (2 g/L), agar power (25.0 g/L), and seawater (Huiquan Bay, Yellow Sea)] and incubated for 30 days at 28 °C. The two fungi were

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.9b00345. Supplementary experimental section; NMR spectra and HRESIMS of compounds 1−6, 1a, and 1b; HPLC analysis of conversions of 2 to 1, 6 to 5, and standard samples; UPLC-MS and HPLC analyses of the 30-day fermentation broth extracts from cocultivation of P. crustosum PRB-2 and Xylaria sp. HDN13-249 and cultured alone (PDF) D

DOI: 10.1021/acs.jnatprod.9b00345 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Note

(20) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1107−1112. (21) Du, L.; Zhu, T.; Liu, H.; Fang, Y.; Zhu, W.; Gu, Q. J. Nat. Prod. 2008, 71, 1837−1842. (22) Andrews, J. M. J. Antimicrob. Chemother. 2001, 48, 43−57. (23) Yu, G.; Wu, G.; Sun, Z.; Zhang, X.; Che, Q.; Gu, Q.; Zhu, T.; Li, D.; Zhang, G. Mar. Drugs 2018, 16, 335.

AUTHOR INFORMATION

Corresponding Author

*Tel: 0086-532-82031619. Fax: 0086-532-82033054. E-mail: [email protected]. ORCID

Qian Che: 0000-0003-0610-1593 Dehai Li: 0000-0002-7191-2002 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (41806167, 41606166), the Fundamental Research Funds for the Central Universities (201941001), the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology (Qingdao) (No. 2018SDKJ0401-2), Project Funded by China Postdoctoral Science Foundation (2017M622286), Taishan Scholar Youth Expert Program in Shandong Province (tsqn201812021), and Qingdao Postdoctoral Applied Research Project Financially Supported by Qingdao Municipal Bureau of Human Resource and Social Security.

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DOI: 10.1021/acs.jnatprod.9b00345 J. Nat. Prod. XXXX, XXX, XXX−XXX