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Four new diphenyl ether derivatives from the mangrove endophytic fungus epicoccum sorghinum

  • Corresponding author: E-mail: xiongyahong@scau.edu.cn (Y. Xiong); chunyuanli@scau.edu.cn (C. Li). Telephone: + 86-20-85280319
  • Available Date: 07-Dec.-2021
  • Four new diphenyl ethers, named epicoccethers K‒N ( 1 - 4 ), were purified from the fermentation medium of a fungus Epicoccum sorghinum derived from Myoporum bontioides, and identified via HRESIMS and NMR spectral analysis. Except that compound 1 showed moderate antifungal activity against Penicillium italicum and Fusarium graminearum, the other three compounds all showed stronger activity against them than triadimefon. All of them showed moderate or weak antibacterial activities towards Staphylococcus aureus and Escherichia coli with O6 and O78 serotypes except that 3 was inactive to E. coli O6.
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    Li C, Chang C, Tsai Y, et al. Anti-inflammatory, antiplatelet aggregation, and antiangiogenesis polyketides from Epicoccum sorghinum: toward an understating of its biological activities and potential applications [J]. ACS Omega, 2020, 5(19): 11092-11099. doi: 10.1021/acsomega.0c01000
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Four new diphenyl ether derivatives from the mangrove endophytic fungus epicoccum sorghinum

    Corresponding author: E-mail: xiongyahong@scau.edu.cn (Y. Xiong); chunyuanli@scau.edu.cn (C. Li). Telephone: + 86-20-85280319
  • 1. Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, P. R. China

Abstract: Four new diphenyl ethers, named epicoccethers K‒N ( 1 - 4 ), were purified from the fermentation medium of a fungus Epicoccum sorghinum derived from Myoporum bontioides, and identified via HRESIMS and NMR spectral analysis. Except that compound 1 showed moderate antifungal activity against Penicillium italicum and Fusarium graminearum, the other three compounds all showed stronger activity against them than triadimefon. All of them showed moderate or weak antibacterial activities towards Staphylococcus aureus and Escherichia coli with O6 and O78 serotypes except that 3 was inactive to E. coli O6.

    • Nowadays, marine fungi with high adaptability to extreme environments of the ocean become one of the most important sources of new drug leads [1-4]. Among them, the Epicoccum sorghinum has produced metabolites with multifunction including anti-inflammatory, antiplatelet aggregation, antiangiogenesis activities, and cytotoxic activity against a triple-negative breast cancer cell line effects [5, 6]. During our effort to search for novel antimicrobial compounds from different endophytes [7-9], a fungus of Epicoccum sorghinum L28 purified from Myoporum bontioides A. Gray collected in mangrove was chemically investigated. Herein, the isolation, identification and antimicrobial evaluation of four new diphenyl ethers (1-4) (Fig. 1) are reported.

      Figure 1.  Structures of compounds 1‒4

    Materials and Methods
    • HRESIMS were evaluated via a LCMS-IT-TOF (Shimadzu Corporation, Tokyo, Japan) mass spectrometer. NMR spectra were recorded via a Bruker AV600 spectrometer (Bruker Biospin GmbH Corporation, Karlsruhe, Germany) with tetramethylsilane (TMS) as the reference. Column chromatography (CC) was carried out using 50‒80 μm silica gel (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China), and Sephadex LH-20 (Merck company, Darmstadt, Germany). HPLC separation utilized an Elite system with a P230p pump and a UV230II wavelength detector (Elite Analytical Instrument Co., Ltd., Dalian, China) using a C18 column (250 × 10 mm, 5 μm, H&E Co., Ltd, Beijing, China). All solvents for separation were analytical grade except the HPLC chromatographic pure methanol.

    • E. sorghinum L28 was isolated from the semi-mangrove plant M. bontioides in Leizhou Peninsula, China, in June 2018. This strain was identified relying on its Internal Transcribed Spacer (ITS) rRNA sequence (no. MZ378789 in GenBank) using the reported procedure [10]. It and the pathogens Penicillium italicum, Fusarium graminearum, Escherichia coli with O6 serotype (E. Coli O6), Escherichia coli with O78 serotype (E. Coli O78) and Staphylococcus aureus were acquired and stored in the College of Materials and Energy, South China Agricultural University.

    • After the initial fermentation on PDA medium, the scale-up culture of E. sorghinum L28 were incubated in 42 × 500 mL Erlenmeyer flasks without rotation at 27 °C for 25 d, with liquid medium (250 mL water, 5 g glucose, 0.6 g tryptone). The obtained fermentation was extracted using ethyl acetate (EtOAc) for 3 times, then the solvent was evaporated to obtain a black crude extract. The extract (30.6 g) was transferred to CC (55 × 6 cm) and partitioned into seven fractions (Fr. A to Fr. G) via gradient elution using the mixture of petroleum ether (PE)/EtOAc (v/v, 21:1, 7:1, 3:1, 1:1, 1:3, 1:7, 1:21). Fr. C (6.2 g) was then partitioned into twenty-three fractions (Fr. C1 to Fr. C23) on CC (45 × 2.5 cm) eluted with PE/EtOAc (v/v, 21:1, 7:1, 3:1, 1:1) according to the TLC properties. Fr. C7 (0.73 g) was submitted to Sephadex LH-20 CC (55 × 1.0 cm, MeOH) to get thirteen subfractions (Fr. C7.1 to Fr. C7.13). Fr. C7.8 (9.5 mg) was further purified by HPLC eluted with MeOH/H2O (v/v, 70:30 to 90:10, 3.0 mL/min, 20 min) to obtain compounds 1 (5.6 mg, tR = 16.6 min). Fr. C9 (0.97 g) was separated on Sephadex LH-20 CC (68 × 1.0 cm, MeOH) to give fifteen subfractions (Fr. C9.1 to Fr. C9.15). Fr. C9.11 (13.3 mg) was ulteriorly separated by HPLC with MeOH/H2O (v/v, 40:60 to 100:0, 3.0 mL/min, 60 min) to get products 3 (4.8 mg, tR = 37.1 min) and 4 (3.4 mg, tR = 40.9 min). Fr. D (8.1 g) was then partitioned into nineteen fractions (Fr. D1 to Fr. D19) on CC (52 × 2.5 cm) eluted with PE/EtOAc (v/v, 7:1, 3:1, 1:1, 1:3) with respect to the TLC properties. Fr. D9 (0.53 g) was partitioned on Sephadex LH-20 CC (68 × 1.0 cm, MeOH) to get seventeen subfractions (Fr. D9.1 to Fr. D9.17). Fr. D9.10 (8.7 mg) was submitted to HPLC eluted with MeOH/H2O (v/v, 60:40 to 80:20, 3.0 mL/min, 20 min) to afford 2 (5.2 mg, tR = 19.1 min).

      Epicoccether K (1). Colorless oil; HRESIMS m/z 347.1130 [M ‒ H] (calcd for C18H19O7, 347.1131); IR (KBr) νmax 3489, 2954, 1730, 1659, 1606, 1488, 1440, 1207, 1155, 1067, 827 cm−1; UV (MeOH) λmax (log ε): 207 (4.51), 255 (3.60), 296 (2.12) nm; 1H and 13C NMR (Table 1).

      position1a2b3a4a
      δH (mult., J in Hz)δCδH (mult., J in Hz)δCδH (mult., J in Hz)δCδH (mult., J in Hz)δC
      1 102.1 101.6 102.8 102.8
      2 163.5 162.6 163.1 163.1
      2-OH 11.19 (s) 10.74 (s) 11.15 (s) 11.11 (s)
      3 6.40 (d, 1.8) 111.5 6.52 (d, 1.8) 112.8 6.43 (d, 1.8) 111.7 6.42 (d, 1.8) 111.7
      4 146.9 147.1 146.5 146.6
      5 5.86 (d, 1.8) 106.2 6.03 (d, 1.8) 106.7 5.96 (d, 1.8) 106.7 5.96 (d, 1.8) 106.6
      6 160.2 158.2 160.0 160.0
      7 172.0 169.7 170.5 171.3
      8 2.12 (s) 22.0 2.18 (s) 22.2 2.16 (s) 21.9 2.16 (s) 21.9
      9 3.93 (s) 52.8 4.52 (q, 7.2) 62.5 1.37 (t, 7.2) 14.5 1.37 (t, 7.2) 14.5
      10 1.42 (t, 7.2) 14.3 4.42 (q, 7.2) 62.2 4.42 (q, 7.2) 62.2
      1′ 134.1 132.4 134.3 134.3
      2′ 137.8 128.5 131.8 131.8
      3′ 6.78 (d, 3.0) 104.3 140.9 6.57 (d, 3.0) 106.6 6.57 (d, 3.0) 106.3
      4′ 158.9 151.3 158.7 158.7
      5′ 6.61 (d, 3.0) 99.7 6.63 (s) 100.9 6.59 (d, 3.0) 103.4 6.59 (d, 3.0) 103.4
      6′ 153.6 145.3 151.5 151.5
      6′-OH 6.06 (s)
      7′ 4.53 (d, 5.4) 59.7 4.59 (s) 56.2 5.00 (s) 61.9 5.05 (s) 62.0
      7′-OH 4.14 (t, 5.4)
      8′ 3.84 (s) 55.9 3.89 (s) 61.9 171.3 172.3
      9′ 3.74 (s) 56.4 3.87 (s) 56.2 1.86 (s) 20.5 2.47 (m) 27.9
      10′ 3.80 (s) 55.8 2.47 (m) 27.9
      11′ 172.6
      12′ 4.06 (q, 7.2) 60.9
      13′ 1.18 (t, 7.2) 14.5
      14′ 3.80 56.0
      aMeasured in CD3OCD3. bMeasured in CDCl3.

      Table 1.  1H (400 MHz) and 13C NMR (100 MHz) data of compounds 1‒4

      Epicoccether L (2). Colorless oil; HRESIMS m/z 379.1390 [M + H] + (calcd for C19H23O8, 379.1393); IR (KBr) νmax 3420, 2934, 1657, 1621, 1489, 1453, 1310, 1252, 1205, 1078, 1003, 828 cm−1; UV (MeOH) λmax (log ε): 208 (4.55), 256 (3.41), 297 (2.33) nm; 1H and 13C NMR (Table 2).

      CompoundP. italicumF. graminearumE. coli O6E. coli O78S. aureus
      1 100 200 25 100 50
      2 50 50 50 200 50
      3 50 100 > 200 100 100
      4 25 50 200 25 100
      Triadimefon 50 150 NT NT NT
      Cefradine NT NT 3.125 12.5 1.0
      Positive control toward fungi. Bacterial positive control.

      Table 2.  Antifungal and antibacterial activities of compounds 1‒4.

      Epicoccether M (3). White solid; HRESIMS m/z 391.1391 [M + H] + (calcd for C20H23O8, 391.1393); IR (KBr) νmax 3430, 2927, 1730, 1655, 1621, 1452, 1311, 1256, 1207, 1155, 1064, 830 cm−1; UV (MeOH) λmax (log ε): 205 (4.65), 255 (3.37), 286 (2.01), 317 (1.97) nm; 1H and 13C NMR (Table 1).

      Epicoccether N (4). Orange oil; HRESIMS m/z 477.1758 [M + H] + (calcd for C24H29O10, 477.1761); IR (KBr) νmax 3430, 2912, 1735, 1658, 1587, 1451, 1217, 1083, 831 cm−1; UV (MeOH) λmax (log ε): 203 (4.51), 257 (3.35), 289 (2.13), 313 (2.03) nm; 1H and 13C NMR (Table 1).

    • Antimicrobial assay against two phytopathogenic fungi p. italicum, and F. graminearum, and three kind of pathogenic bacterial E. coli O6, E. coli O78 and S. aureus was made by the dilution method, in agreement with the previous report [6]. Triadimefon (for fungi) and cefradine (for bacteria) (Aladdin Bio-Chem Tech. Co. Shanghai, China) were the positive controls and PDB:5% DMSO/ H2O=50:50 (v:v) (the solvent) was the negative control.

    3.   Results and Discussion
    • Epicoccether K (1) possessed a molecular formula of C18H20O7 shown by HRESIMS at m/z 347.1130 ([M ‒ H], calcd. 347.1131). There are two groups of meta-positioned aromatic protons at δH 6.40 (1H, d, 1.8 Hz, H-3), 5.86 (1H, 1.8 Hz, H-5), and at δH 6.61 (1H, d, 3.0 Hz, H-3′), 6.78 (1H, d, 3.0 Hz, H-5′) in the 1H-NMR spectrum of 1 (Table 1), revealing two 1, 2, 4, 6-tetrasubstituted benzenes in 1. The 1H-NMR data also contained three methoxys at δH 3.83 (H-8′), 3.74 (H-9′) and 3.93 (H-9), a chelated phenolic hydroxy at δH 11.19 (2-OH), an aromatic methyl at δH 2.12 (H-8), a hydroxymethyl at δH 4.53 (H-7′), and a hydroxy at δH 4.14 (7′-OH). The 13 C-NMR (Table 1) and HSQC spectra displayed signals for twelve aromatic carbons, of which four were methines (δc 111.5, C-3; δc 106.2, C-5; δc 104.3, C-3′; δc 99.7, C-5′) and the others (δc 102.1, C-1; δc 163.5, C-2; δc 146.9, C-4; δc 160.2, C-6; δc 134.1, C-1′; δc 137.8, C-2′; δc 158.9, C-4′; δc 153.6, C-6′; ) were quaternary carbons. Moreover, an ester carbonyl (δc 172.0, C-7), a hydroxymethyl (δc 59.7, C-7), an aromatic methyl (δc 22.0, C-8) and three methoxy (δc 52.8, C-9; δc 55.9, C-8′; δc 56.4, C-9′) carbons were observed. These data was much similar to methyl barceloneate acquired from Penicillium albocoremium [11], except for one more methoxy (C-9′) and one less hydroxyl in 1. HMBC correlation from H-9′ to C-6′ indicated that the methoxy, rather than the hydroxyl, was located at C-6′ in 1, which was different from methyl barceloneate. Thus, the structure of 1 was established and then confirmed by comprehensive analysis of the HMBC correlations (Fig. 2).

      Figure 2.  Key HMBC of compounds 1‒4.

      Epicoccether L (2) possessed a molecular formula of C19H22O8 (nine degrees of unsaturation) shown by HRESIMS at m/z 379.1390 ([M + H] + , calcd. 379.1393). There are two meta-positioned aromatic protons at δH 6.52 (1H, d, 1.8 Hz, H-3), 6.03 (1H, d, 1.8 Hz, H-5), and another aromatic proton at δH 6.63 (1H, s, H-5′) in the 1H-NMR spectrum of 1 (Table 1). Moreover, the 13C-NMR spectrum showed twelve olefinic and one ester carbonyl carbon signals. These suggested that 2 contained two benzenes, one was 1, 2, 4, 6-tetrasubstituted, and the other was pentasubstituted. A contrastive analysis of the 13C NMR data for 2 and 1 (Table 1) showed that the structural unit of benzene ring A in 2 was almost consistent with that of 1. However, the –COOCH3 moiety at C-1 in 1 was replaced by –COOCH2CH3 in 2, which was revealed by 1H-1H COSY correlation between H-9 and H-10 and HMBC correlation from H-9 to C-7. For the benzene ring B in 2, two methoxys (δH 3.87, H-9′ and δH 3.89, H-8′), an aromatic hydroxymethyl (δH 4.59, H-7′), and a hydroxy (δH 6.06, 6′-OH) were visible in the 1H-NMR spectrum (Table 1). HMBC correlations from H-7′ to C-1′, C-2′ and C-3′, from H-8′ to C-3′, from 6′-OH to C-1′, C-5′ and C-6′, from H-5′ to C-3′ and C-4′, and from H-9′ to C-4′, placed them at their own positions shown in Fig. 2 and also implied the connectivity of C-1′ with the oxygen atom at C-6.

      Epicoccether M (3) possessed a molecular formula of C20H22O8 shown by HRESIMS at m/z 391.1391 ([M + H] + , calcd. 391.1393). A contrastive analysis of the NMR data for 3 and 2 (Table 1) showed that the A ring in 2 was completely retained in 3. Comparison of the remaining data of 3 with those of barceloneic acid A produced by a fungus of Phoma sp. [12], revealed that the B ring of 3 had one more acetyl group (δH 1.86, H-9′; δc 171.3, C-8′, 20.5, C-9′) than that of barceloneic acid A. HMBC correlations from H-7′ (δH 5.0) to C-8′, along with the chemical shift of C-8′, suggested that this acetyl group was connected to the oxygen atom attached on C-7′ to form an acetoxy group. Accordingly, the structure was determined, and then its NMR data was completely assigned (Table 1) by analysis of the HMBC correlations (Fig. 2).

      Epicoccether N (4) possessed a molecular formula of C24H28O10 shown by HRESIMS at m/z 477.1758 ([M + H] + , calcd. 477.1761). A contrastive analysis of the NMR data for 4 and 3 (Table 1) showed that the A ring in 4 was identical to that in 3. Comparing the remaining NMR data of 4 with those of barceloneic acid A [12], revealed that the B rings of theirs were quite similar. However, the former had one more ethoxy group (δH 1.18, H-13′, δc 14.5, C-13′; δH 4.06, H-12′, δc 60.9, C-12′), two more carbonyl carbons (δc 172.3, C-8′; δc 172.6, C-11′) and two more methenes (δH 2.47, H-9′ and H-10′; δc 27.9, C-9′ and C-10′), which formed a substitute ‒COCH2CH2COOCH2CH3 revealed by HMBC correlations from H-12′ to C-11′, and from H-9′ and H-10′ to C-8′ and C-11′. HMBC correlations from H-7′ to C-8′ indicated that this substituent was located at 7′-O atom (Fig. 2).

      Except that 1 showed moderate antifungal activity against Penicillium italicum and Fusarium graminearum, the other three compounds all showed stronger activity against them than the positive control triadimefon. Moreover, the activity of 2 and 4 against F. graminearum was three times that of triadimefon, and that of 4 against P. italicum was two times that of triadimefon. For antibacterial assay, all compounds showed moderated or weak activities (MICs 25‒200 μg/mL) towards S. aureus, E. coli (O6 serotype), and E. coli (O78 serotype) except that 3 was inactive to E. coli (O6 serotype) (MIC>200 μg/mL). The results provided new candidates of antimicrobial leads, especially antifungal ones against the pathogens listed above.

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