Polyketides from the Deep-Sea-Derived Fungus Graphostroma sp

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Cite This: J. Agric. Food Chem. 2018, 66, 1369−1376

Polyketides from the Deep-Sea-Derived Fungus Graphostroma sp. MCCC 3A00421 Showed Potent Antifood Allergic Activities Siwen Niu,† Qingmei Liu,‡ Jin-Mei Xia,† Chun-Lan Xie,† Zhu-Hua Luo,† Zongze Shao,† Guangming Liu,‡ and Xian-Wen Yang*,† †

State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources, Fujian Key Laboratory of Marine Genetic Resources, and South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Third Institute of Oceanography, State Oceanic Administration, 184 Daxue Road, Xiamen 361005, China ‡ College of Food and Biological Engineering, Jimei University, 43 Yindou Road, Xiamen 361021, China S Supporting Information *

ABSTRACT: To discover antifood allergic components from deep-sea-derived microorganisms, we performed a systematic chemical investigation of the Atlantic hydrothermal fungus Graphostroma sp. MCCC 3A00421. Consequently, nine new (1−9) and 19 known (10−28) polyketides were isolated. The planar structures of the new compounds were elucidated mainly by detailed analysis of their nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data, while the absolute configurations were established using the modified Mosher’s method in association with electronic circular dichroism spectra. Graphostrin A (1) is a novel chlorinated polyketide derivate bearing an oxazole moiety. All isolates were tested for antifood allergic bioactivities in immunoglobulin E-mediated rat basophilic leukemia-2H3 cells. Reticulol (10) significantly decreased the rates of degranulation and histamine release with IC50 values of 13.5 and 13.7 μM, respectively, suggesting reticulol could be a potential antifood allergic medicine. KEYWORDS: hydrothermal vents, deep-sea, marine microorganism, natural products, food allergy

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chemical shifts are expressed as δ in parts per million with solvent peaks at δH 2.50 and δC 39.5 for dimethyl sulfoxide-d6 (DMSO-d6), δH 3.31 and δC 49.0 for CD3OD, or δH 7.26 and δC 77.2 for CDCl3. Highresolution electrospray ionization mass spectrometry (HRESIMS) data were obtained from a Xevo G2 Q-TOF mass spectrometer. Materials for column chromatography (CC) included silica gel, octadecylsilane (ODS), and Sephadex LH-20. Precoated silica gel plates were used for thin-layer chromatography (TLC) analysis. Fungal Strain. The fungus Graphostroma sp. MCCC 3A00421 was isolated from the deep-sea hydrothermal sulfide deposits of the Atlantic (GPS 13.36 W, 15.17 S) in August 2012 at a depth of 2721 m. ITS sequence (KM190888) analysis indicated 87% sequence similarity to Graphostroma sp. SGLMf27 (GenBank accession number EU715682). Therefore, it was designed as Graphostroma sp. MCCC 3A00421. The strain was deposited in the Marine Culture Collection of China (MCCC) with accession number 3A00421. Fermentation and Extraction. The fungus was cultured on a potato dextrose agar (PDA) medium at 25 °C for 3 days, and the fresh mycelia were cut and inoculated into 30 × 1 L Erlenmeyer flasks with each containing 80 g of rice and 120 mL of distilled water after autoclaving at 15 psi for 25 min. These flasks were incubated under static conditions at 25 °C for 28 days. Then the fermented solid mash was extracted with EtOAc three times to obtain the extract. Isolation and Purification. The extract was redissolved with MeOH and extracted with petroleum ether (PE) three times to remove lipids. The MeOH layer was evaporated to dryness under reduced pressure to yield a defatted extract (7 g). Then it was subjected to CC over ODS with a MeOH/H2O gradient (5 to 100%)

INTRODUCTION The incidence of food allergic diseases might be the result of an inappropriate immune response to irritating or adverse stimuli from a wide range of food allergens, such as milk, eggs, fish, peanuts, and cereal sources, that are ordinarily harmless.1 The immediate hypersensitivity response, the basis of acute allergic reactions, is caused by molecules released by mast cells when an allergen interacts with membrane-bound immunoglobulin E (IgE).2 Over the past several decades, the worldwide increasing incidence of food allergies has become a potentially lifethreatening condition, especially for children.3 Unfortunately, currently there are no approved treatments other than avoidance.4,5 Therefore, it is urgent to search for antifood allergic drugs from nature. In our ongoing research to discover structurally novel compounds from deep-sea-derived microorganisms with potent biological activities,6,7 the fermentation extract of Graphostroma sp. MCCC 3A00421, a deep-seaderived fungus isolated from the Atlantic hydrothermal sulfide deposit, showed a potent anti-inflammatory and antifood allergic effect.8,9 Further investigation of this strain resulted in the isolation of nine new (1−9) and 19 known (10−28) secondary metabolites (Figure 1). Herein, we report the isolation, structural elucidation, and antifood allergic activities of these compounds.

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MATERIALS AND METHODS

Instrumentation. Optical rotations were obtained from a Rudolph IV Autopol automatic polarimeter at 25 °C. Electronic circular dichroism (ECD) spectra were measured on a Jasco J-810 spectrometer. Nuclear magnetic resonance (NMR) experiments were conducted on a Bruker Avance II spectrometer (400 MHz), while © 2018 American Chemical Society

Received: Revised: Accepted: Published: 1369

September 21, 2017 January 11, 2018 January 22, 2018 January 22, 2018 DOI: 10.1021/acs.jafc.7b04383 J. Agric. Food Chem. 2018, 66, 1369−1376

Article

Journal of Agricultural and Food Chemistry

(10:1) and PE and acetone (5:1) to yield 10 (11.6 mg), 16 (18.9 mg), 17 (26.2 mg), and 22 (25.4 mg). 4 (7.8 mg) was obtained by recrystallization from Fr.9-3-4 in MeOH. Fr.10 (603 mg) was fractionated by CC on silica gel using a CHCl3/ MeOH gradient to give five subfractions (Fr.10-1−Fr.10-5). Fr.10-1 (217 mg) was recrystallized in MeOH and H2O (200:1) to give 18 (68.2 mg). Fr.10-2 (72.2 mg) was subjected to CC on Sephadex LH20 (MeOH) to give 20 (3.5 mg) and 26 (38.6 mg). Fr.10-3 (96.0 mg) was purified by CC over silica gel [PE and acetone (5:1)], followed by PTLC [EtOAc and acetone (30:1)] to provide 23 (3.6 mg). Compounds 3 (4.0 mg) and 12 (24.5 mg) were obtained from Fr.10-4 (62.2 mg) using repeated CC on silica gel [PE and acetone (20:1) or CHCl3 and MeOH (50:1)]. Fr.10-5 (25.6 mg) was subjected to CC over Sephadex LH-20 (MeOH) and silica gel [CHCl3 and MeOH (30:1)] to yield 9 (8.2 mg). Graphostrin A (1). White powder; [α]25D + 2.4 (c 0.45, MeOH); 1 H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 270.0535 [M + H]+ (calcd for C12H13ClNO4, 270.0533), m/z 292.0355 [M + Na]+ (calcd for C12H12ClNO4Na, 292.0353). Graphostrin B (2). White powder; [α]25D + 18.9 (c 0.58, MeOH); 1 H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 239.0909 [M − H]− (calcd for C12H15O5, 239.0919). Graphostrin C (3). White powder; [α]25D − 31.3 (c 0.13, MeOH); ECD (MeOH) λmax (Δε) 204 (9.1), 255 (−4.7) nm; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 219.0654 [M − H]− (calcd for C12H11O4, 219.0657). Graphostrin D (4). White powder; [α]25D + 78.9 (c 0.26, MeOH); ECD (MeOH) λmax (Δε) 217 (−1.5), 261 (4.3) nm; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 237.0763 [M − H]− (calcd for C12H13O5, 237.0763). Graphostrin E (5). White powder; [α]25D + 51.8 (c 0.87, MeOH); ECD (MeOH) λmax (Δε) 220 (−2.0), 260 (3.8) nm; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 279.0872 [M − H]− (calcd for C14H15O6, 279.0869). Graphostrin F (6). White powder; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 221.0808 [M − H]− (calcd for C12H13O4, 221.0814). Graphostrin G (7). White powder; [α]25D − 32.2 (c 1.62, MeOH); 1 H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 221.0811 [M − H]− (calcd for C12H13O4, 221.0814). Graphostrin H (8). White powder; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 197.0808 [M + H]+ (calcd for C10H13O4, 197.0814), m/z 219.0631 [M + Na]+ (calcd for C10H12O4Na, 219.0633). Graphostrin I (9). Yellow oil; 1H and 13C NMR data in Tables 1 and 2; HRESIMS m/z 291.1608 [M − H]− (calcd for C17H23O4, 291.1596). Preparation of MPA Esters for Compounds 1−3. Compound 1 (2.0 mg) was dissolved in 600 μL of CHCl3, and then (R)-(−)-αmethoxy-α-phenylacetic acid (R-MPA) (2.5 mg), 4-dimethylaminopyridine (DMAP) (2.0 mg), and N,N′-dicyclohexylcarbodiimide (DCC) (2.5 mg) were added. After 12 h, the reaction products were purified by CC over silica gel eluting with CHCl3 and MeOH (30:1) to yield bis-R-MPA ester 1a (1.8 mg). By the same procedure, bis-S-MPA ester 1b (2.1 mg) was prepared from S-MPA, and R- and SMPA esters 2a and 2b and 3a and 3b were obtained from 2 and 3, respectively. (R)-MPA Ester of 1 (1a). 1H NMR (CDCl3, 400 MHz) δH 7.22− 7.37 (10H, m, phenyl protons), 4.72 (1H, s, CH of MPA), 4.68 (1H, s, CH of MPA), 3.41 (3H, s, OMe of MPA), 3.35 (3H, s, OMe of MPA), 6.98 (1H, s, H-8), 7.35 (1H, d, J = 2.1 Hz, H-2), 7.03 (1H, d, J = 8.6 Hz, H-5), 7.16 (1H, dd, J = 8.6, 2.1 Hz, H-6), 5.93 (1H, d, J = 5.1 Hz, H-11), 5.55 (1H, m, H-12), 1.39 (3H, d, J = 6.4 Hz, Me-13). (S)-MPA Ester of 1 (1b). 1H NMR (CDCl3, 400 MHz) δH 7.22− 7.50 (10H, m, phenyl protons), 4.90 (1H, s, CH of MPA), 4.52 (1H, s, CH of MPA), 3.43 (3H, s, OMe of MPA), 3.35 (3H, s, OMe of MPA), 7.16 (1H, s, H-8), 7.55 (1H, d, J = 2.0 Hz, H-2), 7.07 (1H, d, J = 8.6 Hz, H-5), 7.39 (1H, dd, J = 8.6, 2.0 Hz, H-6), 6.14 (1H, d, J = 5.1 Hz, H-11), 5.41 (1H, m, H-12), 0.97 (3H, d, J = 6.5 Hz, Me-13).

Figure 1. Chemical structures of compounds 1−28. to yield 24 fractions (Fr.1−Fr.24). Fr.7 (624 mg) was separated by Sephadex LH-20 eluting with MeOH to yield four subfractions (Fr.71−Fr.7-4). Fr.7-1 (68.2 mg) was purified by CC over silica gel with CHCl3 and CH3OH (15:1) to yield Fr.7-1-1 and Fr.7-1-2. Fr.7-1-1 (38.2 mg) was further purified by silica gel CC eluting with PE and acetone (3:1) to yield 28 (26.7 mg), while Fr.7-1-2 (12.8 mg) was purified by preparative TLC (PTLC) on a silica gel plate (20 cm × 20 cm) with a mobile phase of EtOAc and MeOH (300:1) to yield 8 (9.6 mg). Fr.7-2 (48.6 mg) was first subjected to silica gel CC elution with CHCl3 and MeOH (15:1) and then semipreparative reversed-phase high-performance liquid chromatography (HPLC) with a mobile phase of MeOH and H2O (32:68) to yield 1 (13.2 mg) and 2 (17.5 mg). Fr.7-3 (86.2 mg) was subjected to the repeated CC over silica gel with PE and acetone (5:1), followed by CHCl3 and MeOH (20:1) to yield 13 (23.2 mg), 15 (18.6 mg), and 21 (4.5 mg). Compound 19 (18.2 mg) was separated from Fr.7-4 (32.5 mg) by CC on silica gel with PE and acetone (1:1). Fr.8 (312 mg) was separated by CC over Sephadex LH-20 (MeOH) to provide three fractions (Fr.8-1−Fr.8-3). Fr.8-1 (26.8 mg) was purified by CC on silica gel eluting with CHCl3 and MeOH (100:1), followed by PTLC with EtOAc and MeOH (200:1) to yield 24 (13.2 mg). Fr.8-2 (52.4 mg) was subjected to CC over silica gel eluting with CHCl3 and MeOH (20:1) to give 6 (32.6 mg). Compounds 11 (6.1 mg) and 14 (15.9 mg) were isolated from Fr.8-3 (64.6 mg) by HPLC eluting with MeOH and H2O (35:65). Fr.9 (420 mg) was subject to CC over Sephadex LH-20 (MeOH) to yield three fractions (Fr.9-1− Fr.9-3). Fr.9-1 (78.0 mg) was purified by repeated CC over silica gel with PE and acetone (3:1) and PE and EtOAc (2:1) to provide 5 (44.8 mg) and 25 (2.8 mg). Fr.9-2 (163.0 mg) was subjected to CC over silica gel eluting with CHCl3 and MeOH (100:1) and CHCl3 and MeOH (150:1) to yield 7 (35.8 mg) and 27 (78.5 mg). Fr.9-3 (116.5 mg) was isolated by CC over silica gel eluting with CHCl3 and MeOH 1370

DOI: 10.1021/acs.jafc.7b04383 J. Agric. Food Chem. 2018, 66, 1369−1376

Article

Journal of Agricultural and Food Chemistry Table 1. 1H NMR (400 MHz) Spectroscopic Data of Compounds 1−9 (δH in parts per million, J in hertz) position

1a

2 3 4

7.67, d (2.1)

5

7.04, d (8.5)

6

7.47, dd (8.5, 2.1)

2a

3b

6.23, d (2.4)

6.90, d (8.4) 7.99, dd (8.4, 1.5)

7.44, s

6.37, dd (8.9, 2.4) 7.77, d (8.9)

3.03, m; 2.94, m 1.90, m; 1.53, m 3.19, m

9 10 11 12 13 14 15 16 OMe-3 OAc-10 OH-2 OH-4 OH-11 OH-12 a

4.29, d (7.4) 3.93, m 1.19, d (6.3)

5a

6b

7a

8a

9b 5.57, d (2.2)

7

8

4b

3.39, m 1.05, d (6.3)

6.77, d (8.3) 7.83, dd (8.3, 1.3)

6.80, d (8.4) 7.72, dd (8.4, 1.4)

6.80, d (8.4) 7.72, dd (8.4, 2.2)

6.17, s

6.09, br s

6.94, s 8.06, br s

7.85, br s

7.77, br s

7.77, d (2.2)

5.11, d (3.8)

3.34, dd (16.3, 7.2) 3.21, dd (16.3, 9.8) 4.91, overlap

3.26, dd (16.4, 7.5) 3.17, dd (16.4, 9.4) 4.81, dd (9.7, 7.8)

3.38, d (7.5)

4.91, overlap

5.62, tq (7.5, 1.3)

6.14, d (15.3) 2.82, dd (16.5, 2.9) 2.50, dd (16.5, 11.8) 4.43, m 1.35, d (6.3)

5.07, br s 4.93, overlap 1.75, s

3.57, d (11.2) 3.51, d (11.2) 1.19, s

4.03, d (11.1) 3.91, d (11.1) 1.09, s

3.98, s 1.77, s

6.37, t (5.8)

7.06, dd (15.3, 10.6)

4.17, d (6.1) 1.77, s

6.25, dd (15.3, 10.6) 6.11, m

1.77, s

2.21, q (7.2)

2.12, s

1.47, 1.36, 1.39, 1.42, 3.71, 1.15, 3.87,

3.71, s

m m m m m d (6.2) s

2.04, s 10.57, br s 5.80, br s 4.76, br s

12.73, br s 10.6, br s 4.47, br s

9.32, s

Recorded in DMSO-d6. bRecorded in CD3OD.

Table 2. 13C NMR (100 MHz) Spectroscopic Data of Compounds 1−9 position 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ac

1a 120.8, 125.9, 120.6, 153.6, 117.6, 124.4, 149.7, 121.4,

C CH C C CH CH C CH

164.3, C 72.1, CH 68.7, CH 20.4, CH3

2a

3b

4b

5a

6b

7a

8a

9b

112.8, C 164.8, C 102.9, CH 165.2, C 108.6, CH 133.4, CH 205.9, C 34.6, CH2 28.6, CH2 74.5, CH 70.1, CH 20.0, CH3

130.3, C 165.3, C 110.6, CH 134.1, CH 125.5, C 129.1, CH 76.7, CH 95.9, CH 143.4, C 112.6, CH2 17.5, CH3 170.1, C

129.3, C 165.4, C 109.6, CH 132.1, CH 124.0, C 127.8, CH 30.2, CH2 87.5, CH 74.5, C 68.1, CH2 19.4, CH3 170.0, C



129.9, C 119.0, C 147.2, C 149.6, C 123.4, CH 130.6, C 32.1, CH2 74.2, CH 20.8, CH3 162.6, C 18.7, CH3

164.6, C 98.6, C 165.3, C 98.4, CH 157.7, C 125.9, C 134.0, CH 58.4, CH2 9.0, CH3 12.6, CH3

166.8, C 88.9, CH 173.8, C 101.8, CH 160.7, C 121.3, CH 137.7, CH 130.6, CH 143.3, CH 34.0, CH2 30.1, CH2 30.4, CH2 26.7, CH2 40.1, CH2 68.5, CH 23.5, CH3

21.1, CH3 170.7, C

OMe-3 a

60.9, CH3

56.9, CH3

Recorded in DMSO-d6. bRecorded in CD3OD.

(R)-MPA Ester of 2 (2a). 1H NMR (CDCl3, 400 MHz) δH 7.31− 7.45 (10H, m, phenyl protons), 4.73 (1H, s, CH of MPA), 4.52 (1H, s, CH of MPA), 3.40 (3H, s, OMe of MPA), 3.36 (3H, s, OMe of MPA), 12.61 (1H, s, OH-2), 6.39 (1H, d, J = 2.4 Hz, H-3), 6.36 (1H, dd, J = 8.7, 2.4 Hz, H-5), 7.41 (1H, d, J = 8.7 Hz, H-6), 2.82 (2H, t, J = 7.5 Hz, H2-8), 1.97 (2H, m, H2-9), 5.19 (1H, dt, J = 9.4, 3.7 Hz, H-10), 4.93 (1H, m, H-11), 0.87 (3H, d, J = 6.5 Hz, Me-12).

(S)-MPA Ester of 2 (2b). 1H NMR (CDCl3, 400 MHz) δH 7.26− 7.48 (10H, m, phenyl protons), 4.77 (1H, s, CH of MPA), 4.48 (1H, s, CH of MPA), 3.42 (3H, s, OMe of MPA), 3.40 (3H, s, OMe of MPA), 12.48 (1H, s, OH-2), 6.34 (1H, d, J = 2.5 Hz, H-3), 6.26 (1H, dd, J = 8.8, 2.5 Hz, H-5), 6.84 (1H, d, J = 8.8 Hz, H-6), 2.14 (2H, m, H2-8), 1.79 (1H, m, H-9a), 1.43 (1H, m, H-9b), 4.84 (1H, dt, J = 10.8, 3.4 Hz, H-10), 5.24 (1H, m, H-11), 1.28 (3H, d, J = 6.5 Hz, Me-12). 1371



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(R)-MPA Ester of 3 (3a). 1H NMR (CDCl3, 400 MHz) δH 7.31− 7.45 (5H, m, phenyl protons), 4.80 (1H, s, CH of MPA), 3.44 (3H, s, OMe of MPA), 4.80 (1H, overlap, H-8), 6.21 (1H, d, J = 3.0 Hz, H-7), 8.15 (1H, d, J = 1.9 Hz, H-6), 8.13 (1H, dd, J = 8.5, 1.9 Hz, H-4), 6.97 (1H, d, J = 8.5 Hz, H-3), 4.89 (1H, br s, H-10a), 4.92 (1H, br s, H10b), 1.62 (3H, s, Me-11). (S)-MPA Ester of 3 (3b). 1H NMR (CDCl3, 400 MHz) δH 7.34− 7.42 (5H, m, phenyl protons), 4.82 (1H, s, CH of MPA), 3.42 (3H, s, OMe of MPA), 5.10 (1H, d, J = 2.7 Hz, H-8), 6.17 (1H, d, J = 2.7 Hz, H-7), 7.90 (1H, d, J = 1.9 Hz, H-6), 8.09 (1H, dd, J = 8.5, 1.9 Hz, H4), 6.95 (1H, d, J = 8.5 Hz, H-3), 4.96 (1H, br s, H-10a), 5.06 (1H, br s, H-10b), 1.74 (3H, s, Me-11). ECD Measurement of the Mo2(OAc)4 Metal Complex of 4. Compound 4 (0.5 mg) and Mo2(OAc)4 (1.1 mg) were dissolved in anhydrous DMSO (1 mL). The first ECD spectrum was measured immediately after dissolution under 250−500 nm. After 20 min, the stationary ICD spectrum was reached, which was used to subtract the first ECD spectrum. The sign of the Cotton effect at ∼310 nm in the ICD spectrum was correlated to the absolute configuration of the 1,2diol moiety. Theoretically Calculated ECD Spectra of 8S,9R-4 and 8R,9R4. Because the absolute configuration of C-9 of 4 was determined as R on the basis of Snatzke’s method, there are two possible configurations of 4 (8S,9R-4 and 8R,9R-4). The calculated method was performed with Gaussian 09.10 In brief, conformational analyses were performed with Sybyl-X 2.0 using the MMFF94S force field.11 The conformers were reoptimized by the density functional theory (DFT) method at the B3LYP/6-31+G(d) level in the gas phase and then calculated by the time-dependent density functional theory (TD-DFT) method at the B3LYP/6-311++G(d,p) level in MeOH. ECD spectra were simulated by the program SpecDis12 with a Gaussian band shape of 0.3 eV, and finally calculated ECD spectra were obtained by averaging each conformer using the Boltzmann distribution theory and their relative Gibbs free energy (ΔG). Degranulation Assay. As previously reported,13 the antifood allergic bioactivity was measured by the inhibition rate of the RBL2H3 cell (CRL-2256, ATCC, Manassas, VA) degranulation using an IgE-mediated mast cell allergic reaction, and berberine and loratadine (Sigma, St. Louis, MO) were used as two positive controls. In brief, RBL-2H3 cells were seeded into a 96-well plate at a density of 1.0 × 105 cells/well and incubated at 37 °C for 16 h with anti-DNP-IgE (0.1 μg/mL). Then, the IgE-sensitized RBL-2H3 cells were washed twice with prewarmed (37 °C) Tyrode’s buffer and pretreated with the tested compounds at different concentrations for 1 h. Subsequently, the cross-linking antigen DNP-BSA (0.5 μg/mL) as a stimulator was added in Tyrode’s buffer at 37 °C for 1 h. Degranulation was terminated by placing the 96-well plate on ice for 20 min. The βhexosaminidase activity was measured with 4-methylumbelliferyl-Nacetyl-β-D-glucosaminide (β-hexosaminidase substrate). The activity results are presented as the percentage of β-hexosaminidase activity in supernatants compared to the total level in corresponding cell lysates. To measure the total activity, the cells were lysed with 0.1% Triton X100 prior to removal of the supernatant. The supernatants (25 μL) and the cell-lysed liquid (25 μL) were separately placed in a 96-well plate and mixed with 4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (100 μL) reacting at 37 °C for 30 min. The β-hexosaminidase activity was quantified by detecting the fluorescence intensity using a spectrofluorometer (Infinite M200PRO, Tecan, Männedorf, Switzerland) with 360 nm excitation and 450 nm emission. Histamine Assay. RBL-2H3 cells were seeded at a density of 2 × 105 cells/well in 48-well plates and incubated overnight with 200 ng/ mL anti-DNP-IgE. The IgE-sensitized RBL-2H3 cells were preincubated with tested compounds for 1 h and then stimulated with 500 ng/ mL DNP-BSA for 15 min. The concentrations of histamine in the cell culture supernatant were determined by enzyme-linked immunosorbent assay kits according to the manufacturer’s instructions.

Article

RESULTS AND DISCUSSION

The EtOAc extract of the fermented solid mash of Graphostroma sp. MCCC 3A00421 was separated by repeated column chromatography (CC) over silica gel, ODS, and Sephadex LH20, followed by preparative TLC (PTLC) and semipreparative HPLC to give 28 compounds (Figure 1). By comparison of the NMR and MS data with those reported in the literature, 19 known compounds were identified as reticulol (10),14 6,7,8trihydroxy-3-methylisocoumarin (11),15 8-hydroxy-6,7-dimethoxy-3-methylisocoumarin (12),15 6,8-dihydroxy-7-methoxy3-hydroxymethylisocoumarin (13),16 8-hydroxy-6,7-dimethoxy3-hydroxymethylisocoumarin (14),16 6,8-dihydroxy-3-hydroxymethyl-1H-2-benzopyran-1-one (15),17 orthosporin (16),18 7,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin (17),19,20 5methylmellein (18),21 scytalone (19),22,23 RF-3192C (20),24 hydroxysulochrin (21),25 sulochrin (22),26 hydroxyemodin (23),27 phomopyrone A (24),28 3-methyl-4-hydroxy-6-(1methyl-trans-1-propenyl)-2-pyrone (25),29,30 nectriapyrone (26),31 acropyrone (27),32 and phomopyronol (28).33 Compound 1 was isolated as a white powder. The HRESIMS spectrum showed a sodium adduct molecule peak at m/z 292.0365 [M + Na]+, which was ∼3 times higher than that of its isotope molecule peak at m/z 294.0328 [M + 2 + Na]+, indicating the presence of a chlorine atom. This was coincident with the molecular formula C12H12NO4Cl of 1, requiring seven double-bond equivalents. The 1H NMR spectrum exhibited the presence of a typical ABX benzene moiety [δH 7.04 (1H, d, J = 8.5 Hz, H-5), 7.47 (1H, dd, J = 2.1, 8.5 Hz, H-6), 7.67 (1H, d, J = 2.1 Hz, H-2)], in addition to one sp2 (δH 7.44, s, H-8) and two oxygenated sp3 methines [δH 4.29 (d, J = 7.4 Hz, H-11), 3.93 (m, H-12)], one methyl doublet (δH 1.19, d, J = 6.3 Hz, Me-13), and three exchangeable protons (δH 4.76, 5.80, and 10.57). The 13C NMR spectrum combined with the HSQC spectrum showed 12 carbons, with six corresponding to the ABX phenyl group (δC 153.6 s, 125.9 d, 124.4 d, 120.8 s, 120.6 s, and 117.6 d), three to sp3 carbons (δC 72.1 d, 68.7 d, and 20.4 q), and the remaining three to sp2 carbons (δC 164.3 s, 149.7 s, and 121.4 d). In the COSY spectrum, correlations of OH-11 via H-11 to H-12 and H-12 to OH-12/Me-13 established a 1,2-propanediol fragment. Because an aromatic unit and three sp2 carbons accounted for six double-bond equivalents, 1 was deduced to bear one more ring system. In the HMBC spectrum, correlations from H-8 to C-7 and C-10 in association with the molecular formula established the ring as an oxazole moiety (Figure 2). Altogether, three fragments were deduced for 1, including one 1,2,4-trisubstituted benzene, one 1,2-propanediol, and one oxazole group. They could be connected to construct the planar structure of 1 as a novel chlorinated oxazole derivative based on the HMBC correlations from H-11/H-12 to C-10 and from H-2/H-6 to C-7 (Figure 2).

Figure 2. Key COSY (bold) and HMBC (arrow) correlations of 1, 3, 7, and 8. 1372


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(prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-carboxylic acid and named graphostrin C. Compound 4 gave a molecular formula of C12H14O5 as indicated by HRESIMS (m/z 237.0763 [M − H]−). The 1H and 13C NMR spectroscopic data were quite similar to those of (+)-5-formyl-2-(1′,2′-dihydroxypropyl)-2,3-dihydrobenzofuran.41 The only difference was that a carboxyl group instead of an aldehyde moiety was located at C-5, which was validated by the shielded chemical shift of C-12 (δC 170.0 s) and the absence of the aldehyde proton (δH 9.88, s) in 4. To establish the absolute configuration of C-9 at the soft chain, the Mo2(OAc)4 complex of 4, a metal complex as an auxiliary chromophore, was obtained in DMSO. The induced positive Cotton effect at 324 nm reflecting the O−C−C−O torsion angle was consistent with positive helicity, which revealed an R configuration of C-9 (Figure 4).42,43 The 8S configuration was

To determine the absolute configuration, the modified Mosher’s method was adopted.34 Compound 1 was separately esterified with R- and S-MPA to provide the bis-R-MPA (1a) and bis-S-MPA (1b) derivatives, respectively. The ΔδH values [ΔδH = δR − δS (Figure 3)] of H-11 (−0.21), H-12 (0.14), and

Figure 3. ΔδH (δR − δS) values of the MPA esters of 1−3 in CDCl3.

Me-13 (0.42) revealed the 11S and 12R configurations according to the acyclic 1,2-diol rules.34 Therefore, 1 was established as (1S,2R)-1-[5-(3-chloro-4-hydroxyphenyl)oxazol2-yl]propane-1,2-diol and named graphostrin A. The commercially available product 2-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]ethan-1-ol is structurally similar to 1 except for the absence of a phenolic hydroxy group and the different alkyl side chain. Biogenetically, 1 could be constructed by condensation of styrylamine and 2,3-dihydroxybutyramide, followed by hydroxylation at C-7, chlorination at C-3, and cyclization between C-7 and C-10 to form the oxazole ring.35,36 Compound 2 exhibited a [M − H]− molecule peak at m/z 239.0909 in the negative HRESIMS spectrum, establishing the molecular formula C12H16O5. The 1H NMR spectrum showed three sp2 methines characteristic of an ABX aromatic moiety [δH 6.23 (1H, d, J = 2.4 Hz, H-3), 6.37 (1H, dd, J = 8.9, 2.4 Hz, H-5), 7.77 (1H, d, J = 8.9 Hz, H-6)], besides two oxygenated sp3 methines [δH 3.19 (1H, m, H-10), 3.39 (1H, m, H-11)]. The 13C NMR spectrum showed 12 carbon signals, including four nonprotonated carbons, five methines, two methylenes, and one methyl. These data were very similar to those of caproylresorcinol,37 except that two methylenes were displaced by two oxygenated methines (δC 70.1, 74.5), suggesting the presence of two additional hydroxy groups in 2. According to the COSY correlations from H2-8 through H2-9 to H-10/H-11/ H3-12 and HMBC correlations from Me-12 to C-10/C-11, the two hydorxy groups were assigned the attachment to C-10 and C-11 positions. The absolute configurations were determined to be 10R and 11S by the modified Mosher’s method (Figure 3). Consequently, 2 was assigned as (10R,11S)-10,11dihydroxycaproylresorcinol and named graphostrin B. Compound 3 had a molecular formula of C12H12O4 as evidenced by negative HRESIMS at m/z 219.0654 [M − H]−. The one-dimensional NMR spectroscopic data of 3 were nearly identical to those of 3-hydroxy-2-isopropenyl-dihydrobenzofuran-5-carboxylic acid methyl ester,38 except for the absence of a methoxyl group. By detailed analysis of its HSQC, COSY, and HMBC spectra (Figure 2), 3 was established as 3-hydroxy-2isopropenyl-dihydrobenzofuran-5-carboxylic acid. The relative configurations of C-7 and C-8 were established as a trans relationship based on the small coupling constant of H-7 and H-8 (J = 3.8 Hz),39 and the absolute configuration was further determined as 7R by the modified Mosher’s method (Figure 3).40 Accordingly, 3 was elucidated as (2S,3R)-3-hydroxy-2-

Figure 4. ICD spectrum of the Mo2(AcO)4 complex of 4 in DMSO.

determined by comparison of the experimental and theoretical calculation of the ECD spectra (Figure 5). On the basis of the evidence provided above, we then concluded 4 was (S)-2-[(R)1,2-dihydroxypropan-2-yl]-2,3-dihydrobenzofuran-5-carboxylic acid and named graphostrin D.

Figure 5. Experimental ECD spectra of 4 and 5 in MeOH and the theoretically calculated ECD spectra of 8S,9R-4 and 8R,9R-4.

The molecular formula of 5 was assigned as C14H16O6 from negative HRESIMS at m/z 279.0872 [M − H]−. The 1H and 13 C NMR spectra of 5 closely resembled those of 4, except for an additional acetyl group (δH 2.04; δC 21.1, 170.7). In the HMBC spectrum, correlations were found from H2-10 to the carbonyl unit of the acetyl group, which established the attachment of the acetyl unit to C-10 (δC 68.5 t). On the basis of the identical ECD spectra of 5 and 4 (Figure 5), 5 was 1373


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Journal of Agricultural and Food Chemistry established to be a 10-acetylated derivate of 4 and named graphostrin E. Compound 6 was assigned a molecular formula of C12H14O4 by negative HRESIMS (m/z 221.0808, [M − H]−). Inspection of the 1H and 13C NMR data of 6 indicated they were considerably similar to those of 4-hydroxy-3-prenylbenzoic acid,44 except for an additional hydroxyl moiety at C-10. This was confirmed by the HMBC correlations from Me-11 to C-8/ C-9/C-10. The double bond at C-8 was established as E geometry on the basis of the NOESY correlations from H2-7 (δH 3.38) to Me-11 (δH 1.77) and from H-8 (δH 5.62) to H2-10 (δH 3.98). Therefore, 6 was elucidated as (E)-4-hydroxy-3-(4hydroxy-3-methylbut-2-en-1-yl)benzoic acid and named graphostrin F. Compound 7 gave a molecular formula of C12H14O4, according to negative HRESIMS at m/z 221.0811 [M − H]−, requiring six double-bond equivalents. The 1H NMR spectrum showed the presence of one methoxyl, two methyls, one sp2 and one oxygenated sp3 methine, one methylene, and one exchangeable proton, while the 13C NMR spectrum exhibited 12 carbon signals, including six nonprotonated sp2 carbons, two methines, three methyls, and one methylene. These data were very similar to those of (3R)-7-hydroxy-5-methylmellein,45 except for a methoxyl (δH 3.71, s; δC 60.9 q, OMe-3) instead of a hydroxy group at C-3 in 7. The assumption was confirmed by the HMBC correlations from OH-4 (δH 9.32) to C-3/C-4/C-5 (Figure 2), and compound 7 was thereby established as (R)-7hydroxy-8-methoxy-3,5-dimethylisochroman-1-one and named graphostrin G. Compound 8 was isolated as a white powder. It showed a molecular formula of C10H12O4 as deduced by positive HRESIMS at m/z 219.0631 [M + Na]+. The 1H and 13C NMR data of 8 were very similar to those of gulypyrone B,46 except that a hydroxy group instead of a methoxyl was located at C-3. This assumption was supported by detailed analysis of the two-dimensional (2D) NMR spectra (Figure 2). Therefore, 8 was identified as 3-demethylgulypyrone B and named graphostrin H Compound 9 exhibited a [M − H]− molecule peak at m/z 291.1608 via negative HRESIMS, corresponding to a molecular formula of C17H24O4. The 1H NMR spectrum showed the presence of six olefinic protons, one oxygenated methine, one methoxy, and one methyl doublet, while the 13C NMR spectrum exhibited 17 carbons, including three nonprotonated carbons, six sp2 methines and one sp3 (δC 68.5) methine, five methylenes, and two methyls. These 1H and 13C NMR data were similar to those of crotonpyrone B,47 except for an additional hydroxy group at C-15 and two conjugated double bonds located at Δ6,7 and Δ8,9 positions in 9 instead of one double bond at Δ10 in crotonpyrone B. The 6E and 8E configurations were established according to the large coupling constants (3JH6,H7 = 15.3 Hz; 3JH8,H9 = 15.3 Hz). By detailed analysis of its 2D NMR spectra, 9 was then established as (6E,8E)-10,11-dihydro-6,8-dien-15-hydroxycrotonpyrone B and named graphostrin I. All isolated compounds (1−28) were evaluated for their antifood allergy activities in RBL-2H3 cells. Reticulol (10) showed potent degranulation-inhibitory activity with an IC50 value of 13.5 μM, which was approximately 7-fold stronger than the commercially available antifood allergy medicine, loratadine (IC50 = 91.6 μM), while 7,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin (17) and hydroxyemodin (23) showed weak effects with IC50 values of 154.1 and 139.3 μM, respectively (Table 3).

Table 3. Rates of Inhibition of Compounds 1−28 on RBL2H3 Cell Degranulation (n = 3; means ± standard deviation) compound

IC50 (μM) 13.5 154.1 139.3 >200 5.7 91.6

10 17 23 othersa BBRb loratadinec

± 1.6 ± 18.6 ± 11.9 ± 0.2 ± 7.3

a

Other compounds, including 1−9, 11−16, 18−22, and 23−28. Berberine was the positive control. cLoratadine was a commercially available antifood allergic medicine. b

Preliminary analysis of structure−activity relationships of isocoumarin-type derivatives (10−16) revealed that methyl at C-3, the hydroxy group at C-6, and the methoxyl group at C-7 were necessary for the antifood allergy activities. To further verify the inhibitory influence of reticulol (10) on the function of mast cell, the release of histamine was measured in RBL-2H3 cells. It showed a significant inhibitory effect with an IC50 value of 13.7 μM, indicating the potential application of reticulol as an antiallergic medicine. In conclusion, from the deep-sea-derived fungus Graphostroma sp. MCCC 3A00421, nine new and 19 known polyketides were obtained. Compound 1 (graphostrin A) is a novel chlorinated polyketide featuring a rare oxazole ring. Compound 10 (reticulol) exhibited potent in vitro antifood allergy activities.

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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.jafc.7b04383. HRESIMS, 1H, 13C, HSQC, COSY, and HMBC NMR spectra of 1, 1H NMR spectra of 1a−3a and 1b−3b, and 1 H and 13C NMR spectra of 2−9 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Telephone and fax: +86-592-2195319. E-mail: yangxianwen@ tio.org.cn. ORCID

Siwen Niu: 0000-0002-1845-0582 Guangming Liu: 0000-0002-8689-0504 Xian-Wen Yang: 0000-0002-4967-0844 Funding

This study was supported by grants from the Xiamen Ocean Economic Innovation and Development Demonstration Project (16PZP001SF16), the China Postdoctoral Science Foundation (2016M602056), and the National Natural Science Foundation of China (41606185, 41676130, and 21372233). Notes

The authors declare no competing financial interest.

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REFERENCES

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