Bioactive Resorcylic Acid Lactones with Different Ring Systems from

a new natural product (2) and four known ones (3, 6, 7 and 10) with different ring. 28 systems were isolated from the desert plant endophytic fungus ...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/JAFC

Cite This: J. Agric. Food Chem. 2018, 66, 8976−8982

Bioactive Resorcylic Acid Lactones with Different Ring Systems from Desert Plant Endophytic Fungus Chaetosphaeronema hispidulur Xiao-Yan Zhang,† Zhan-Liang Liu,‡ Bing-Da Sun,§ Shu-Bin Niu,∥ Meng-Hua Wang,† Xiang-Mei Tan,† Zhong-Mei Zou,† and Gang Ding*,†

J. Agric. Food Chem. 2018.66:8976-8982. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 08/29/18. For personal use only.

†

Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, People’s Republic of China ‡ School of Pharmaceutical Science, Taishan Medical University, Taishan 271016, People’s Republic of China § Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China ∥ School of Biological Medicine, Beijing City University, Beijing 100083, People’s Republic of China S Supporting Information *

ABSTRACT: Five new resorcylic acid lactones (RALs) hispidulactones A−E (1, 4, 5, 8, and 9), a new natural product (2), and four known ones (3, 6, 7, and 10) with different ring systems were isolated from the desert plant endophytic fungus Chaetosphaeronema hispidulur. The new compounds were characterized by NMR data, CD spectra, and X-ray experiment. The new natural product (2) displayed strongly biological effects on the seedlings growth of Arabidopsis thaliana, Digitaria sanguinalis, and Echinochloa crusgalli with a dose-dependent relationship. Compounds 1, 2, and 6 were also tested cytotoxic activities against three cancer cell lines HCT116, Hela, and MCF7 and only did the new natural product (2) display biological activities with IC50 values at 54.86 ± 1.52, 4. 90 ± 0.02, and 20.04 ± 4.00 μM, respectively, whereas the IC50 values of the positive control cis-platinum were 11.36 ± 0.42, 3.54 ± 0.12, and 14.32 ± 1.01 μM, respectively. KEYWORDS: endophytic fungus, Chaetosphaeronema hispidulur, resorcylic acid lactones (RALs), phytotoxicity, cytotoxicity

■

INTRODUCTION Resorcylic acid lactones (RALs) are a big member of mycotoxins with a resircinol moiety fused to the α, β-position of a macrocyclic lactone ring. According to the ring size, this member of secondary metabolites are further divided into 8-membered, 10-membered, 12-membered, and 14-membered ring subgroups, though the 10-membered ring analogs rarely occurred in nature.1−3 This group of secondary metabolites exhibited versatile biological effects, including antitumor, antibacterial, and antimalarial activities, and recently the 14-membered ring RALs with a cis-enone group in the macrocyclic ring have been reported to display irreversible but selective inhibition against different protein kinases due to the hetero-Michael reaction with a conserved cysteine in the ATP binding pocket.3−5 In 1999, Pearl and co-workers obtained the cocrystal structure of the RAL radicicol with Hsp90, implying that the carbonyl group in the macrocycle and 9/11-OH on the aromatic ring were the potentially biological functionalities, mimicking the adenosines’s binding interactions with different amino acids groups in Hsp90 by hydrogen-bonds.6 Investigation of RALs biogenetic pathway revealed that this class of mycotoxins were originated from two polyketide synthases (PKSs) including one highly reducing one and another nonreducing one, which formed the corresponding macrocyclic lactone ring and resorcylate core, respectively.1,2,7,8 Our lab recently initiated chemical investigation of plant endophytic fungi isolated from desert and grassland plants inhabiting in Northwest of China, including Ning-xia, Qing-hai, Shaan-xi, Xin-jiang, Inner Mongolia Provinces, and a series of secondary metabolites © 2018 American Chemical Society

with diverse structural features and a wide range of biological effects were purified.9−13 During our ongoing to obtain bioactive natural products from this member of special fungi, five new RAL analogs hispidulactones A−E (1, 4, 5, 8, and 9), a new natural product (2)14 and four known analogs (3, 6, 7, and 10)15−18 with different ring systems were purified from the plant endophytic fungus Chaetosphaeronema hispidulur (Number: TS-8-1) collected from the desert plant Bassia dasyphylla in Teng−Ge−Li desert, Ning-xia Province of West China (Figure 1). The structural elucidation, biological evaluation, and possible biosynthetic pathway of these compounds were presented in this report.

■

MATERIALS AND METHODS

General Experimental Procedures. UV data were taken by UV-2102 (Unico, Shanghai, China). CD spectra were recorded by JASCO J-815 spectropolarimeter. Optical rotations were recorded on a 241 polarimeter (PerkinElmer, Waltham, America). The FTIR8400S spectrophotometer (Shimadzu, Kyoto, Japan) was used to measure the IR spectra. One-dimensional (1D) and two-dimensional (2D) NMR spectra (1H, 500 MHz; 13C, 125 MHz) were measured on a Bruker 500 spectrometer. Semipreparative HPLC separation was performed on a Shimadzu LC-6AD instrument packed with a YMC-Pack ODS-A column. HRESIMS spectra were obtained using a TOF-ESI-MS (Waters Synapt G2, America). Sephadex LH-20 and Received: Revised: Accepted: Published: 8976

May 21, 2018 August 1, 2018 August 6, 2018 August 10, 2018 DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

Article

Journal of Agricultural and Food Chemistry

Figure 1. Structures of compounds 1−10. Hispidulactone C (5): Colorless crystals; [α]D25 +92.3 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 301 (3.8), 264 (4.1), 216 (4.3) nm; IR (neat) νmax 3730, 2939, 2844, 1646, 1511, 1257, 1041, 852, and 667 cm−1; NMR data were depicted in Table 1. HRESIMS: m/z 281.1388 [M + H]+ (calcd. C15H21O5, 281.1389). Hispidulactone D (8): White powder; UV (MeOH) λmax (log ε) 337 (3.9), 246 (4.4) nm; IR (neat) νmax 3747, 2939, 2852, 1707, 1654, 1511, 1457, 1117, 841, and 670 cm−1; NMR data were depicted in Table 1. HRESIMS: m/z 305.1398 [M + H]+ (calcd. C17H21O5, 305.1389). Hispidulactone E (9): White powder; [α]D25 +18.0 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 368 (2.6), 328 (3.6), 244 (4.5) nm; IR (neat) νmax 3755, 2934, 2852, 1682, 1651, 1513, 1457, 1165, 1075, 1038, and 847 cm−1; NMR data were depicted in Table 1. HRESIMS: m/z 315.0846 [M + Na]+ (calcd. C15H16O6Na, 315.0845). Crystallographic Data and X-ray Structure Analysis of Compound 1. The Crystallographic Data and X-ray Structure Analysis of compound 1 were provided in the Supporting Information. Preparation of (S)- and (R)-MTPA Esters of Compound 9.19 The procedures of chemical reactions was depicted as in ref 19. Seedling Growth Test.20,21 The procedures of seedling growth test was depicted as in refs 20 and 21. Cytotoxic Evaluation.22 The cytotoxic activities of 1, 2, and 6 were tested on three cancer cell lines including HCT116, Hela, and MCF7 on the basis of MTT colorimetric approach with cis-platinum as positive controls. The IC50 values of the cis-platinum were 11.36 ± 0.42, 3.54 ± 0.12, and 14.32 ± 1.01 μM, respectively.

silica gel were purchased from Pharmacia (Biotech, Sweden) and Shanghai Titan Scientific Co.,ltd. (Shanghai, China), respectively. The SHELXL-97 with full-matrix least-squares techniques were used to proceed with structure solution and refinement. Chemicals and Reagents. The reagents of HPLC grade were purchased from Tedia Company (Ohio, U.S.A). 3-(4,5-dimethyl-2thiazolyl)-2,5-diphenyltetrazolium bromide (MTT), (S)-methoxy-2(trifluoromethyl) phenylacetyl chloride [(S)-MTPA-Cl], (R)-methoxy-2-(trifluoromethyl) phenylacetyl chloride [(R)-MTPA-Cl] were all purchased from Sigma-Aldrich (St. Louis, U.S.A.). Fungal Material. The strain of Chaetosphaeronema hispidulur (TS-8-1) was provided and identified by Dr Bing-Da Sun (Genbank Accession No. JF964996). The fermentation procedure is described as in our previous work.10−12 Extraction and Isolation. Using EtOAc (3 × 500 mL) extracted the fermented rice substrate three times to afford 8.1 g of crude extract by evaporating the organic solvent under vacuum. The crude extract was separated by a silica gel column chromatography (CC) eluted with petroleum ether-acetone (25:1, 15:1, 5:1, 2:1 and 0:1, v/v, each 450 mL) to obtain nine fractions (Fr.C1 to Fr.C9). Fr.C2 (2.45 g) was then purified by HPLC (90% CH3OH in H2O, v/v, 2 mL/min) to afford 1 (50.3 mg, tR 10.0 min). Fr.C4 (219 mg) was separated by HPLC (80% CH3OH in H2O, v/v, 2 mL/min) to afford 2 (51.6 mg, tR 27.1 min) and 6 (2.1 mg, tR 43.2 min). Fr.C5 (639 mg) was separated by a silica gel CC eluted with petroleum ether- acetone (30:1, 20:1, 15:1, 10:1, 5:1 and 0:1, v/v, each 78 mL) to get 10 subfractions (Fr.C5.1-Fr.C5.10). Fr.C5.4 (192 mg) was applied by HPLC (40−100% CH3OH-H2O for 30 min, v/v, 2 mL/min) to afford 5 (2.0 mg, tR 23.8 min) and 7 (5.0 mg, tR 26.2 min). Separation of Fr.C5.5 (64.6 mg) was further purified by HPLC (70−100% CH3OH−H2O for 30 min, v/v, 2 mL/min) to afford 10 (2.0 mg, tR 10.8 min) and 8 (2.1 mg, tR 21.3 min). Fr.C6 (449 mg) was separated by a silica gel CC eluted with petroleum ether−acetone gradient elution (6:1, 4:1, 3:1, 1:1 and 0:1, v/v, each 57 mL) to give nine fractions (Fr.C6.1 to Fr.C6.9). Fr.C6.4 (22.8 mg) was then purified by HPLC (60% CH3OH in H2O, v/v, 2 mL/min) to afford 3 (1.0 mg, tR 17.1 min) and 4 (2.8 mg, tR 20.4 min). Fr.C6.6 (88.7 mg) was separated by HPLC (60% CH3OH in H2O, v/v, 2 mL/min) to produce 9 (1.3 mg, tR 19.2 min). Hispidulactone A (1): colorless crystals; [α]D25 + 47.9 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 299 (3.3), 264 (3.6), 215 (3.9) nm; IR (neat) νmax 2937, 1657, 1616, 1572 cm−1; NMR data were depicted in Table 1. HRESIMS: m/z 287.1255 [M + Na]+, (calcd. C15H20O4Na, 287.1259). Hispidulactone B (4): colorless crystals; [α]D25 +65.9 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 300 (3.8), 264 (4.1), 217 (4.3) nm; IR (neat) νmax 3390, 1663, 1616, 1454 cm−1; NMR data were depicted in Table 1. HRESIMS: m/z 267.1232 [M + H]+, (calcd. C14H19O5, 267.1232).

■

RESULTS AND DISCUSSION The molecular formula of 1 was characterized to be C15H20O4 (six unsaturation degrees) by its HRESIMS (m/z 287.1255 [M + Na]+, Calcd 287.1259). The NMR data revealed two methyl (one methoxyl), five methylenes, one oxygenated methine unit, six aromatic carbons, and one ester carboxyl group in the structure 1 (Table 1). This information accounted for all the NMR signals, requiring 1 to possess two rings. Considering the chemical shift values of H-8/H-10 and their coupling relationship, together with the intramolecular hydrogen bond between 11-OH and C-12 implied a benzenediol ring presented in the structure 1, which was further supported by HMBC correlation (Figure 2). The 1H−1H COSY spectrum revealed an isolated proton spin-system as the corresponding fragment of − C-1−C-2−C-3−C-4−C-5−C-6−C-7−. HMBC correlations from H-2 to an ester carboxyl group (C-12), from −CH2−7 to C-7a, C-8, and C-11a together with from −OMe to C-9 confirmed the planar structure of 1 to be a benzenediol lactone analog. Fortunately, the single-crystal of 1 was 8977

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

a

8978

d (6.5) m m m m m m m m m ddd (12.5, 9.5, 2.5) ddd (12.5, 9.0, 7.5)

3.79, s 11.60, s

6.32, d (3.0)

6.28, d (3.0)

1.38, 5.30, 1.77, 1.69, 1.86, 1.66, 1.52, 1.45, 1.80, 1.44, 3.32, 2.32,

H

1

55.3

148.8 110.8 163.9 98.7 165.5 105.3 170.6

34.9

28.9

28.0

19.4

19.8 71.6 32.7

C

13

4

m m m m

6.15, d (2.5)

6.21, d (2.5)

1.79, 1.31, 3.29, 2.26,

2.30, m 1.50, dd (14.5, 4.5) 1.62, m

1.36, d (6.5) 5.29, dq (6.5, 6.5) 3.87, m

H

1

150.3 112.3 164.1 101.8 166.5 105.1 171.6

34.9

30.8

27.1

29.8

13.5 73.7 71.6

C

13

5

m m m m ddd (12.5, 8.5, 4.0) dt (12.5, 8.5)

d (6.5) m m m m

3.78, s

6.32, d (3.0)

6.31, d (3.0)

1.81, 1.46, 1.81, 1.46, 3.36, 2.32,

1.46, 5.41, 2.15, 1.82, 4.22,

H

1

56.8

150.5 100.9 166.7 112.5 167.6 107.2 172.7

37.2

29.7

38.0

68.3

21.1 71.7 43.8

C

13

H

8

3.79, s 3.98, s 3.99, s

6.47, s

6.45, br.s

2.53, t (6.0)

2.38, m

1.63, br.d (7.0) 5.51, m 5.43, m

1

134.1 135.2 159.6 94.9 157.7 102.1 159.7 61.2 55.9 56.5

96.9

158.1

33.7

29.9

17.9 126.4 129.2

C

13

H

1

9

3.86, s

6.48, d (2.0)

6.34, d (2.0)

6.32, br.s

2.70, dd (15.0, 8.0) 2.64, dd (15.0, 6.0)

2.76, dd (18.0, 3.0) 2.68, dd (18.0, 7.0) 4.47, m

2.21, s

Assignments were based on HSQC, HMBC and 1H−1H COSY experiments. bNMR spectroscopic data were recorded at 500 MHz (1H NMR), 125 MHz (13C NMR).

7a 8 9 10 11 11a 12 8-OCH3 9-OCH3 11-OH/11-OCH3

7

6

5

4

1 2 3

position

1

Table 1. NMR Data of 1, 8, and 9 in CDCl3 and 4, 5 in CD3OD (δ in ppm and J in Hz)a,b C

56.1

139.0 101.5 166.9 100.5 163.6 100.0 166.1

106.4

153.8

40.0

65.2

30.8 209.2 48.9

13

Journal of Agricultural and Food Chemistry Article

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

Article

Journal of Agricultural and Food Chemistry

Figure 2. Key 2D NMR correlations and X-ray structure of compound 1.

cultivated suitably for X-ray analysis, which determined the stereochemistry of C-2 as R-configuration. The structure of 2 was determined to be the demethyl product of 1 at C-9, which was ever synthesized by Yang et al.14 Compound 3 were determined to be a known natural product recently isolated from a mangrove plant endophytic fungus, and the stereochemistry of 3 was assigned to be 2R, 4R by X-ray diffraction method.15 The molecular formula of hispidulactone B (4) was assigned to be C14H18O5 on the basis of its HRESIMS (m/z 267.1232 [M + H]+, Calcd 267.1232). This compound (4) had near the same 1H NMR spectrum as that 3, which implied that 4 might be the stereoisomer of at C-4, whereas the 2D NMR spectra including HSQC, COSY and HMBC revealed that the hydroxyl group at C-4 in 3 was actually put at C-3 in 4 (Figure 3). This confirmed that 4 was a new 10-membered RAL. The relative configuration of C-3 and C-4 was characterized based on coupling constant and ROESY spectrum. The large coupling constant of H-2/H-3 (J = 6.5 Hz)23 together with the ROESY correlations from 1-Me to H-3 confirmed the trans-configuration of H-2 with H-3 (Figure 3). The molecular formula of 5 was established to be C15H20O5 (six unsaturation degrees) based on its HRESIMS (m/z 281.1388 [M + H]+, Calcd 281.1389). The NMR data of 5 were near same as those 3 and 4, except that one more methoxyl unit was observed in 5, implying that one of the 4, 9, 11-OH in 3 was replaced by a methoxyl in 5. The HMBC correlation confirmed that the additional −OMe was anchored at C-9, which established the planar structure of 5 (Figure 3). The ROESY correlations between 1-Me and H-4 in 5 revealed the same face of these protons on the macrocyclic ring system (Figure 3). The limited amount of 5 precluded its further reaction with Mosher’s reagents. On account of the same biosynthetic pathway, and nearly same CD spectra of these compounds 3−5 (Figure 4), the stereochemistry of C-2 in 4 and 5 was suggested to be same as that of 3, of which the absolute configuration was established by X-ray diffraction result. The high-resolution ESI-MS of 8 determined its molecular formula as C17H20O5 (five unsaturation degrees). The 1H and

Figure 4. CD Spectra of compounds 3−5. 13

C NMR data together with HSQC spectrum revealed 4 methyl (three methoxyl), 2 methylenes, 10 olefilic carbons (2 of which was protonated), and 1 ester carboxyl group in structure 8 (Table 1). An isolated proton spin-systems as the corresponding fragment of − C-1−C-2−C-3−C-4−C-5− was given by the COSY spectrum. The Key HMBC cross peaks from three methoxyls to C-8, C-9, and C-11, from H-7 to C-6, C-7a, C-8, and C-11a, and from H-10 to C-8, C-9, C-10, C-11, and C-11a, especially to C-12 established a 1H-isochromene unit.7,8 HMBC correlations between −CH2-5 and C-6, C-7 connected the aliphatic chain − C-1−C-2−C-3−C-4−C-5− with the 1H-isochromene unit, and the olefinic bond (C-2 and C-3) was suggested as Z-configuration on the ROESY correlation from 1-CH3 to H-3 and 4-CH2 to H-2, which established the structure of 8 (Figure 5).

Figure 5. Key 2D NMR correlations of compounds 8 and 9.

The high-resolution ESI-MS (m/z 315.0846 [M + Na]+, Calcd 315.0845) assigned the molecular formula of 9 to be C15H16O6 (five degrees of unsaturation). The structure 9 also possessed a 1H-isochromene unit except that C-8 had an olefinic proton and C-11 had a free hydroxyl group compared with that of 8, which was supported by HMBC spectrum (Figure 5). The 1H−1H COSY correlations gave an isolated proton spin-systems as the corresponding fragment of −C-3− C-4−C-5−. The HMBC correlations from −CH3-1 to C-2 and C-3, and from −CH2−5 to C-6 and C-7 determined the structure of 9. Considering a free hydroxyl group anchored at C-4 in 9, modified Mosher’s reaction was tried to further

Figure 3. Key 2D NMR correlations of compounds 3−5. 8979

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

Article

Journal of Agricultural and Food Chemistry

Figure 6. Possible biosynthetic pathway of compounds 1−9.

Figure 7. Compound 2 significantly retarded seedling growth of Arabidopsis thaliana (A), Digitaria sanguinalis (B), and Echinochloa crusgalli (C).

establish the stereochemistry of this chiral carbon C-4,19 whereas the reactions of 9 with (S)-MTPA-Cl and (R)-MTPACl were not successful (Supporting Information). Though compounds 1−5, 6/7, and 8/9 possess different macrocyclic ring system (10-membered, 12-membered, and pyran2-one), those secondary metabolites might be originated from the

same biosynthetic pathway. The possible biosynthetic pathway of 1−9 was suggested (Figure 6). Two polyketide synthases including one highly reducing one and another nonreducing one shape resorcylate core and macrocyclic lactone ring, respectively.1,2,6,7 Resorcylic acid lactones displayed a diverse biological activities especially the inhibitory activities against heat shock 8980

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

Article

Journal of Agricultural and Food Chemistry protein 90 and different protein kinases.1 Compound 2 displayed strongly biological effects against the seedlings growth of Arabidopsis thaliana and of weed Digitaria sanguinalis and Echinochloa crusgalli with a dose-dependent relationship (Figure 7). Additionally, compounds 1, 2, and 6 were evaluated cytotoxic activities against three cancer cell lines HCT116, Hela, and MCF7, and only did the new natural product (2) display biological activities against these three cell lines with IC50 values at 54.86 ± 1.52, 4.90 ± 0.02, and 20.04 ± 4.00 μM, respectively, whereas the IC50 values of the positive control were 11.36 ± 0.42, 3.54 ± 0.12, and 14.32 ± 1.01 μM, respectively.

(2) Winssinger, N.; Barluenga, S. Chemistry and biology of resorcylic acid lactones. Chem. Commun. 2007, 38, 22−36. (3) Patocka, J.; Soukup, O.; Kuca, K. Resorcylic acid lactones as the protein kinase inhibitors, naturally occuring toxins. Mini-Rev. Med. Chem. 2013, 13, 1873−1878. (4) Barluenga, S.; Dakas, P. Y.; Boulifa, M.; Moulin, E.; Winssinger, N. Resorcylic acid lactones: a pluripotent scaffold with therapeutic potential. C. R. Chim. 2008, 11, 1306−1317. (5) Jackson, P. A.; Widen, J. C.; Harki, D. A.; Brummond, K. M. Covalent modifiers: a chemical perspective on the reactivity of α, βunsaturated carbonyls with thiols via hetero-michael addition reactions. J. Med. Chem. 2017, 60, 839−885. (6) Winssinger, N.; Fontaine, J.; Barluenga, S. Hsp90 inhibition with resorcyclic acid lactones (RALs). Curr. Top. Med. Chem. 2009, 9, 1419−1435. (7) Xu, Y.; Zhou, T.; Espinosaartiles, P.; Tang, Y.; Zhan, J.; Molnár, I. Insights into the biosynthesis of 12-membered resorcylic acid lactones from heterologous production in Saccharomyces cerevisiae. ACS Chem. Biol. 2014, 9, 1119−1127. (8) Xu, Y.; Zhou, T.; Zhou, Z.; Su, S.; Roberts, S. A.; Montfort, W. R.; Zeng, J.; Chen, M.; Zhang, W.; Lin, M.; Zhan, J.; Molnár, I. Rational reprogramming of fungal polyketide first-ring cyclization. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 5398−5403. (9) Tan, X. M.; Chen, A. J.; Wu, B.; Zhang, G. S.; Ding, G. Advance of swainsonine biosynthesis. Chin. Chem. Lett. 2018, 29, 417−422. (10) Tan, X. M.; Li, L. Y.; Sun, L. Y.; Sun, B. D.; Niu, S. B.; Wang, M. H.; Zhang, X. Y.; Sun, W. S.; Zhang, G. S.; Deng, H.; Xing, X. K.; Zou, Z. M.; Ding, G. Spiciferone analogs from an endophytic fungus Phoma betae collected from desert plants in West China. J. Antibiot. 2018, 71, 613−617. (11) Li, L. Y.; Sun, B. D.; Zhang, G. S.; Deng, H.; Wang, M. H.; Tan, X. M.; Zhang, X. Y.; Jia, H. M.; Zhang, T.; Zou, Z. M.; Ding, G.; et al. Polyketides with different post-modifications from desert endophytic fungus Paraphoma sp. Nat. Prod. Res. 2018, 32, 939−943. (12) Li, L. Y.; Zhang, X. Y.; Sun, B. D.; Deng, H.; Zou, Z. M.; Ding, G. Phenolic acid analogs from the endophytic fungus Embellisia chlamydospora isolated from desert medicinal plant Artemisia desertorum. Mycosystema. 2018, 37, 88−94. (13) Li, L. Y.; Song, B.; Chen, A. J.; Sun, B. D.; Zhang, G. S.; Deng, H.; Ding, G. Advance on secondary metabolites of grassland and desert plants endophytic fungi. Microbio. China. 2018, 45, 1146− 1160. (14) Yang, Q.; Toshima, H.; Yoshihara, T. Syntheses of β-resorcylic acid derivatives, novel potato micro-tuber inducing substances isolated from Lasiodiplodia theobromae. Tetrahedron 2001, 57, 5377−5384. (15) Li, K. K.; Lu, Y. J.; Song, X. H.; She, Z. G.; Wu, X. W.; An, L. K.; et al. The metabolites of mangrove endophytic fungus ZH6-B1 from the South China Sea. Bioorg. Med. Chem. Lett. 2010, 20, 3326− 3328. (16) Rudiyansyah; Garson, M. J. Secondary metabolites from the Wood Bark of Durio zibethinus and Durio kutejensis. J. Nat. Prod. 2006, 69, 1218−1221. (17) Poling, S. M.; Wicklow, D. T.; Rogers, K. D.; Gloer, J. B. Acremonium zeae, a protective endophyte of maize, produces dihydroresorcylide and 7-Hydroxydihydroresorcylides. J. Agric. Food Chem. 2008, 56, 3006−3009. (18) Sankawa, U.; Shimada, H.; Sato, T.; Kinoshita, T.; Yamasaki, K. Biosynthesis of scytalone. Tetrahedron Lett. 1977, 18, 483−486. (19) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. A new aspect of the high-field NMR application of Mosher’s method. The absolute configuration of marine triterpene sipholenol A. J. Org. Chem. 1991, 56, 1296−1298. (20) Fan, P. H.; Hostettmann, K.; Lou, H. X. Allelochemicals of the invasive neophyte Polygonum cuspidatum Sieb. & Zucc. (Polygonaceae). Chemoecology 2010, 20, 223−227. (21) Jiao, Y.; Zhang, X.; Wang, L.; Li, G.; Zhou, J. C.; Lou, H. X. Metabolites from Penicillium sp., an endophytic fungus from the

■

CONCLUSION Ten polyketides 1−10 including nine resorcylic acid lactones with different structural features were purified from the desert plant endophytic fungus C. hispidulur, and the structures of new compounds were characterized by using NMR, CD spectra, and X-ray diffraction. More than 180 benzenediol lactones with different postmodification were isolated from diverse fungal origins, but 10-membered RALs very rarely occurred in nature and only three analogs were found up-todate. The results in this paper implied that plant endophytic fungi living special environments such as desert areas might conserve unique genetic information with the potentials to produce a diverse of new natural products with unique skeletons displaying a wide range of biological effects.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.8b02648.

■

Crystallographic data and X-ray structure analysis (CIF) NMR, UV, IR, CD, and HRESIMS spectra of new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*Tel: +86 010 57833281. Fax: +86 010 57833281. E-mail: [email protected]; [email protected]. ORCID

Zhong-Mei Zou: 0000-0002-8178-4788 Funding

Two foundations including The National Key Research and Development Program of China “Research and Development of Comprehensive Technologies on Chemical Fertilizer and Pesticide Reduction and Synergism” (2017YFD0201402 for D.G) and CAMS Initiative for Innovative Medicine (2017I2M-4-004 for D.G) were gratefully acknowledged. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS Dr. Jinwei Ren is gratefully acknowledged for his kindness to measure the NMR spectrum. REFERENCES

(1) Shen, W.; Mao, H.; Huang, Q.; Dong, J. Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities. Eur. J. Med. Chem. 2015, 97, 747−777. 8981

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982

Article

Journal of Agricultural and Food Chemistry liverwort Riccardia multifida (l.) S. Gray. Phytochem. Lett. 2013, 6, 14−17. (22) Chen, L.; Niu, S. B.; Li, L.; Ding, G.; Yu, M.; Zhang, G. S.; Wang, M. H.; Li, L. Y.; Zhang, T.; Jia, H. M.; Zhang, H. W.; Shang, H.; Liu, X. Z.; Zou, Z. M. Trichoderpyrone, a unique polyketide hybrid with a cyclopentenone−pyrone skeleton from the plant endophytic fungus Trichoderma gamsii. J. Nat. Prod. 2017, 80, 1944−1947. (23) Sultan, S.; et al. Evolving trends in the dereplication of natural product extracts. 3: further lasiodiplodins from Lasiodiplodia theobromae, an endophyte from Mapania kurzii. Tetrahedron Lett. 2014, 55, 453−455.

8982

DOI: 10.1021/acs.jafc.8b02648 J. Agric. Food Chem. 2018, 66, 8976−8982