Two New Phenol Derivatives from the Cold Seep-Derived Fungus Aspergillus insuetus SD-512

Article abstract of DOI:10.1002/cbdv.202100512

Two new phenol derivatives, namely insphenol A (1) and acetylpeniciphenol (2), along with seven known analogs (3–9), were isolated from the deep-sea cold seep-derived fungus, Aspergillus insuetus SD-512. The structures of 1 and 2 were established by extensive interpretation of NMR and mass spectroscopic data. The absolute configuration of 1 was determined by the combination of coupling constant analysis and acid hydrolysis. Among the isolated compounds, insphenol A (1) represents the first example of isopentenyl phenol derivative with a unique 1-glycosylation from the species Aspergillus insuetus. The isolated new compounds were evaluated for antibacterial activities against six human or aquatic pathogens, while compound 2 exhibited inhibitory effect against Edwardsiella tarda, Vibrio alginolyticus, and V. vulnificus, with MIC values of 4, 8, and 8 μg/mL, respectively.

Full text of DOI:10.1002/cbdv.202100512

Title: Two new phenol derivatives from the cold seep-derived fungus
Aspergillus insuetus SD-512
Authors: Lu-Ping Chi, Xiao-Ming Li, Yu-Peng Wan, Yan-He Li, Xin Li,
and Bin-Gui Wang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Biodiversity 10.1002/cbdv.202100512
Link to VoR: https://doi.org/10.1002/cbdv.202100512

10.1002/cbdv.202100512
Chemistry & Biodiversity
Chem. Biodiversity
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Two new phenol derivatives from the cold seep-derived fungus
Aspergillus insuetus SD-512
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Lu-Ping Chi,a,b,c Xiao-Ming Li,a,b Yu-Peng Wan,a Yan-He Li,a,b,c Xin Li,*,a,b and Bin-Gui Wang,*,a,b,d
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a Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071,
People’s Republic of China, e-mails: lixin@qdio.ac.cn; wangbg@ms.qdio.ac.cn
b Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Wenhai Road 1, Qingdao
266237, People’s Republic of China
c University of Chinese Academy of Sciences, Yuquan Road 19A, Beijing 100049, People’s Republic of China
d Center for Ocean Mega-Science, Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071, People’s Republic of China
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Two new phenol derivatives, namely insphenol A (1) and acetylpeniciphenol (2), along with seven known analogues (3–9), were isolated from
the deep-sea cold seep-derived fungus, Aspergillus insuetus SD-512. The structures of 1 and 2 were established by extensive interpretation of
NMR and mass spectroscopic data. The absolute configuration of 1 was determined by the combination of coupling constant analysis and acid
hydrolysis. Among the isolated compounds, insphenol A (1) represents the first example of isopentenyl phenol derivative with a unique 1-
glycosylation from the species Aspergillus insuetus. The isolated new compounds were evaluated for antibacterial activities against six human or
aquatic pathogens, while compound 2 exhibited inhibitory effect against Edwardsiella tarda, Vibrio alginolyticus, and V. vulnificus, with MIC values
of 4, 8, and 8 μg/mL, respectively.
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Keywords: Aspergillus insuetus, cold seep-derived fungus, marine natural products, antibacterial activity
Introduction
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Deep-sea has been proved to be a great treasure for structural unique and biological active natural products in last two decades.[1-3] Cold seeps
are the typical deep-sea chemosynthetically-driven ecosystems, characterized as methane-rich fluid emissions and distinctive sulfur oxidation-
reduction reactions, which led to high abundance of specialized cold seep microorganism.[4-5] Microorganisms from deep-sea cold seeps, which
could be a new source for biomedically important compounds, are only beginning to be investigated.[6-7] The great potential of the capability
for natural product biosynthesis of deep-sea cold seep microbes will undoubtedly accelerated investigation of deep sea microbes for new
drugs.
In our continuing research for bioactive compounds from deep sea extreme environment-derived fungi,[8-10] we perform chemical investigations
on the extract of the fungus A. insuetus SD-512, a strain of deep sea-derived fungus isolated from the sediments in cold seep area in the South
China Sea at a depth of 1331m. As a result, two new phenol derivatives, insphenol A (1) and acetylpeniciphenol (2), together with seven known
compounds, penicisochroman E (3),[11] asperisocoumarin D (4),[12] (−)-brassicadiol (5),[13] daldinin C (6),[14] penicisochroman I (7),[13] TMC-120B (8)
and C (9)[15] (Figure 1), were isolated and identified. Among the isolated compounds, insphenol A (1) represents the first example of isopentenyl
phenol derivative with a unique 1-glycosylation from the species Aspergillus insuetus. The assignment of the absolute configuration of 1 was
confirmed by the coupling constant of the oxygenated methine proton and acid hydrolysis. This paper describes the isolation, structural
elucidation, and biological evaluation of the isolated compounds.
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Results and Discussion
Structure Elucidation of Compounds 1 and 2
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10.1002/cbdv.202100512
Chemistry & Biodiversity
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Figure 1. Chemical structures of the identified compounds 1–9.
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Compound 1 was obtained as colorless oil. The elemental composition was established to be C21H32O7 supported by ion peak at m/z
419.2038 [M + Na]+ (calculated for C21H32O7Na), indicating 6 degrees of unsaturation. In the 1H NMR spectrum, the signals for a pair of typical
ortho-coupled aromatic protons were present at δH 6.93 (d, J = 7.8 Hz, H-C(4))/δH 6.99 (d, J = 7.8 Hz, H-C(5)), suggesting the presence of a
1,2,3,4-tetra-substituted benzene ring system. Meanwhile, a tri-substituted double bond (δH 5.26, t, J = 7.4 Hz, H-C(12)) were also observed.
The 13C NMR spectrum revealed signals attributable to three methyls, five sp3-hybridized methylenes (two oxygenated), three sp2- and five sp3-
hybridized methines, and five quaternary carbons. Further detailed analysis of 1D and 2D NMR data indicated that a hydroxymethyl group, a n-
propyl group, an isoprenyl group, and a glucopyranose moiety were attached to the benzene ring bonded to C(2), C(3), C(6), and C(1),
respectively (Figure S3, S4, and S5). Thus, the planar structure of 1 was determined and it was named as insphenol A.
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Figure 2. Key COSY (bold lines in black) and HMBC (arrows in red) correlations for compounds 1 and 2.
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]
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The coupling constant of the anomeric proton at H-C(1') (δH 4.52, d, J = 7.8 Hz) revealed the β-configuration of the glycosidic linkage in 1.[
To confirm the identity of the glucose and to establish its absolute configuration, hydrolysis of 1 was performed with 3N HCl to give the sugar
residue, which, together with the authentic D- and L-glucose, was further derivatized with L-cysteine methyl ester hydrochloride and σ-
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tolylisothiocyanate (Scheme 1).[ ] HPLC analysis showed that the retention time of the derivative of sugar residue of 1 was identical with that of
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D-glucose (Figure S8). Thus, the sugar in 1 was determined as β-D-glucose.
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Scheme 1. Determination of absolute configurations of 1 by chemical derivatization.
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10.1002/cbdv.202100512
Chemistry & Biodiversity
Chem. Biodiversity
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Table 1. 1H- and 13C-NMR data of compounds 1 and 2.
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2
Position
δ(H) (Mult, J in Hz)[a]
δ(C), Type[b]
δ(H) (Mult, J in Hz)[c]
δ(C), Type[d]
1
152.5, C
133.4, C
141.0, C
125.4, CH
128.7, CH
131.7, C
156.4, C
2
3
4
5
6
122.2, C
134.6, C
6.93, d (7.8)
6.59, d (7.8)
120.5, CH
126.8, CH
115.8, CH
6.99, d (7.8)
7.15, t (7.8)
6.86, d (7.8)
7α
7β
α 4.72, dd (8.2, 6.8)
β 4.45, dd (8.2, 6.8)
55.0, CH2
4.84, s
60.4, CH2
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2.59-2.69, m
1.51-1.61, m
0.93, t (7.3)
3.46, d (7.4)
5.26, t (7.4)
33.8, CH2
24.2, CH2
14.2, CH3
27.4, CH2
123.6, CH
131.3, C
6.68, d (11.3)
131.3, CH
128.2, CH
61.0, CH2
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5.83, dt (11.3, 6.7)
4.56, dd (6.7, 1.2)
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12
13
14
1.69, s
25.6, CH3
17.8, CH3
104.3, CH
74.0, CH
76.4, CH
70.5, CH
76.5, CH
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1.68, s
1'
4.52, d (7.8)
170.6, C
2'
3.31, td (7.8, 2.7)
3.23, t (7.8)
2.02, s
20.4, CH3
3'
4'
3.05-3.09, m (overlap)
3.05-3.09, m (overlap)
α 3.36-3.40, m
β 3.66, dd (11.7, 3.9)
5'
6'α
6'β
1-OH
7-OH
2'-OH
3'-OH
4'-OH
6'-OH
61.4, CH2
7.69, s
2.87, s
4.43, d (6.8)
5.59, d (2.7)
5.14, s
5.04, s
4.70, t (3.9)
[a] Data collected at 600 MHz in DMSO-d6. [b] Data collected at 150 MHz in DMSO-d6. [c] Data collected at 500
MHz in CDCl3. [d] Data collected at 125 MHz in CDCl3.
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Compound 2, acquired as colorless oil, was assigned the molecular formula C12H14O4 by the analysis of HR-ESI-MS data, suggesting the
requirement of 6 degrees of unsaturation. The observed signals in 1H NMR spectrum of 2 for three aromatic protons at δH 7.15 (t, J = 7.8 Hz),
δH 6.86 (d, J = 7.8 Hz) and δH 6.59 (d, J = 7.8 Hz) were indicative of a 1,2,3-trisubstituted benzene ring system. Meanwhile, protons for a cis
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disubstituted olefin, two oxygenated methylenes, a methyl and two changeable protons were also found in the 1H NMR spectrum. The 13
C
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NMR data of 2 revealed the presence of a methyl group, two oxygenated methylenes, five olefinic/aromatic methines, and four quaternary
carbon atoms (including three aromatic carbons and one carbonyl group). Exhaustive comparison of its 1H-NMR data with those of
peniciphenol, a known analogue isolated from the sea fan-derived fungus Penicillium sp. PSU-F40,[11] revealed the structural similarity between
2 and peniciphenol, except that an additional acetyl group were observed in the NMR spectra of 2. Compared with peniciphenol, obvious
deshielded shift for H-C(10) was also observed. The above observation suggested that compound 2 was a 10-OH acetylated derivative of
peniciphenol, which was confirmed by HMBC correlation from H-C(10) to C(1'). Besides, the 1H NMR data (δH 6.68, d, J = 11.3 Hz; δH 5.83, dt, J
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13
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= 11.3, 6.7 Hz) indicated the cis-disubstituted double bond in 2. Thus, the planar structure of 2 was established, and the trivial name
acetylpeniciphenol was assigned to compound 2.
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10.1002/cbdv.202100512
Chemistry & Biodiversity
Chem. Biodiversity
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In addition, seven known compounds, including penicisochroman E (3),[11] asperisocoumarin D (4),[12] (−)-brassicadiol (5),[13] daldinin C (6),[14]
1
penicisochroman I (7),[13] TMC-120B (8) and C (9),[15] were also isolated and identified. Their structures were elucidated by comparing H- and
13C-NMR data with those reported in literature.
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Antibacterial Activities
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In bioassay, the isolated compounds were assayed for their antimicrobial activities against zoonotic aquatic pathogens in 96-well plates (Table
2). Compound 2 showed activity against Edwardsiella tarda, Vibrio alginolyticus, and V. vulnificus, with MIC values of 4, 8, and 8 μg/mL, respectively,
while the MIC values of the positive control chloramphenicol for those three bacteria are all 0.5 μg/mL.
Table 2. Antimicrobial activities of compounds 1 and 2 (MIC, μg/mL).
Strains
1
2
Positive control[b]
[a]
E. tarda
-
4
8
8
0.5
0.5
0.5
V. alginolyticus
V.vulnificus
-
-
[a] (–) = MIC > 64 μg/mL. [b] Chloramphenicol as positive control.
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Conclusions
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In summary, nine compounds (1–9), including two new phenol derivatives (1 and 2), were isolated from culture extract of the deep sea cold
seep-derived fungus A. insuetus SD-512. Among them, compound 1 was the first report of isoprenyl phenol derivative with a unique 1-
glycosylation from species A. insuetus. The absolute configuration was determined on the basis of the combination of coupling constant
analysis, acid hydrolysis, chemical derivatization and HPLC analysis. The result of antibacterial activities exhibited that compound 2 could inhibit
three aquatic pathogens with MIC values ranging from 4~8 μg/mL, which may be useful for the discovery of antibacterial agents. Due to the
characteristic chemosynthetically-driven ecosystems in the cold seep area, secondary metabolites from deep-sea cold seep-derived fungi may
be a new source of structurally unique and biologically active compounds.
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Experimental Section
General
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Optical rotations were measured by an Optical Activity AA-55 polarimeter. UV spectra were recorded on PuXi TU-1810 UV-visible
spectrophotometer. CD spectra were acquired on a JASCO J-715 spectropolarimeter. The NMR spectra were recorded on Bruker Avance 500
MHz spectrometer, using solvent chemical shifts (DMSO-d6: δH/δC 2.50/39.52; CDCl3: δH/δC 7.26/77.16) as reference. Mass spectra were obtained
on a VG Autospec 3000 mass spectrometer.
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Fungal Material
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The fungus A. insuetus SD-512 was isolated from the deep sea-sediment sample collected in September 2017, from the cold seep area of South
China Sea at a depth of 1331 m. Besides, the sequenced data of ITS region derived from the fungal strain have been deposited in GenBank
(accession no. MN696202), and the fungus was identified as A. insuetus according to a BLAST search result, which showed that the sequence was
most similar (100%) to the sequence of A. insuetus (compared to accession no. MN 650839). The strain is preserved at the Key Laboratory of
Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences.
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Fermentation
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For chemical investigations, the fungus SD-512 was fermented statically at 28 ºC in rice solid medium containing rice (70 g/flask), peptone (0.3
g/flask), yeast extract (0.5 g/flask), corn steep liquor (0.2 g/flask), monosodium glutamate (0.1 g/flask) and naturally sourced and filtered seawater
(obtained from the Huiquan Gulf of the Yellow Sea near the campus of IOCAS, 100 mL/flask) in 1L flasks (×120).
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10.1002/cbdv.202100512
Chemistry & Biodiversity
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Extraction and Isolation
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After incubation of 35days, the fungal culture was extracted thoroughly with ethyl acetate (EtOAc) to give an extract (70.0 g). The EtOAc extract
was fractionated by silica gel VLC (vacuum liquid chromatography) using a stepwise gradient of a mixture of petroleum ether (PE)/EtOAc (20:1
to 1:1), and then CH2Cl2/MeOH (20:1 to 1:1) to yield nine fractions (Frs. 1−9). Fr. 4 (2.9 g), eluted with PE/EtOAc (2:1), was subjected to CC over
RP-18 eluting with MeOH/H2O gradient (from 1:9 to 1:0) to afford nine subfractions (Frs. 4.1−4.9). Fr.4.1 (107 mg), Fr.4.3 (68 mg) and Fr.4.5 (115
mg) were combined and purified by preparative TLC as well as CC on Sephadex LH-20 (MeOH) to give 3 (11.3 mg), 2 (3.1 mg) and 9 (16.9 mg),
respectively. Fr.4.4 (597 mg) was split by CC on silica gel (200–300 mesh) eluted with a CH2Cl2/EtOAc gradient, from 50:1 to 1:1, to acquire 4 (11.0
mg), 5 (98.8 mg), 8 (23.8 mg). Fr. 6 (10.1 g), eluted with CH2Cl2/MeOH (20:1), was further purified by CC over RP-18, preparative TLC and then CC
on Sephadex LH-20 (MeOH) to obtain 6 (135.6 mg). Fr. 7 (4.3 g), eluted with CH2Cl2/MeOH (10:1), was applied to CC over RP-18, eluting stepwise
from MeOH/H2O 1:9 to 1:0, to give nine subfractions (Frs. 7.1−7.9). Fr.7.2 (381 mg) and Fr.7.6 (72 mg) was purified to preparative TLC and CC
over Sephadex LH-20 (MeOH) to yield 7 (31.5 mg) and 1 (11.0 mg), respectively.
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Insphenol A (1). White amorphous powder; [α]2D5 +46.2 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 202 (3.95) nm, 220 (3.36) nm, 269 (2.30) nm; ECD
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(3.8 mM, MeOH) λmax (Δε) 203 (–2.11), 226 (–0.52); IR vmax 3239, 2959, 2922, 2870, 1425, 1379, 1196, 1085,1043, 1020, 990 cm-1; 1H- and 13C-NMR
data, Table 1; HR-ESI-MS m/z 419.2038 [M + Na]+ (calcd for C21H32O7Na, 419.2040).
Acetylpeniciphenol (2). Colorless oil; UV (MeOH) λmax (logε) 209 (4.07) nm, 286 (3.08) nm; IR vmax 3348, 2917, 1716, 1582, 1466, 1374, 1256,
1023, 993 cm-1; 1H- and 13C-NMR data, Table 1; HR-ESI-MS m/z 245.0791 [M+Na]+ (calcd for C12H14O4Na, 245.0784).
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Acid hydrolysis and determination of the absolute configuration of glucose
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Compound 1 (1.0 mg) was dissolved in 3 N HCl (0.5 mL) and heated to 100 °C for 2 h. Then, the sugar residue was obtained from the aqueous
layer after extracting with EtOAc. The sugar residue was dissolved in 0.5 mL pyridine with the presence of 0.5 mg of L-cysteine methyl ester
hydrochloride and heated to 60 °C for 1 h. Then, 10 μL of σ-tolylisothiocyanate was added to the mixture and the heating was continued for 1
h. After that, the reaction mixture was subjected to HPLC analysis and the HPLC condition was 10% to 100% MeCN gradient with 0.1% TFA over
40 min (Elite, SinoChrom ODS-BP, 250 mm × 4.60 mm, 5 μm; UV detection 254nm; flow rate 1.0 mL/min).[16]
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Antibacterial Assays
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The antibacterial activities against human pathogenic bacteria (Escherichia coli QDIO-1 and Pseudomonas aeruginosa QDIO-2) and aquatic
pathogens (Edwardsiella tarda QDIO-8, Vibrio alginolyticus QDIO-7, V. anguillarum QDIO-9, and V. vulnificus QDIO-4 were determined by a
serial dilution technique using 96-well microtiter plates.[17] The human or aquatic pathogenic strains were offered by IOCAS. Tested compounds
and positive control (chloramphenicol) were dissolved in DMSO to give a stock solution.
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Supplementary Material
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Supporting information for this article is available on the WWW under https://doi.org/10.1002/cbdv.2021xxxxx
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Acknowledgements
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This work was financially supported by the National Key R&D Program of China (2018YFC0310800), the National Natural Science Foundation of
China (42076090 and U2006203), and the Shandong Provincial Natural Science Foundation (ZR2019ZD18). X.L. appreciates the Basic Applied
Research program of Qingdao (19-6-2-40-cg), and B.-G.W. acknowledges the support of the Senior User Project of RV KEXUE
(KEXUE2020GZ02), Center for Ocean Mega-Science, Chinese Academy of Sciences and the Taishan Scholar Project from Shandong Province
(ts201511060). The samples were collected by RV KEXUE.
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Author Contribution Statement
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10.1002/cbdv.202100512
Chemistry & Biodiversity
Chem. Biodiversity
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L.P. C. performed the experiments for the isolation, structure elucidation, acid hydrolysis and chemical derivatization, antibacterial evaluation and
prepared the manuscript; X.M. L. performed the 1D and 2D NMR experiments; Y.P. W. contributed to the isolation of compounds from the fungal
strain SD-512; Y.H. L. contributed to the acid hydrolysis and chemical derivatization of compound 1. X. L. revised the manuscript; B.G. W.
supervised the research work and revised the manuscript.
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10.1002/cbdv.202100512
Chemistry & Biodiversity
Chem. Biodiversity
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Two New Phenol Derivatives, Insphenol A and Acetylpeniciphenol, with Unique 1-Glycosylation and Antibacterial Activities from
Cold Seep Derived Fungus Aspergillus insuetus SD-512 by B.-G. Wang et al., Institute of Oceanology, CAS, China
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