Reactive oxygen species altering the metabolite profile of the marine-derived fungus Dichotomomyces cejpii F31-1

Article abstract of DOI:10.1080/14786419.2019.1611816

To investigate the influence of reactive oxygen species (ROS) on the secondary metabolites of the marine-derived fungus Dichotomomyces cejpii F31-1, hydrogen peroxide (H₂O₂) was added to the GPY culture medium. The HPLC chromatogram of the EtOAc extract of the culture broth was distinct from that of the H₂O₂ free GPY medium. Further study of the metabolites in the GPY medium with H₂O₂ resulted in the discovery of eight known compounds. Among them, (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3β-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were present in the highest concentration, while ergosterol and diketopiperazines are abundant in the H₂O₂ free medium. Additionally, a new compound, dichocetide D (1) containing a chlorine element and a known ergosterol (10) were isolated from the H₂O₂ free medium. (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3β-ol (2) exhibited moderate cytotoxic activity against human prostate cancer cell line LNCaP-C4-2B.

Full text of DOI:10.1080/14786419.2019.1611816

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Reactive oxygen species altering the metabolite
profile of the marine-derived fungus
Dichotomomyces cejpii F31-1
Sharpkate Shaker, Ting-Ting Sun, Liang-Yue Wang, Wen-Zhe Ma, Dong-Lan
Wu, Yong-Wei Guo, Jun Dong, Yan-Xiu Chen, Long-Ping Zhu, De-Po Yang, Hou-
Jin Li & Wen-Jian Lan
To cite this article: Sharpkate Shaker, Ting-Ting Sun, Liang-Yue Wang, Wen-Zhe Ma, Dong-Lan
Wu, Yong-Wei Guo, Jun Dong, Yan-Xiu Chen, Long-Ping Zhu, De-Po Yang, Hou-Jin Li & Wen-Jian
Lan (2019): Reactive oxygen species altering the metabolite profile of the marine-derived fungus
Dichotomomycesꢀcejpii F31-1, Natural Product Research, DOI: 10.1080/14786419.2019.1611816
To link to this article: https://doi.org/10.1080/14786419.2019.1611816
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1611816
Reactive oxygen species altering the metabolite profile of
the marine-derived fungus Dichotomomyces cejpii F31-1
Sharpkate Shakera, Ting-Ting Suna, Liang-Yue Wangc, Wen-Zhe Mad, Dong-Lan
Wua, Yong-Wei Guoa, Jun Donge, Yan-Xiu Chena, Long-Ping Zhua, De-Po Yanga,
Hou-Jin Lib and Wen-Jian Lana
b
aSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; School of Chemistry,
c
Sun Yat-sen University, Guangzhou, China; School of Bioscience & Bioengineering, South China
d
University of Technology, Guangzhou, China; State Key Laboratory of Quality Research in Chinese
Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science
e
and Technology, Taipa, Macau, China; School of Traditional Chinese Medicine, Guangdong
Pharmaceutical University, Guangzhou, China
ABSTRACT
ARTICLE HISTORY
Received 23 January 2019
Accepted 22 April 2019
To investigate the influence of reactive oxygen species (ROS)
on the secondary metabolites of the marine-derived fungus
Dichotomomyces cejpii F31-1, hydrogen peroxide (H2O2) was
added to the GPY culture medium. The HPLC chromatogram of
the EtOAc extract of the culture broth was distinct from that of
the H2O2 free GPY medium. Further study of the metabolites in
the GPY medium with H2O2 resulted in the discovery of eight
known compounds. Among them, (22E)-5a, 8a-epidioxyergosta-6,
22-dien-3b-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were
present in the highest concentration, while ergosterol and diketo-
piperazines are abundant in the H2O2 free medium. Additionally,
a new compound, dichocetide D (1) containing a chlorine
element and a known ergosterol (10) were isolated from the
H2O2 free medium. (22E)-5a, 8a-epidioxyergosta-6, 22-dien-3b-ol
(2) exhibited moderate cytotoxic activity against human prostate
cancer cell line LNCaP-C4-2B.
KEYWORDS
Dichotomomyces cejpii;
reactive oxygen species;
secondary metabo-
lites; steroids
CONTACT De-Po Yanga
Guangzhou, 510006, China; Hou-Jin Lib
lssydp@mail.sysu.edu.cn
School of Pharmaceutical Sciences, Sun Yat-sen University,
ceslhj@mail.sysu.edu.cn
School of Chemistry, Sun Yat-sen University,
Guangzhou, 510275, China; Wen-Jian Lan
Sun Yat-sen University, Guangzhou, 510006, China.
lanwj@mail.sysu.edu.cn School of Pharmaceutical Sciences,
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1611816.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
S. SHAKER ET AL.
1. Introduction
Reactive oxygen species (ROS) comprising radical and non-radical oxygen, including
superoxide anion (O2-), hydroxyl radical (OH-), and hydrogen peroxide (H2O2) are pro-
duced as natural byproducts of aerobic metabolism. ROS at low concentrations play
indispensable roles in cell signaling and homeostasis. However, at higher levels, ROS
can influence the progression of a variety of human disease (Devasagayam et al. 2004;
Rajendran et al. 2014). When encountering environmental stress, such as drought, sal-
inity, UV light or heat exposure, ROS concentrations can dramatically increase, result-
ing in damage to the cell membrane and changes in metabolism (Caverzan et al.
2016). Thus, to adapt to environmental changes, a counteracting oxidant response,
referred to as the oxidative stress response, is triggered.
The synthesis of certain secondary metabolites is triggered by ROS accumulation, and
the biosynthesis of mycotoxins can be influenced by the presence of reactive oxygen
species (Reverberi et al. 2010). For example, oxidative stress triggers the production of
citrinin in the fungus Penicillium verrucosum (Schmidt-Heydt et al. 2015). Oxidative stress
also initiates aflatoxin B1 biosynthesis in Aspergillus flavus (Grintzalis et al. 2014). ROS
regulates the biosynthesis of lovastatin in Aspergillus terreus (Miranda et al. 2013, 2014).
To investigate the influence of oxidative stress on the secondary metabolites
of the target fungus, ROS culture strategy was applied, in which one of the exogenous
reactive oxygen species, H2O2, was added to the culture medium. Then the natural
products produced by the fungus under the stress condition were studied. The fungus

NATURAL PRODUCT RESEARCH
3
Figure 1. Chemical structures of compounds 1–10.
Dichotomomyces cejpii F31-1 was isolated from the soft coral Lobophytum crassum.
In our previous work, more than thirty compounds of chemical diversity were discov-
ered from the marine-derived fungus Dichotomomyces cejpii F31-1 (Chen et al. 2017;
Wu et al. 2018). The tremendous biosynthetic potential of this fungal strain inspired
us to study it further. Using a small-scale 2 L culture, we found that the HPLC
chromatograms of the EtOAc extracts of the culture broth obtained by using GPY
medium supplemented with H2O2 and without H2O2 were distinct (Figure S6 and S7
in Supplementary material). Using a 50 L-scale culture, eight compounds, including
(22E)-5a,8a-epidioxyergosta-6,22-dien-3b-ol (2) (Kwon et al. 2002), ergosta-4,6,8(14),
22-tetraene-3-one (3) (Schulte et al. 1968), pityriacitrin (4) (Mexia et al. 2015), sartory-
mensin (5) (Buttachon et al. 2012), fiscalin B (6) (Wong et al. 1993), 6-acetylbis-(methyl-
thio)-gliotoxin (7) (Watts et al. 2010), 1-acetyl-8-hydroxy-b-carboline (8) (Zhou et al.
1998), 4-hydroxy-benzaldehyde (9) (Huang and Wang 2004) were obtained in
the medium added with H2O2, and most of these compounds were not appeared in
the previous research without H2O2. Additionally, a new compound, dichocetide D (1)
and an ergosterol (10) (Goad and Akihisa 1997) were isolated as part of our previous
investigation of the metabolites from H2O2 free medium. Other compounds isolated
from the medium without H2O2 are the same with previously reported in our research
(Chen et al. 2017; Wu et al. 2018). (Figure 1).
2. Results and discussion
2.1. Structure determination
Dichocetide D (1) was acquired as a brown oil. It had the molecular formula
of C21H26Cl2O4 with eight degrees of unsaturation, which was established on the basis

4
S. SHAKER ET AL.
of the high resolution electrospray ionization mass spectroscopy (HR-ESI-MS) at m/z
411.11342 [M ꢀ H]ꢀ (calcd. 411.11354). The relative abundance ratio [M: (M þ 2):
(M þ 4) ¼ 9: 6: 1] verified the presence of two chlorine atoms. Further analysis of the
1 D NMR data and HSQC spectrum indicated the highly symmetric structure of this
compound. The 1 D NMR displayed 26 proton and 21 carbon signals, comprising four
pairs of symmetric aromatic sp2 methine groups [dC 114.0, dH 6.82 (d, J ¼ 8.4); dC
128.0, dH 7.14 (d, J ¼ 8.8)], two pairs of symmetric sp2 quaternary carbons (dC 144.0,
156.2), two pairs of symmetric methylene groups [dC 46.1, dH 3.74 (ddt, J ¼ 5.1, 10.0,
13.6); dC 68.5, dH 4.07 (m)], symmetric sp3 methines [dC 70.0, dH 4.20 (ddd, J ¼ 5.0, 5.1,
10.0)], and symmetric methyls (dC 31.1, dH 1.64, s) attached to the sp3 quaternary car-
bon (dC 41.9). The aromatic sp2 methine groups as well as COSY correlation between
dH 6.82 (d, J ¼ 8.4) and dH 7.14 (d, J ¼ 8.8) implied the existence of para-substituted
benzene moities. The HMBC correlations from H3-11 to C-10, C-7 indicated the sym-
metric methyls attached to one quaternary carbon as a bridge between para-substi-
tuted phenyl-rings. The 1-chlorobutan-1-ol moiety and the ether bond were
determined from the careful analysis of the characteristic down-field shift of C-3 (dC
68.5) and the H-1/H2-2, H2-2/H2-3 cross-peaks in the COSY spectrum, as well as the
HMBC correlations from H2-3 to C-4, C-1. Besides, the hydroxyl and chlorine at C-1 vali-
dated by the characteristic down-field shift of C-1 (dC 70.0), which were in accordance
with the molecular formula C21H26Cl2O4. Finally, the planar structure of dichocetide D
(1) was established as shown in Figure 1. To determine the stereochemistry of dicho-
cetide D (1), the optical rotation was conducted. It was found that the experimental
OR value is zero. Therefore, dichocetide D (1) was subjected to the chiral-phase HPLC,
however, dichocetide D (1) could not be resolved by chiral-phase HPLC to afford a
pair of enantiomers, and it was determined as a mesomer.
2.2. Interconversion among ergosterol (10) and compounds 2–3
By careful analysis of the amounts and chemical structures of the compounds
obtained from two different kinds of media, it was found that (in decreasing order of
abundance) diketopiperazines, indole alkaloids and polyketides (including polyketide
alkaloids) are privileged in the H2O2 free GPY medium, while in the GPY medium with
H2O2, steroids, indole alkaloids as well as a little amount of a diketopiperazine are
dominant (Figure S6 and S7 in Supplementary material). The result is consistent with
the literature report that the metabolite of Aspergillus niger treated with H2O2 was
a steroid analogue (Lv et al. 2015). Probably the production of the steroids (22E)-5a,
8a-epidioxyergosta-6,22-dien-3b-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) was
associated with the addition of H2O2. In the chemical structure point of view, (22E)-5a,
8a-epidioxyergosta-6,22-dien-3b-ol (2) was the oxidation product of ergosterol (10).
The cleavage of the peroxide bond furnished the intermedia with a two adjacent
hydroxyl groups. The dehydration of two hydroxyl groups resulted in the formation
of the intermedia b. Finally, further oxidation of the hydroxyl group at C-3 position of
b generated ergosta-4,6,8(14),22-tetraene-3-one (3) (Scheme 1). For this transform-
ation, the formation of the peroxide bridge in compound 2 was supposed to be
related to H2O2.

NATURAL PRODUCT RESEARCH
5
Scheme 1. Interconversion among ergosterol (10) and compounds 2–3.
Among eight compounds (2-9) from the medium with H2O2, the sterol (22E)-5a,
8a-epidioxyergosta-6,22-dien-3b-ol (2) has the highest content 1.01mg/L, and the yield
of ergosta-4,6,8(14),22-tetraene-3-one (3) came second with 0.82 mg/L. Interestingly,
ergosterol (10) was not found from the medium with H2O2, however, the content
of ergosterol (10) was higher than 1.00mg/L in the H2O2 free medium. Obviously,
H2O2 induces the increase and oxidation formation of compound 2. Oxidative-stress of
the fungus activates the related reductase, resulting in the breakage of the peroxide
bridge and further production of 3.
2.3. Cytotoxic bioassay
All of the compounds were screened for their cytotoxic activities against human
prostate cancer cells LNCaP-C4-2B, murine melanoma cells B 16 and human breast
cancer cells MDA-MB 231. Among them, (22E)-5a, 8a-epidioxyergosta-6, 22-dien-3b-ol
(2) exhibited moderate cytotoxic activity against the LNCaP-C4-2B cell line with an IC50
value of 35.53 lM and weak cytotoxic activity against B 16 cell line with an IC50 value
of 78.77 lM respectively. Fiscalin B (6) showed weak cytotoxic activity against the
LNCaP-C4-2B cancer cell line with an IC50 value of 60.91 lM.
3. Experimental section
3.1. Fungal material, culture, extraction, and isolation
The marine fungus Dichotomomyces cejpii F31-1 was obtained from the inner tissue
of the soft coral Lobophytum crassum collected from Hainan Sanya National Coral
Reef Reserve, P. R. China. This fungal strain was conserved in 15% (v/v) glycerol
aqueous solution at ꢀ80 ꢁC. A voucher specimen was deposited in the School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P. R. China. By BLAST

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S. SHAKER ET AL.
database screening, the ITS rDNA of the strain F31-1 showed a 100% match to the
model strain Dichotomomyces cejpii NRRL 26980 (Accession No. GenBank EF669956).
The fungal strain was identified as Dichotomomyces cejpii. The marine fungus
Dichotomomyces cejpii F31-1 was cultured in the medium which contained 20 g/L glu-
cose, 5 g/L peptone, 2 g/L yeast extract, 2 g/L Trp, 2 g/L Phe, 30 g/L sea salt, 1 mL/L
H2O2 (30%) and 1 L H2O at pH 7.5. Fungal mycelia were cut and transferred aseptically
to 1 L Erlenmeyer flasks, each adding 600 mL of sterilized liquid medium. The flasks
were incubated at 25 ꢁC for 60 days. Fifty liters of liquid culture were filtered through
cheesecloth to separate the culture broth and the mycelia. The culture broth was suc-
cessively extracted three times with EtOAc (30 L) and then was concentrated by low-
temperature rotary evaporation to give a crude extract (18 g).
The extract from the GPY medium with H2O2 was chromatographed on a silica
gel column (diameter: 8 cm, length: 80 cm, silica gel: 180 g) with a gradient of petrol-
eum ether-EtOAc (10:0–0:10, v/v) followed by EtOAc-MeOH (10:0–0:10, v/v) to afford
13 fractions (Fr. 1–Fr. 13). Fr. 3 and Fr. 4 were subjected to a Sephadex LH-20 col-
umn and eluted with CH2Cl2-MeOH (1:1, v/v) to give four sub-fractions (Fr. 3-1–Fr. 3-
4 and Fr. 4-1–Fr. 4-4) respectively. Then compounds 2 (50.3 mg), 3 (40.8 mg) were
obtained from Fr. 4-2, which is chromatographed on silica gel column using a step
gradient elution with CHCl3-EtOAc (10:0–0:10, v/v). Fr. 4-3 was further purified with a
preparative RP HPLC (MeCN-H2O, 35:65, v/v) to acquire 7 (8.3 mg), 8 (2.3 mg). Fr. 9
was purified by silica gel column using a step gradient elution with petroleum ether-
EtOAc (10:0–0:10, v/v) to get 10 subfractions (Fr. 9.1–Fr. 9.10) after gathering the
similar fractions as monitored by TLC analyses. Compounds 5 (2.0 mg) and 6 (2.5 mg)
were obtained from Fr. 9.4 with a preparative RP HPLC with MeOH-H2O (38:62, v/v).
Fr. 9.7 was separated via Sephadex LH-20 (MeOH) to give 4 (2.0 mg), 9 (8.0 mg). The
extracts from the H2O2 free GPY medium also were chromatographed on a silica gel
column (diameter: 8 cm, length: 80 cm, silica gel: 300 g) with a gradient of petroleum
ether-EtOAc (10:0–0:10, v/v) followed by EtOAc-MeOH (10:0–0:10, v/v) to afford 9
fractions (Fr. 1–Fr. 9). Fr. 2 was purified by silica gel column using a step gradient
elution with petroleum ether-EtOAc (10:0–0:10, v/v) to get 7 subfractions (Fr. 2-
1–Fr.2-7) after gathering the similar fractions as monitored by TLC analyses. Fr. 2-3
was separated via Sephadex LH-20 (MeOH) to give compound 1 (7.2 mg). Fr. 4 was
loaded on a silica gel column using a step gradient elution with petroleum ether-
EtOAc (10:0–0:10, v/v) to get 9 subfractions (Fr. 4-1–Fr.4-9) after gathering the similar
fractions as monitored by TLC analyses. Fr. 4-3 was subjected to ODS (octadecylsilyl)
column using a step gradient elution with MeOH-H2O (6:4–10: 0, v/v) to give com-
pound 10 (48.2 mg).
3.2. Characterization of dichocetide D (1)
Dichocetide D (1) isolated as a brown oil; [a] ¼ 0 (c 0.10, MeOH). UV (MeOH) kmax nm
(log e): 201 (4.61), 227 (4.20), 276 (3.55), 284 (3.51); IR (KBr) mmax 3375, 2963, 2929,
2872, 1705, 1607, 1583, 1508, 1458, 1295, 1244, 1182, 1107, 1084, 828, 750 cmꢀ1
HRESIMS (-) m/z 411.11342 [M ꢀ H]ꢀ (calcd for C21H28Cl2O4, 411.11354, D ꢀ0.29 ppm).
.

NATURAL PRODUCT RESEARCH
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1H NMR: (400 MHz, CDCL3) d: 7.14 (H ꢂ 4, d, J ¼ 8.8 Hz, 5/50/9/90), 6.82 (H ꢂ 4, d,
J ¼ 8.4 Hz, 6/60/8/80) , 4.20 (H ꢂ 2, ddd, J ¼ 5.0, 5.1, 10.0), 4.07 (H2ꢂ2, m, 3/30), 3.74
(H2ꢂ2, (ddt, J ¼ 5.1, 10.0, 13.6 Hz, 2/20), 1.64 (H, s, 11/110)
13C NMR: (100 MHz, CDCL3) d: 156.2 (C-4/40), 144.0 (C-7/70), 128.0 (CH-6/60/8/80),
114.1 (CH-5/50/9/90), 70.0 (CH2-1/10), 68.5 (CH2-3/30), 46.1 (CH2-2/20), 41.9 (C-10), 31.1
(CH3-11/110)
3.3. Cytotoxicity assay
All the compounds were evaluated cytotoxic activity against human prostate cancer
cells LNCaP-C4-2B, murine melanoma cells B 16 and human breast cancer cells MDA-
MB 231 by the colorimetric MTT assay. Briefly, LNCaP-C4-2B, B 16 and MDA-MB 231
cells were cultured in 96-well plates at a density of 5 ꢂ 103 per well and incubated at
37 ꢁC for 24 h, respectively. Then, various concentrations (0.125-100 lM) of the com-
pounds were added to the wells. After 48 h culture, 20 microliters MTT (Genview,
Houston, TX, USA) solution (5 mgꢃmLꢀ1) was added into each well. These cells were
cultured at 37 ꢁC for another 4 h. In the end, the supernatant was discarded and the
sediment was dissolved by dimethyl sulfoxide (DMSO) (100 microliters per well). The
absorbance was read at 490 nm, and the data was calculated by SPSS software.
4. Conclusion
In conclusion, one new compound (1) and a known ergosterol were isolated from the
culture broth of the H2O2 free medium, and eight known compounds were obtained
from the culture broth of the H2O2 added medium. among eight compounds obtained
from H2O2 added medium, six of them were not discovered from the fungus
Dichotomomyces cejpii F31-1 in our previous research. In addition, this study showed
that the ROS culture strategy alters the metabolite profile of the marine-derived fun-
gus Dichotomomyces cejpii F31-1, inducing the fungus to produce high content and
bioactive steroids. However, it is unclear whether the metabolite profile of dominant
steroids is specific for the fungus Dichotomomyces cejpii F31-1 or it is common for the
fungi. To elucidate this issue, the ROS culture strategy will be applied to a variety of
fungi in the near future.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This research was funded by the National Natural Science Foundation of China (No. 81872795,
41271263), Natural Science Foundation of Guangdong Province (No. 2018A030313157),
Guangdong Provincial Science and Technology Research Program (No. 2014A020217004,
2015A020216007 and 2016A020222004), and the National Science and Technology Major
Project for New Drug Innovation and Development (No. 2017ZX09305010).

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S. SHAKER ET AL.
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