Pestarhamnoses A-C, Rhamnosylated Phenol Derivatives from the Soft Coral-Derived Fungus Pestalotiopsis sp.

Article abstract of DOI:10.1007/s10600-015-1497-z

Reinvestigation of the secondary metabolites of the soft coral-derived fungus Pestalotiopsis sp. (ZJ-2009-7-6), cultured in a bromine-modified medium, led to the isolation of three new rhamnosylated phenol derivatives, pestarhamnoses A-C (1 - 3), together with the former metabolites, (±)-pestalachlorides C and D (4 and 5). Their structures were elucidated through extensive 1D and 2D NMR spectroscopy and mass spectrometry. The relative configurations of the rhamnosyl moieties were determined as α-rhamnoses by their anomeric ¹ J _CH coupling constants. The absolute configurations of 1 - 3 were determined as L-rhamnose residues by HPLC analysis of their thiocarbamoyl-thiazolidine derivatives and that of authentic L-rhamnose. This is the first report of phenol glycosides with α-L-rhamnose in nature.

Full text of DOI:10.1007/s10600-015-1497-z

DOI 10.1007/s10600-015-1497-z
Chemistry of Natural Compounds, Vol. 51, No. 6, November, 2015
PESTARHAMNOSES A–C, RHAMNOSYLATED PHENOL
DERIVATIVES FROM THE SOFT CORAL-DERIVED
FUNGUS Pestalotiopsis sp.
Qian Xing, Dan Li, Zhi-Yong Guo,3
1
1,2
1
*
1*
Chang-Yun Wang, and Chang-Lun Shao
Reinvestigation of the secondary metabolites of the soft coral-derived fungus Pestalotiopsis sp. (ZJ-2009-7-6),
cultured in a bromine-modified medium, led to the isolation of three new rhamnosylated phenol derivatives,
pestarhamnoses A–C (1–3), together with the former metabolites, (ꢀ)-pestalachlorides C and D (4 and 5).
Their structures were elucidated through extensive 1D and 2D NMR spectroscopy and mass spectrometry.
The relative configurations of the rhamnosyl moieties were determined as ꢁ-rhamnoses by their anomeric
1
JCH coupling constants. The absolute configurations of 1–3 were determined as L-rhamnose residues by
HPLC analysis of their thiocarbamoyl-thiazolidine derivatives and that of authentic L-rhamnose. This is the
first report of phenol glycosides with ꢁ-L-rhamnose in nature.
Keywords: rhamnosylated phenol derivative, bromine-modified medium, Pestalotiopsis sp.
Pestalone, a chlorinated benzophenone antibiotic, was isolated from the co-culture of a Pestalotia fungus and a unicellular
marine bacterium (strain CNJ-328) by Fenical and co-workers in 2001 [1]. Recently, pestalone was re-evaluated to display
significant antimicrobial activity against different MRSA strains and several plant pathogens [2]. In 2008, Che and co-workers
reported the discovery of the antifungal pestalachlorides A–C from the plant endophytic fungus Pestalotiopsis adusta [3]. As part
of our ongoing investigation on new natural antibacterial and cytotoxic products from marine fungi in the South China Sea [4–7],
our group discovered another similar new antibiotic, (ꢀ)-pestalachloride D, from the soft coral-derived fungus Pestalotiopsis sp.
collected from the Yongxing Island in the South China Sea [8]. Since all the above natural compounds possess chlorine atoms,
these chlorine atoms should have originated from the cultivation medium and natural seawater. Expecting that bromine-containing
compounds might be obtained by the use of a medium in which a bromide solution replaces seawater, we cultivated the same
strain in a bromine-modified medium. Although we were unable to isolate the brominated compounds, we succeeded in isolating
three new rhamnosylated phenol derivatives, pestarhamnoses A–C (1–3), which share the same biogenetic phenol moiety of
chlorinated diphenylmet, together with (ꢀ)-pestalachlorides C and D (4 and 5) [3, 8]. Herein, we report the cultivation with
bromine-modified medium and isolation, structure determination, and biological evaluation of pestarhamnoses A–C (1–3).
8
Cl
5
OCH
H
3
R
1
R
2
CHO
OH
OH
O
1
3
OH
Cl
5
'
O
6
'
1'
7
O
HO
R
3
'
HO
OH
1 - 3
4, 5
1
: R = CH , R = H; 2: R = H, R = CH ; 3: R = R = H; 4: R = ꢂH; 5: R = ꢁH
1
3
2
1
2
3
1
2
1
) Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy,Ocean
University of China, 266003, Qingdao, P. R. China, fax: 86 532-82031381; 86 532-82031536, e-mail: shaochanglun@163.com,
changyun@ouc.edu.cn; 2) Changzhou Jiaerke Pharmaceutical Group Co., Ltd., 213111, Changzhou, P. R. China; 3) College
of Chemistry and Life Science, China Three Gorges University, 443002, Yichang, P. R. China. Published in Khimiya Prirodnykh
Soedinenii, No. 6, November–December, 2015, pp. 931–934. Original article submitted April 15, 2014.
0
1
080
0009-3130/15/5106-1080 2015 Springer Science+Business Media New York

TABLE 1. H and 13C NMR Data for 1–3 (ꢄ, ppm, J/Hz)
1
1a
2a
3b
C atom
ꢄC
ꢄH
ꢄC
ꢄH
ꢄC
ꢄH
1
2
3
4
5
6
7
8
9
157.0
115.2
154.1
113.0
135.3
120.2
10.0
19.9
12.7
105.1
71.8
72.2
–
–
–
152.8
110.9
153.5
116.4
134.3
108.4
11.1
8.4
19.7
98.7
71.0
–
–
–
–
–
156.5
111.5
156.9
110.7
137.1
107.7
8.4
–
–
–
6.51 s
–
–
2.12 s
2.13 s
6.29 s
–
6.45 s
1.99 s
2.18 s
–
6.57 s
2.10 s
2.09 s
2.20 s
21.5
–
2.09 s
1
ꢃ
4.90 (d, J = 1.5)
4.26 (dd, J = 3.3, 1.5)
3.90 (dd, J = 9.3, 3.3)
3.53 (t, J = 9.3)
4.07 m
5.39 (d, J = 1.5)
4.05 (dd, J = 3.4, 1.5)
3.87 (dd, J = 9.4, 3.4)
3.49 (t, J = 9.4)
3.67 m
99.6
72.2
72.4
73.8
70.5
17.9
5.33 (d, J = 1.8)
3.99 (dd, J = 3.5, 1.8)
3.86 (dd, J = 9.5, 3.5)
3.43 (t, J = 9.5)
3.63 m
2
ꢃ
3ꢃ
71.6
72.8
69.3
17.4
4
ꢃ
72.9
71.0
17.9
5
ꢃ
6ꢃ
1.26 (d, J = 6.2)
1.20 (d, J = 6.3)
1.22 (d, J = 6.1)
_
_____
a
1
13
b
1
13
Measured at 600 MHz ( H) and 150 MHz ( C), acetone-d ; measured at 600 MHz ( H) and 150 MHz ( C), methanol-d .
6
4
O
OH
O
OH
O
OH
O
O
O
HO
HO
HO
HO
HO
HO
OH
OH
OH
1
2
3
COSY
HMBC
1
1
Fig. 1. Key H– H COSY and HMBC correlations of 1–3.
Compound 1 was isolated as a colorless solid with a molecular formula of C H O as established by HR-EI-MS
1
5 22 6
1
3
with five degrees of unsaturation. The glycosidic moiety in 1 was evident from the C NMR chemical shifts (Table 1) of
methine carbons C-2ꢃ to C-5ꢃ resonating between ꢄ 71.0 and 72.9, which are typical of carbons attached to oxygen. The 13C NMR
resonance of C-1ꢃ was shifted further downfield to ꢄ 105.1, as expected for an acetal carbon, whereas C-6ꢃ, resonating at
ꢄ 17.9, showed a highfield shift, indicating the existence of a deoxy sugar. The presence of a rhamnose residue was confirmed
by the contiguous spin system formed by correlations of five oxygen-bearing methines and one doublet methyl signal at
3
3
3
ꢄ 1.26 in the COSY spectrum (Fig. 1) together with the vicinal coupling J
values ( J
= 1.5 Hz, J
= 3.3 Hz,
HH
1ꢃ, 2ꢃ
2ꢃ, 3ꢃ
3
3
3
1
2
J3ꢃ, 4ꢃ = 9.3 Hz, J
= 9.3 Hz, and J
= 6.2 Hz) in the H NMR spectrum (Table 1). Six sp carbon signals (ꢄ 157.0, 154.1,
4ꢃ, 5ꢃ
5ꢃ, 6ꢃ
1
35.3, 120.2, 115.2, 113.0) together with characteristic UV absorption spectrum (ꢅmax 199, 224, 280 nm) indicated the presence
of one phenyl ring. Further comprehensive analysis of 2D NMR data, especially HMBC data (Fig. 1), enabled the determination
of the complete planar structure of 1. Importantly, the connection of the rhamnosyl moiety to the benzene core unit via an ether
bond was established at the C-1 position by the HMBC correlation from H-1ꢃ (ꢄ 4.90) to the aromatic carbon (C-1) at ꢄ 157.0.
Generally, the relative configuration of the glycosidic residue could be determined by the chemical shift of the anomeric
3
carbon and the vicinal coupling JHH values. Because of the unusual feature of rhamnose, the large range of chemical shifts of
the anomeric carbons of rhamnosides in natural compounds, in the case of ꢁ-rhamnosyl residues from ꢄ 98 to 105 [9–12], is
C
not suitable for identifying the relative configuration of rhamnosyl residues. It was reported that the ꢁ- and ꢂ-rhamnosides
1
could be determined by their anomeric J coupling constants (172 Hz for the ꢁ- and 156 Hz for the ꢂ-rhamnoside) [13].
CH
1
In present study, the anomeric J
coupling constant of 1 was determined to be 168.5 Hz, which differs noticeably
CH
from that of a ꢂ-rhamnoside (below 160 Hz). Therefore, the rhamnosyl residue of 1 was deduced to be in the ꢁ-configuration.
1
081

To determine the absolute configuration of the rhamnosyl residue, 1 was hydrolyzed with CF COOH to obtain the
3
monosaccharide residue, which was subsequently derived with L-cysteine methyl ester hydrochloride and phenyl isothiocyanate
to yield the thiocarbamoyl-thiazolidine derivative. The absolute configuration of monosaccharide in 1 was identified as a
L-rhamnose by directly comparing the specific optical rotation of the monosaccharide from the acid hydrolysis of 1
2
6
26
(
[ꢁ] –59.1ꢆ (c 0.1 H O)) with that of authentic L-rhamnose ([ꢁ] –63.3ꢆ (c 0.1 H O)). The L-rhamnosyl moiety was also
D 2 D 2
verified by the retention time in HPLC of the thiocarbamoyl-thiazolidine derivative of the monosaccharide from 1 (21.3 min)
compared with that of the standard sample of L-rhamnose (21.3 min). Since there are no commercial standard samples of
D-rhamnose available, 1 was tentatively determined as 1-O-[ꢁ-L-rhamnopyranosyl]-2,5,6-trimethyl-3-phenol and named
pestarhamnose A.
Compound 2 was also obtained as a colorless solid with the same molecular formula as 1 as established by HR-ESI-MS.
1
13
13
The H and C NMR data of 2 were similar to those of 1 (Table 1). The significant difference in the C NMR spectrum of 2
was the anomeric carbon shifted upfield from ꢄ 105.1 to 98.7. Furthermore, the position of the only aromatic proton was at
C-6 (ꢄ 108.4), which was confirmed on the basis of the HMBC correlations from H-6 (ꢄ 6.57) to C-1 (ꢄ 152.8), C-2 (ꢄ 110.9),
C-4 (ꢄ 116.4), and C-9 (ꢄ 19.7). The glycosidic unit, with an anomeric proton at ꢄ 5.39 (d, J = 1.5 Hz) and a methyl doublet
H
at ꢄ 1.20 (d, J = 6.3 Hz), was identified as L-rhamnose [14], which was further confirmed by comparison of the retention time
of the monosaccharide derivatives in the HPLC spectra. The small coupling constant of the anomeric proton (1.5 Hz) and the
chemical shift of C-5ꢃ (ꢄ 69.3) indicated the usual ꢁ-configuration for this sugar [14], which was further confirmed by the
1
1
13
anomeric J
coupling constant (169.4 Hz). The H– C long-range couplings from H-1ꢃ (ꢄ 5.39) to C-1 (ꢄ 152.8)
CH
established the connectivity between the sugar and the benzene moiety (Fig. 1). Compound 2 was therefore established
as 1-O-[ꢁ-L-rhamnopyranosyl]-2,4,5-trimethyl-3-phenol and named pestarhamnose B.
Compound 3 was isolated as a colorless solid with a molecular formula of C H O (five degrees of unsaturation)
1
4 20 6
1
13
through HR-ESI-MS. The H and C NMR data of 3 were similar to those of 2 (Table 1). The main difference was that 3
1
showed two aromatic protons revealed by the H NMR spectrum,which was also confirmed by the presence of a methine
1
3
carbon at C-4 (ꢄ 110.7) in 3 instead of a quaternary carbon at C-4 (ꢄ 116.4) in 2 in the C NMR spectra. The sugar moiety, the
1
13
same as that of 2, was also identified as ꢁ-L-rhamnose through H NMR, C NMR, and HPLC analysis of the acid hydrolysate
derivative. Compound 3 was designated as 1-O-[ꢁ-L-rhamnopyranosyl]-2,5-dimethyl-3-phenol and named pestarhamnose C.
Pestarhamnoses A–C (1–3) have possibly similar phenol units compared with (ꢀ)-pestalachlorides C and D from the
same fungal strain in a different cultivation medium in our previous study [8]. Based on this point, we proposed that these
compounds were probably produced by the same biogenetic pathway. Our current research further confirmed the possibility of
our proposed biogenetic pathway of (ꢀ)-pestalachlorides C and D before [8]. Obviously, the production of pestarhamnoses A–C
(
1–3) was partly affected by the addition of KBr in the modified culture medium. Thus, it may be possible to use a
bromine-modified medium to discover new natural compounds from the same microorganism resources.
The antimicrobial activities of 1–3 against a panel of pathogenic bacteria, including Gram-positive bacteria
(
Bacillus subtilis, B. cereus, Kocuria rhizophila, Staphylococcus epidermidis, S. aureus, and S. albus) and Gram-negative
bacteria (Pseudomonas putida, Acinetobacter calcoaceticus, and Klebsiella pneumoniae), along with seven agricultural
pathogenic fungi (Colletotrichum capsici, Thielaviopsis paradoxa, Glorosprium musarum, Pestalotia mangiferae, Pestalotiopsis
theae, Setosphaeria turcica, and Aspergillus niger), were evaluated using a standard screening protocol [15]. However,
pestarhamnoses A–C (1–3) only showed weak antimicrobial activities in these assays.
Moreover, compounds 1–3 were also evaluated for their cytotoxic activities against human cervical carcinoma cell
line HeLa, human lung carcinoma cell line A549, human promyelocytic leukemia cell line HL-60, and human erythroleukemia
cell line K562 at a concentration of 20 ꢇM [16]. Pestarhamnoses A–C (1–3) only exhibited weak cytotoxic activities against
the tested cell lines.
In conclusion, three new rhamnosylated phenol derivatives, pestarhamnoses A–C (1–3), were isolated from a soft
coral-derived fungus Pestalotiopsis sp. cultured in a bromine-modified medium. The relative configurations of the rhamnosyl
1
moieties were determined by their anomeric J coupling constants, while the absolute structures were determined by HPLC
CH
analysis of the thiocarbamoyl-thiazolidine derivatives of the acid hydrolysates. To the best of our knowledge, this is the first
report of phenol glycosides with ꢁ-L-rhamnose in nature. PestarhamnosesA–C (1–3) showed weak antimicrobial and cytotoxic
activities.
1
082

EXPERIMENTAL
Melting points were determined on an X-6 micromelting point apparatus and are uncorrected. Optical rotations were
measured on a JASCO P-1020 digital polarimeter. UV spectra were obtained on a Beckman DU 640 spectrophotometer.
IR spectra were recorded on a Bruker EQUINOX 55 spectrometer using KBr pellets. NMR spectra were recorded on a JEOL
1
13
JEM-ECP NMR spectrometer (600 MHz for H and 150 MHz for C) and on a Bruker Avance 400 spectrometer (400 MHz
1
13
for H and 100 MHz for C). Chemical shifts ꢄ are reported in ppm using TMS as internal standard, and coupling constants
J) are in Hz. EI-MS spectra were measured on a Thermo DSQ EI-mass spectrometer, and HR-EI-MS on a Thermo MAT95XP
(
high-resolution mass spectrometer.APCIMS spectra were measured on an amaZon SLBRUKER spectrometer, and HR-ESI-MS
on a Thermo LTQ Orbitrap XL spectrometer. HPLC analysis and separation was performed in a Waters 1525 preparative
HPLC system coupled with a Waters 2996 photodiode array detector. A Kromasil C18 preparative HPLC column (250 ꢈ 10 mm,
5
4
ꢇm) was used. Silica gel (Qing Dao Hai Yang Chemical Group Co.; 200–300 mesh), octadecylsilyl silica gel (Unicorn;
5–60 ꢇm), and Sephadex LH-20 (GE Healthcare) were used for column chromatography (CC). Precoated silica gel plates
(
Yan Tai Zi Fu Chemical Group Co.; G60, F-254) were used for thin-layer chromatography (TLC).
Isolation of the Fungal Material and Identification of Fungal Cultures.The procedures are the same as in [8].
Fermentation, Extraction, and Isolation. The fungal strain Pestalotiopsis sp. (ZJ-2009-7-6) was cultivated on solid
rice medium (composition of artificial seawater: sea salt 15 g and KBr 15 g in 1 L distilled water; composition of medium:
parboiled rice in bromine-modified artificial seawater, in 1 L Erlenmeyer flask each containing 30 g rice and 30 mL
bromine-modified artificial seawater) in 60 Erlenmeyer flasks at 27ꢆC without shaking for 4 weeks. Then the culture was
extracted three times with an equal volume of CHCl –MeOH (1:1, v/v). The organic extracts were combined and concentrated
3
under vacuum to afford a dry crude extract. The resulting extract (9.8 g) was subjected to silica gel column chromatography
(
CC) (petroleum ether, EtOAc, v/v, gradient elution) to afford four fractions (Fr.1–Fr.4). Fraction 2 was subjected to silica gel
CC with petroleum ether–EtOAc (4:1, v/v) and Sephadex LH-20 CC eluting with mixtures of petroleum ether–CHCl –MeOH
3
(
2:1:1, v/v/v). Further purification by semipreparative HPLC using a C18 column eluting with 90% of MeOH–H O at a flow
2
rate of 2.0 mL/min yielded compounds 4 (7.7 mg) and 5 (3.5 mg). Fraction 4 was subjected to silica gel CC with CHCl –MeOH
3
(
9:1, v/v) and Sephadex LH-20 CC eluting with mixtures of CHCl –MeOH (1:1, v/v). Further purification by semipreparative
3
HPLC using an ODS C18 column eluting with 50% of MeOH–H O at a flow rate of 2.0 mL/min yielded 1 (8.0 mg), 2 (6.0 mg),
2
and 3 (3.5 mg).
2
6
Pestarhamnose A (1). Colorless solid, mp 72–74ꢆC; [ꢁ] ꢉ85.0ꢆ (c 0.405, MeOH). UV (MeOH, ꢅ , nm) (log ꢊ):
D
max
–
1
1
1
99 (2.88), 224 (2.76), 280 (2.67). IR (KBr, ꢋmax, cm ): 3456, 2925, 1643, 1562, 1416, 1375, 1262, 1148. For H NMR and
C NMR, see Table 1. EI-MS m/z 298 [M] ; HR-EI-MS m/z 298.1406 [M] (calcd for C H O , 298.1411).
Pestarhamnose B (2). Colorless solid, mp 169–171ꢆC; [ꢁ] –82.2ꢆ (c 0.190, MeOH). UV (MeOH, ꢅ , nm) (log ꢊ):
00 (2.51), 225 (2.32), 278 (2.18). IR (KBr, ꢋmax, cm ): 3456, 2927, 1643, 1556, 1458, 1386, 1129, 1057. For H NMR and
1
3
·+
·+
1
5 22 6
2
6
D
max
–
1
1
2
1
3
–
+
C NMR, see Table 1. APCIMS m/z 297.1 [M – H] ; HR-ESI-MS m/z 299.1485 [M + H] (calcd for C H O , 299.1489).
1
5 23 6
2
6
Pestarhamnose C (3). Colorless solid, mp 92–95ꢆC; [ꢁ] –90.3ꢆ (c 0.035, MeOH). UV (MeOH, ꢅmax, nm) (log ꢊ):
D
–
1
1
2
02 (3.05), 226 (2.93), 270 (2.86). IR (KBr, ꢋmax, cm ): 3439, 2918, 1654, 1555, 1450, 1378, 1269, 1133. For H NMR and
C NMR, see Table 1. APCIMS m/z 283.0 [M – H] ; HR-ESI-MS m/z 285.1329 [M + H] (calcd for C H O , 285.1333).
1
3
–
+
1
4 21 6
Acid Hydrolysis and Absolute Configuration Determination of Pestarhamnoses A–C (1–3). Pestarhamnoses A–C
1–3) (each 0.5 mg) were dissolved in 2 M CF COOH (aqueous) (1.0 mL) at 120ꢆC for 6 h. The mixture was evaporated to
(
3
dryness, and the residue was partitioned between CH Cl and H O. The aqueous phase was concentrated to furnish a
2
2
2
monosaccharide residue. After drying under vacuum, the residue was dissolved in 0.5 mL of pyridine containing 2 mg of
L-cysteine methyl ester hydrochloride and heated at 60ꢆC for 1 h. Phenyl isothiocyanate (2 ꢇL) was then added, and the
mixture was heated at 60ꢆC for 1 h. The reaction mixture was analyzed by reversed-phase HPLC with a Kromasil C18 preparative
HPLC column (250 ꢈ 10 mm, 5 ꢇm) at 30ꢆC with isocratic elution of 25% of MeOH–H O at a flow rate of 2.0 mL/min. The
2
injection volume was 10 ꢇL, and peaks were detected at 254 nm. The reaction conditions for authentic L-rhamnose were the
same as described above. The absolute configurations of the rhamnosyl moieties were determined by comparison of the
retention time of the thiocarbamoyl-thiazolidine derivative of the acid hydrolysate of 1–3 with that of standard samples of
L-rhamnose.
1
083

AntimicrobialAssays. The antimicrobial activities against nine pathogenic bacteria (B. subtilis, B. cereus, K. rhizophila,
S. epidermidis, S. aureus, S. albus, P. putida, A. calcoaceticus, and K. pneumoniae) and seven agricultural pathogenic fungi
(
C. capsici, T. paradoxa, G. musarum, P. mangiferae, P. theae, S. turcica, and A. niger) were evaluated by a serial dilution
technique using 96-well microtiter plates [15]. Ciprofloxacin and carbendazim were used as positive control in antibacterial
and antifungal assays, respectively. The results were observed with a Multiskan Mk3 (Thermo Labsystems).
Cytotoxicity Assays. The cytotoxic activities were evaluated against four human cancer cell lines (human cervical
carcinoma HeLa, human lung carcinoma A549, human promyelocytic leukemia HL-60, and human erythroleukemia K562) by
the MTT method [16]. Adriamycin was used as a positive control.
ACKNOWLEDGMENT
We thank Dr. X. Liu (Beijing CIQ) for HR-ESI-MS spectra and acknowledge funding from the Program of National
Natural Science Foundation of China (Nos. 41130858; 41322037; 41176121; 81172977), the Natural Science Foundation of
Shandong Province (Nos. ZR2011DQ019; ZR2011HM085), and the Program for New Century Excellent Talents in University,
Ministry of Education of China (No. NCET-11-0472).
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