Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780

Article abstract of DOI:10.1038/s41429-019-0143-6

Two new glutarimide antibiotics, 9-methylstreptimidone 2-α-d-glucopyranoside (1), and hydroxyiso-9-methylstreptimidone (2), along with a known compound, 9-methylstreptimidone (3), have been isolated from the broth of Streptomyces sp. HS-NF-780. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. By modified Mosher’s method and acid hydrolysis, the absolute configurations of compounds 1 and 2 were established. Compounds 1 and 2 exhibited moderate cytotoxic activity.

Full text of DOI:10.1038/s41429-019-0143-6

The Journal of Antibiotics
https://doi.org/10.1038/s41429-019-0143-6
BRIEF COMMUNICATION
Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780
Xue-Li Zhao1 Han Wang1 Zheng-Lian Xue2 Jian-Song Li3 Huan Qi3 Hui Zhang3 Tian Zhao1 Ji-Dong Wang2,3
Wen-Sheng Xiang1
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Received: 27 October 2018 / Revised: 8 January 2019 / Accepted: 11 January 2019
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2019
Abstract
Two new glutarimide antibiotics, 9-methylstreptimidone 2-α-D-glucopyranoside (1), and hydroxyiso-9-methylstreptimidone (2),
along with a known compound, 9-methylstreptimidone (3), have been isolated from the broth of Streptomyces sp. HS-NF-780.
Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as
ESI-MS and comparison with data from the literature. By modified Mosher’s method and acid hydrolysis, the absolute
configurations of compounds 1 and 2 were established. Compounds 1 and 2 exhibited moderate cytotoxic activity.
The antibiotics of the glutarimide group are structurally
characterized by the presence of glutarimide ring bearing a
side chain at the 1-position [1]. A number of distinct sub-
stances belonging to this class such as 9-methylstreptimidones
[2], cycloheximide [3, 4], and migrastatin [5, 6] have been
isolated from various species of Streptomyces [7]. Among
them, 9-methylstreptimidone showed strong inhibitory
activity against yeasts and filamentous fungi [1]. Besides,
9-methylstreptimidone inhibited NO production and iNOS
expression in LPS-stimulated RAW264.7 cells, and induced
apoptosis in Jurkat cells and adult T-cell leukemia cells,
similar to other NF-κB inhibitors [8]. In the course of our
screening program for novel microbe-derived bioactive
secondary metabolites, two new glutarimide derivatives
named 9-methylstreptimidone 2-α-D-glucopyranoside (1) and
hydroxyiso-9-methylstreptimidone (2), along with a known
compound, 9-methylstreptimidone (3) (Fig. 1), were isolated
from the culture broth of Streptomyces sp. HS-NF-780. In this
paper, we describe the fermentation, isolation, structure elu-
cidation, and bioactivity of the two new compounds.
The producing strain HS-NF-780 was isolated from a
soil sample collected from Linyi, Shandong province,
China using the standard dilution plate method. The strain
was identified as the genus Streptomyces because its
16S rRNA sequence (accession no: MH362834 in the
GenBank) exhibited a high-sequence similarity of 100%
with that of Streptomyces sp. NEAU-BGG209 (accession
no: MG820043).
Strain HS-NF-780 was grown and maintained for 7 days
at 28 °C on the YMS medium consisting of yeast
extract 4.0 g, malt extract 10.0 g, glucose 4.0 g, CoCl2·6H2O
0.005 g and agar 20.0 g in 1.0 l tap water at pH 7.0. The
stock culture was transferred into 1 l Erlenmeyer flasks
containing 250 ml of the seed medium and incubated at 28 °
C for 48 h on a rotary shaker at 250 r.p.m. The seed medium
was composed of glucose 4.0 g, malt extract 10.0 g and
yeast extract 4.0 g in 1.0 l tap water, pH 7.0. All of the
media were sterilized at 121 °C for 20 min. The seed culture
(5%) was transferred into 1 l Erlenmeyer flasks containing
25% volume of production medium. The production med-
ium was composed of glucose 1%, soluble starch 4%, yeast
extract 0.4%, malt extract 1%, CaCO3 0.2%, FeSO4·7H2O
0.1%, ZnSO4·7H2O 0.1%, and MnCl2·4H2O 0.1% at pH
7.2–7.4. The flasks were incubated at 28 °C for 7 days,
shaken at 250 r.p.m.
Supplementary information The online version of this article (https://
doi.org/10.1038/s41429-019-0143-6) contains supplementary
material, which is available to authorized users.
* Ji-Dong Wang
jdwang@hisunpharm.com
* Wen-Sheng Xiang
xiangwensheng@neau.edu.cn
1
Life Science and Biotechnology Research Center, School of Life
Science, Northeast Agricultural University, Harbin, China
2
College of Biochemical Engineering, Anhui Polytechnic
University, Wuhu, China
The final 20 l fermentation broth was filtered to sepa-
rate mycelial cake and supernatant. The mycelial cake was
washed with water (3 l) and subsequently extracted with
3
Zhejiang Key Laboratory of Antifungal Drugs, Zhejiang Hisun
Pharmaceutical Co., Ltd, Taizhou, China

X.-L. Zhao et al.
12
7
11
5
10
9
MS and HR-ESI-MS spectra were taken on a Q-TOF
Micro LC-MS-MS mass spectrometer (Waters Co, Mil-
ford, MA, USA).
1
3
O
2
4
Compound 1 was isolated as colorless oil with [α]2D5 + 125
(c 0.03, EtOH) and UV (EtOH) λmax nm (log ε): 233 (4.02).
Its molecular formula was determined to be C23H35NO9 by
HRESIMS at m/z 492.2207 [M + Na]+ (calcd as 492.2204 for
C23H35NO9Na) and NMR data (Table 1). In the IR spectrum
of 1, absorption at 3447, 3197, and 1689 cm−1 indicated the
presence of hydroxyl, imide, and carbonyl groups, respec-
tively. Analysis of 1H NMR spectrum (Table 1) of 1 revealed
the presence of three olefinic protons at δH 5.19 (1 H, br d, J
= 9.8 Hz), 5.48 (1 H, m), 5.82 (1 H, br d, J = 11.6 Hz), one
anomeric proton at δH 4.87 (1 H, d, J = 3.9 Hz), one oxyge-
nated methylene at δH 3.64 (1 H, dd, J = 11.9, 5.3 Hz), 3.78
(1 H, dd, J = 11.9, 2.1 Hz), five oxygenated methine protons
from δH 3.27 to δH 4.19, two olefinic methyls at δH 1.77 (3 H,
dd, J = 7.2, 2.6 Hz), 1.86 (3 H, d, J = 1.2 Hz), one
doublet aliphatic methyl at δH 1.14 (3 H, d, J = 6.8 Hz). The
13C NMR and DEPT135 spectra (Table 1) of 1 showed 23
resonances attributable to one carbonyl carbon at δC 212.1,
two amide carbonyl carbons at δC 175.4 and 175.4, three sp2
methines at δC 125.8, 129.7, 134.1, one sp2 quaternary carbon
at δC 136.7, one anomeric carbon at δC 99.1, five oxygen-
bearing aliphatic methines between 71.6 and 75.0 ppm, one
oxygenated methylene at δC 62.5, two aliphatic methines at δC
28.2, 48.2, four aliphatic methylenes at δC 37.9, 39.2, 41.4,
44.8, and three methyl carbons at δC 15.0, 16.7, 17.5. Com-
parison of the 1H and 13C NMR data (Table 1) of 1 with those
of 3 revealed significant similarities. The differences between
1 and 3 were that 1 showed six extra 13C resonances. The six
extra 13C resonances were postulated to glucose moiety
according to one doublet anomeric proton (δH 4.87), one
oxygenated methylene (δH 3.64, 3.78) and four oxygenated
1'
3'
6
8
HN
OR
O
5'
O
1 R = a-D-glucose
3 R = H
12
11
OH
1
3
O
2
4
5
9
7
1'
3'
10
8
6
HN
OH
O
5'
O
2
Fig. 1 Structures of compounds 1, 2, and 3
MeOH (3 l) and the supernatant was subjected to a Diaion
HP-20 resin (Mitsubushi Chemical, Tokyo, Japan) col-
umn eluting with 95% EtOH (5 l). The MeOH extract and
the EtOH eluents were evaporated under reduced pressure
at 55 °C to yield the crude extract. The crude extract was
chromatographed on a silica gel (Qingdao Haiyang Che-
mical Group, Qingdao, China; 100-200 mesh) column and
successively eluted with a stepwise gradient of CHCl3/
MeOH (100:0-50: 50, v/v) to give three fractions (Fr.1-
Fr.3) based on the TLC profiles. TLC was performed on
silica-gel plates (HSGF254, Yantai Chemical Industry
Research Institute, Yantai, China) with solvent system of
CHCl3/MeOH (9:1, v/v) and the developed TLC plates
were observed under a UV lamp at 254 nm or by heating
after spraying with sulfuric acid-ethanol, 5:95 (v/v). The
Fr.2 was subjected to another silica gel column eluted
with CHCl3/MeOH (95:5-60:40, v/v) to give six fractions
(Fr.2-1-Fr.2-6). The Fr.2-4 was further purified by semi-
preparative HPLC (Agilent 1100, Zorbax SB-C18, 5 μm,
3
methine protons. The relatively small JHH value (3.9 Hz) of
the anomeric proton suggested an α linkage [9]. The linkage
of the glucose to the aglycone was established by the HMBC
correlation (Fig. 2) from H-1″ to C-2. The NOESY correla-
tions (Fig. 2) between H-5 and H3-12, H-6 and H-8 demon-
strated the geometry of Δ6,7 was E. In the 1H NMR spectrum
of 1, the coupling constant between H-8 and H-9 was 11.6
Hz, indicating the geometry of Δ8,9 was Z. Furthermore, the
presence of glucose was evidenced by the acid hydrolysis.
Compound 1 (2.5 mg) was dissolved in 2 ml of 2 M HCl and
heated for 2 h at 80 °C, followed by neutralization with
NaHCO3. The reaction mixture was extracted with CHCl3 to
separate a sugar moiety-containing aqueous fraction from the
aglycone-containing fraction. The aqueous fraction was
identified by cochromatography with authentic glucose on
TLC analysis using ethyl acetate/pyridine/glacial acetic acid/
H2O (8: 5: 1: 1.5, v/v) as a developing solvent. Spots were
detected by heating after spraying with sulfuric acid-ethanol
(5:95, v/v). The identical Rf values of the aqueous fraction
250 × 9.4 mm inner diameter; 1.5 ml min−1
; 254 nm;
Agilent, PaloAlto, CA, USA) eluting with CH3CN/H2O
(20:80, v/v) to obtain compound 1 (tR 24.68 min, 18.0
mg). The Fr.2-3 was separated by semi-preparative HPLC
eluting with CH3CN/H2O (25:75, v/v) to afford compound
2 (tR 20.13 min, 14.2 mg). The Fr.1 was subjected to a
Sephadex LH-20 (GE Healthcare, Glies, UK) column
eluted with CHCl3/MeOH (1:1, v/v) and detected by TLC
to give two subfractions (Fr.1-1-Fr.1-2). The Fr.1-2 was
isolated by semi-preparative HPLC eluting with CH3CN/
H2O (35:65, v/v) to give compound 3 (tR 25.06 min, 23.5
mg). 1H and 13C NMR spectra were measured with a
Bruker DRX-400 (400 MHz for H and 100 MHz for 13C)
spectrometer (Bruker, Rheinstetten, Germany). The ESI-
1

Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780
Table 1 The NMR spectroscopic data of compounds 1–3
Position
1 (in CD3OD)
2 (in CD3OD)
3 (in CDCl3)
δH (J in Hz)
δC
41.4
δH (J in Hz)
δC
42.9
δH (J in Hz)
1
2
3
1.50 m 1.73 m
4.19 m
1.51 m1.56 m
4.20 m
1.29 m 1.54 m
4.08 m
72.6
44.8
66.8
46.3
2.72 dd (17.6, 7.5)
2.96 dd (17.6, 4.6)
2.81 dd (16.2, 4.6)
2.98 dd (16.2, 7.6)
2.55 m
2.64 m
4
212.1
48.2
203.2
137.2
144.7
133.5
140.4
65.2
5
3.55 m
3.62 m
6
5.19 br d (9.8)
129.7
136.7
134.1
125.8
15.0
6.99 s
5.12 d (9.6)
7
8
5.82 br d (11.6)
5.48 m
5.63 d (8.2)
4.66 m
5.74 d (11.7)
5.42 m
9
10
11
12
1′′
2′
3′
4′
5′
1″
2″
3″
4″
5″
6″
1.77 dd (7.2, 1.8)
1.14 d (6.8)
1.86 d (1.2)
1.28 d (6.3)
1.95 s
23.4
1.72 dd (7.2, 1.7)
1.11 d (6.8)
1.80 d (1.2)
16.7
13.2
17.5
1.92 s
16.7
175.4
39.2
175.6
38.0
2.31 m 2.60 m
2.35 m
2.36 m 2.75 m
2.38 m
2.24 m 2.70 m
2.40 m
28.2
28.7
2.31 m 2.77 m
37.9
2.38 m2.68 m
39.2
2.24 m 2.70 m
175.4
99.1
175.5
4.87 d (3.9)
3.34 m
73.2
3.27 t (12.4)
3.57 m
71.6
74.5
3.52 m
75.0
3.78 dd (11.9, 2.1)
3.64 dd (11.9, 5.3)
62.5
with that of authentic glucose indicated that the sugar moiety
of 1 was glucose. The aglycone-containing fraction was
subjected to reverse phase HPLC for analysis, with a Zorbax
B-C18 column (Agilent 1100, 250 × 9.4 mm inner diameter,
5 μm), mobile phase of CH3CN/H2O (35:65, v/v), flow rate at
1.5 ml min−1, and detection wavelength at 220 nm. Under
these conditions, the aglycone-containing fraction gives peak
at tR (min) = 25.06. The peak of the known compound
9-methylstreptimidone (3) was detected at tR (min) = 25.11.
The retention time of the aglycone moiety of 1 was in good
agreement with 3, which suggested that the aglycone moiety
of 1 was 9-methylstreptimidone. In order to determine the
absolute configuration of the glucose moiety in 1, the sugar
residue was dissolved in pyridine (3 ml) containing L-cysteine
methyl ester hydrochloride (1 mg) and heated at 60 °C for 1 h.
A total of solution of O-torylisothiocyanate (25 μl) was added
to the mixture, which was heated at 60 °C for a further 1 h.
The mixture was analyzed by reversed-phase HPLC (Ame-
thyst C18-H, 5 μm, 250 × 4.6 mm inner diameter; 0.8 ml min
−1; 250 nm) at 35 °C eluting with CH3CN/H2O (25:75, v/v).
Under these conditions, standard sugar gave peak at tR (min)
= 21.658 for D-glucose. The peak of the sugar residue was
detected at tR (min) = 21.789, which identified as D-glucose
by comparison with the retention time of the authentic sample
[10–12].
Compound 2 was isolated as pale yellowish oil with
optical rotation of [α]2D5 + 105 (c 0.03, EtOH) and UV
(EtOH) λmax nm (log ε): 276 (4.10). HR-ESI-MS showed a
molecular ion peak at m/z 346.1625 [M + Na]+ (calcd for
C17H25NO5Na, 346.1625), indicating a molecular formula
of C17H25NO5. In the IR spectrum of 2, absorption at 3419
and 1684 cm−1 indicated the presence of hydroxyl and
1
carbonyl groups, respectively. Analysis of H NMR spec-
trum (Table 1) of 2 revealed the presence of two olefinic
protons at δH 5.63 (1 H, d, J = 8.2 Hz), 6.99 (1 H, s), two
oxygenated methine protons at δH 4.20 (1 H, m), 4.66
(1 H, m), two olefinic methyl carbons at δH 1.92 (3 H, s),
1.95 (3 H, s), one doublet aliphatic methyl at δH 1.28 (3 H,
d, J = 6.3 Hz). The 13C NMR and DEPT135 spectra
(Table 1) of 2 showed 17 resonances attributable to one
carbonyl carbon at δC 203.2, two amide carbonyl carbons at
δC 175.5 and 175.6, two sp2 methines at δC 140.4, 144.7,

X.-L. Zhao et al.
MTPA
O
+0.14
+0.18
+0.07
+0.11
-0.30
-0.37
O
O
+0.14
-0.12
+0.13
+0.15
+0.21
HN
O
O
HN
O
O
H
APTM
1''
O
OH
O
O
Fig. 3 Δδ values for the MTPA esters (1a, 1b); Δδ (ppm) = δS 1a − δR 1b
3''
5''
MTPA
O
OH
+0.12
+0.18
+0.09
+0.12
-0.30
-0.34
HO
OH
O
+0.13
1
+0.17
-0.02
+0.13
+0.21
OH
HN
O
O
APTM
O
O
Fig. 4 Δδ values for the MTPA esters (2a, 2b); Δδ (ppm) = δS 2a − δR 2b
HN
OH
O
2
O
modified Mosher’s method [14, 15]. To a solution of
compound 2 (2.5 mg) in dry pyridine (200 μL) was added
(−)-MTPA chloride (15 μl), and the solution was stirred at
room temperature for 1 h. The reaction mixture was frac-
tionated by semi-preparative HPLC eluting with CH3CN/
H2O (80:20, v/v) to afford (S)-MTPA esters 1a (tR
19.82 min, 1.2 mg) and 2a (tR 20.39 min, 1.0 mg). In the
same way, by using (+)-MTPA chloride, the compound 2
(2.5 mg) was converted into a mixture. The mixture was
isolated by semi-preparative HPLC eluting with CH3CN/
H2O (85:15, v/v) to obtain (R)-MTPA esters 1b (tR 26.18
min, 1.0 mg) and 2b (tR 27.43 min, 1.0 mg). Based on the
1H-1H COSY
HMBC
NOESY
Fig. 2 Key H-1H COSY, HMBC, and NOESY correlations of com-
1
pounds 1 and 2
two sp2 quaternary carbons at δC 133.5, 137.2, one aliphatic
methine at δC 28.7, two oxygenated methines at δC 65.2,
66.8, four methylenes at δC 38.0, 39.2, 42.9, 46.3, and three
methyl resonances at δC 13.2, 16.7, 23.4. The complete
assignment of all H and 13C NMR spectral data of 2 was
1
subsequently accomplished by the H-1H COSY, HSQC
MTPA determination rule, calculating △δ (ppm) = δS 1a
−
1
and HMBC spectra. The correlations between H-3′/H2-1/H-
δ
R 1b (Fig. 3), the absolute configuration at C-2 was assigned
1
2/H2-3, H-8/H-9/H3-10 protons in the H-1H COSY spec-
as R and the absolute configuration at C-9 was assigned as
R. However, calculating △δ (ppm) = δS 2a − δR 2b (Fig. 4),
the absolute configuration at C-2 was assigned as R and the
absolute configuration at C-9 was assigned as S. It showed
that 2 was a C-9 epimeric mixture. Chiral HPLC analysis of
2 with a CElluose-C column and mobile phase of
CO2/MeOH further indicated that 2 was the epimeric mix-
ture in a ratio of ~3:2.
Compound 3 was isolated as pale yellowish oil. Its
structure was elucidated as 9-methylstreptimidone by ana-
lysis of its 1H NMR and ESI-MS spectral data (Table 1) and
comparison with literature values [16].
The cytotoxicity of 1 and 2 was assayed for growth-
inhibition activity in vitro against three human tumor cell
lines, human erythroleukemia cell line K562, human breast
cancer cell line MCF-7, and human colon carcinoma cell
line HCT-116 according to the CCK8 colorimetric method
as reported in our previous papers [17, 18] using
trum (Fig. 2) indicated the presence of two structural units
of C-3′–C-3 and C-8–C-10. The observed HMBC correla-
tions (Fig. 2) from H-2, H-6 to C-4, from H3-11 to C-4, C-5,
C-6, from H3-12 to C-6, C-7, C-8 established the linkage of
C-3′–C-10. A glutarimide ring was defined by two amide
carbonyl carbons at δC 175.5 and 175.6, which were cou-
pled long range in an HMBC experiment to the protons
(Table 1) of a four protons pair of methylene signals at δH
2.36 (1 H, m), 2.38 (1 H, m), 2.68 (1 H, m), 2.75 (1 H, m),
which were in turn coupled in a 1H-1H COSY spectrum to a
single methine proton signal at δH 2.38 (1 H, m) [13]. On
the basis of the above spectroscopic data, a gross structure
of 2 was established (Fig. 1). The NOESY correlation
(Fig. 2) between H3-11 and H3-12 demonstrated the geo-
metry of Δ5,6 was E. The geometry of Δ7,8 was also
assigned as E by the NOESY correlation between H-6 and
H-8. The absolute configuration of 2 was determined by the

Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780
Table 2 Cytotoxic activity of 1 and 2 against selected human tumor
cell lines
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Acknowledgements This work was supported in part by grants from
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