Oridamycins A and B, anti- saprolegnia parasitica indolosesquiterpenes isolated from streptomyces sp. KS84

Article abstract of DOI:10.1021/np1000522

Oridamycins A (1) and B (2) were isolated from the fermentation broth of Streptomyces sp. strain KS84 as selective anti-Saprolegnia parasitica antibiotics. Their structures were elucidated as pentacyclic indolosesquiterpenes by the combination of NMR and spectroscopic analyses. The absolute configuration of 1 was determined by ROESY analyses after the advanced Mosher analysis. Compound 1 exhibited anti-S. parasitica activity with an MIC value of 3.0 μg/mL, but was much less active against the phytopathogenic fungus Phoma sp. and the yeast Saccharomyces cerevisiae.

Full text of DOI:10.1021/np1000522

698
J. Nat. Prod. 2010, 73, 698–701
Oridamycins A and B, Anti-Saprolegnia parasitica Indolosesquiterpenes Isolated from
Streptomyces sp. KS84
Kentaro Takada,† Hisatsugu Kajiwara,‡ and Nobutaka Imamura*,†,‡
Laboratory of Microbial Chemistry, College of Pharmaceutical Sciences, Ritsumeikan UniVersity, 1-1-1 Noji-Higashi, Kusatsu,
Shiga 525-8577, Japan, and College of Science and Engineering, Ritsumeikan UniVersity, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan
ReceiVed January 25, 2010
Oridamycins A (1) and B (2) were isolated from the fermentation broth of Streptomyces sp. strain KS84 as selective
anti-Saprolegnia parasitica antibiotics. Their structures were elucidated as pentacyclic indolosesquiterpenes by the
combination of NMR and spectroscopic analyses. The absolute configuration of 1 was determined by ROESY analyses
after the advanced Mosher analysis. Compound 1 exhibited anti-S. parasitica activity with an MIC value of 3.0 µg/mL,
but was much less active against the phytopathogenic fungus Phoma sp. and the yeast Saccharomyces cereVisiae.
Saprolegnia spp. is one genus of water molds, with characteristics
of both fungi and algae. A series of morphological alterations
including sporangial formation, sporulation, and the extension of
vegetative hyphae are similar to those of fungi.1 Taxonomically,
the genus Saprolegnia belongs to the division Oomycota. Sapro-
legnia spp. infect freshwater fish and ova, creating a condition
referred to as saprolegniasis, and can be easily detected by visible
white patches of filamentous mycelia on fish skin. Saprolegniasis
causes severe damage in commercial aquacultures, including those
of salmon, trout, and sea eels, and in noncommercial aquariums.
Saprolegnia infects the surface of the fish body after an invasion
of epidermal tissues, causing epidermal damage and cellular
necrosis. Severe Saprolegnia infections can be fatal. In the past,
malachite green, an organic dye, had been used to prevent
Figure 1. (a) Summary of 2D NMR analyses: (bold lines) 1H-1H
Saprolegnia infections in aquacultures.2 However, this practice has
COSY correlations; (arrows) key HMBC correlations. (b) ROE
been banned worldwide because malachite green is toxic to human
correlations to determine the position of the NH group in DMSO-
cells and induces liver tumor formation.3,4 Therefore, there is an
urgent need for developing novel alternative compounds to control
d6.
saprolegniasis.
of multistep fractionation procedures, resulting in the isolation of
In the course of discovering anti-S. parasitica compounds from
two anti-Saprolegnia compounds, named oridamycins A (1, 6.4 mg)
microorganism extracts, we found an extract that was more active
and B (2, 2.0 mg).
against S. parasitica than against the fungus Phoma sp. or the yeast
The molecular formula of oridamycin A (1) was determined as
Saccharomyces cereVisiae. In the work described herein, we show
C23H25NO3 by its HRFABMS spectrum. The IR spectrum implied
the isolation, structure elucidation, and biological activity of two
the presence of a carboxylic acid group (1610 cm-1) and hydroxy
novel indolosesquiterpenes, oridamycins A (1) and B (2), which
are the first indolosesquiterpenes from prokaryotes.
1
group (3405 cm-1). An initial analysis of the H NMR spectrum
of 1 showed that there were six aromatic protons, an oxymethine
proton, and two aliphatic methyl groups. Analyses of 13C NMR,
DEPT, and HMQC spectra indicated the presence of an oxymethine
group, an aliphatic methine group, four methylene groups, and nine
quaternary carbons (one carbonyl, six aromatic, and two aliphatic
carbons). Furthermore, four successively coupled aromatic protons
and two isolated aromatic protons suggested the presence of two
aromatic rings, one of which was 1,2-disubstituted and the other
of which was 1,2,4,5-tetrasubstituted. A 1H-1H COSY analysis in
the aliphatic region revealed two partial structures, C-1 to C-3 and
C-5 to C-7 (Figure 1a, bold lines), both of which are connected by
HMBC correlations from two methyl groups, H-18/C-1, C-5, C-14a
Results and Discussion
The bacterial source of these compounds was isolated from a
and H-17/C-3, C-4, C-5 (Figure 1a, arrows). Further HMBC
soil sample collected in Uji, Kyoto, Japan, and was identified as a
correlations of H-3, H-5, and H-17/C-16 indicated that the car-
Streptomyces sp. by 16S rDNA phylogenetic analysis. The fer-
boxylic acid group was connected to C-4. Further HMBC correla-
mentation of the strain was performed for 168 h in starch-casein
tions of H-8/C-7 and H-14/C-15 revealed that the bicyclic moiety
medium at 30 °C with agitation and aeration. The filtrate of this
was conjugated to an aromatic ring involving the singlet aromatic
culture (8 L) broth was extracted with EtOAc, followed by a series
protons H-8 and H-14. The remaining functional group from the
molecular formula was an NH group. This amine group was clearly
* To whom correspondence should be addressed. Tel: +81-77-561-2825.
located between two benzene rings, bridging either C-8a and C-9a
Fax: +81-77-561-5203. E-mail: imamura@ph.ritsumei.ac.jp.
† College of Pharmaceutical Sciences.
‡ College of Science and Engineering.
or C-13a and C-13b. To determine the whole planar structure of 1,
a ROESY spectrum was acquired in DMSO-d6. This experiment
10.1021/np1000522  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/06/2010

Anti-Saprolegnia parasitica Indolosesquiterpenes
Journal of Natural Products, 2010, Vol. 73, No. 4 699
droplet synthesis in macrophages19 and was the first metabolite with
an indolosesquiterpene core obtained from a microorganism.
Lecanindole D (6) and three congeners, lecanindoles A-C, are
additional indolosesquiterpenes isolated from the terrestrial fungus
Verticillium lecanii 6144.20 Compound 6 exhibited potent and
selective agonist activity at the progesterone receptor. The novel
compounds (1 and 2) from the broth of a Streptomyces sp. in this
study are the first indolosesquiterpenes isolated from a prokaryote.
A biosynthetic study of sespendole by feeding experiments with
acetate, anthranilic acid, and tryptophan revealed that the indolos-
esquiterpene core was constructed by a cyclization after the
condensation of a farnesyl residue derived from the mevalonate
pathway with an anthranilate-derived indole-3-glycerol phosphate.21
In the current study, feeding experiments with anthranilic acid and
tryptophan resulted in a broth that did not contain the desired
compounds (data not shown). This inconclusive result prevents any
conclusions regarding the biosynthesis of the indole units in 1
and 2.
Figure 2. Key ROE correlations. Solid and dashed arrows indicate
ROE correlations on the R- and ꢀ-faces, respectively.
Figure 3. Results of the advanced Mosher’s method. ∆δ (δS -
δR) values were obtained from the 1H NMR and COSY spectra of
(R)- and (S)-MTPA esters.
yielded several cross-peaks including δ 10.86 (NH)/δ 7.03 (H-8)
and δ 10.86 (NH)/δ 7.35 (H-10), indicating that the position of the
amine group was as described in Figure 1b. Thus, the planar
structure of 1 was determined to be that of a pentacyclic indolos-
esquiterpene.
The biological activity of compounds 1 and 2 was assessed with
S. parasitica, Phoma sp., and S. cereVisiae assays. Compound 1
exhibited an anti-S. parasitica activity with an MIC value of 3.0
µg/mL. It was much less active toward Phoma sp. (242 µg/mL)
and exhibited no activity against S. cereVisiae even at a concentra-
tion of 1000 µg/mL. Compound 2, the 17-hydroxymethyl analogue
of 1, exhibited 100-fold lower activity against S. parasitica
compared to that of 1. These results demonstrate the efficacy of 1
as a selective anti-S. parasitica antibiotic.
The relative configuration of the bicyclic moiety in 1 was
determined by the ROESY spectrum in CD3OD (Figure 2). ROESY
correlations between H-2R and H-18 and between H-6R and H-18
indicated that H-2R, H-6R, and H-18 were located on the same
R-face, while H-1ꢀ, H-3, H-5, and H-17 were on the ꢀ-face. The
absolute configuration at C-3 was determined by applying the
advanced Mosher’s method to the secondary hydroxyl group.5
Compound 1 was treated with (S)-(+)- and (R)-(-)-MTPA chloride
to afford (R)-(+)- and (S)-(-)-MTPA esters (3 and 4), respectively.
After the purification of each derivative, all 1H NMR chemical shifts
in 3 and 4 were assigned by a combination of COSY and HMQC
analyses. A consistent distribution of positive and negative ∆δ
values around C-3 (Figure 3) revealed that the absolute configuration
of C-3 was S, thereby resulting in the configurational assignment
of 4R, 5R, and 15S.
Experimental Section
General Experimental Procedures. Optical rotations were measured
on a Perkin-Elmer 343 digital polarimeter in MeOH. UV absorptions
were measured on a Jasco V-630 spectrophotometer. IR spectra were
1
recorded on a Shimadzu FT/IR-8600 spectrometer. H and 13C NMR
and all 2D NMR spectra were recorded on a JEOL ECA600 NMR
spectrometer at 293 K for both compounds. 1H and 13C NMR chemical
shifts were referenced to the solvent peaks: δH 3.30 and δC 49.0 for
CD3OD and δH 2.49 and δC 40.0 for DMSO-d6. ESI mass spectra were
obtained on an Applied Biosystem API-3200 triple quadrupole mass
spectrometer using a MeCN/H2O with 0.1% AcOH solvent system.
Isolation of Oridamycins A and B. Streptomyces sp. KS84 was
isolated from a soil sample collected in Uji City, Kyoto, Japan. The
taxonomy of the strain was determined by a 16 rDNA analysis
(accession no. AB550852). Streptomyces sp. KS84 was deposited in a
culture collection of the National Institute of Advanced Industrial
Science and Technology (AIST), Japan (accession no. FERM AP-
21858). The fermentation was performed in starch-casein medium
(1.0% starch, 0.03% casein, 0.2% NaCl, 0.2% K2HPO4, 0.005% MgSO4,
0.002% CaCO3, 0.001% FeSO4, pH 7.2, 10 L) for 168 h at 30 °C with
agitation and aeration. The filtrate of this culture broth was extracted
with EtOAc. The active EtOAc extract was separated by ODS
chromatography with aqueous MeCN. The 50% MeCN eluate was
purified by reversed-phase HPLC (Cosmosil ARII; 10 × 250 mm) with
a 30%-60% MeCN gradient to afford oridamycins A (1, 6.4 mg) and
B (2, 2 mg).
The molecular formula of oridamycin B (2) determined as
C23H25NO4 by its HRFABMS spectrum revealed an extra oxygen
compared to 1. The characteristic UV absorptions at 215, 237, 261,
and 300 nm and IR spectrum (1635, 3385 cm-1) implied that 2
had a similar structure to that of 1. Indeed, the appearance of an
oxymethylene signal (δ 3.92 and 4.09) and the lack of a methyl
1
group in the H NMR spectrum of 2 suggested that the methyl
group in 1 was replaced by a hydroxymethyl group. HMBC
correlations between H-17R (δ 3.92)/C-3, C-4, and C-5 suggested
that the hydroxymethyl group was bound to C-4. The remaining
structure of 2 was the same as that of 1, as elucidated by standard
1D and 2D NMR analyses. Also, all relative configurations in 2
were the same as those of 1 by ROESY analysis.
Several indolosesquiterpenes such as polyalthenol,6 suaveolin-
dole,7 greenwayodendrine,8 polyavolinamide,9 polyveoline,10 and
3-farnesylindole derivatives11,12 have been reported from plants.
Until recently, no indolosesquiterpenes had been isolated from
bacteria, although indoloditerpenes, such as paspalicine,13 pax-
illine,14 janthitrems,15 lolitrems,16 and penitrems,17 have been
isolated from fungi. Sespendole18 (5) was isolated from the
filamentous fungus Pseudobotrytis terrestri as an inhibitor of lipid
Oridamycin A (1): pale yellow solid; [R]20D +92 (c 0.10, MeOH);
UV (MeOH) λmax (log ε) 216 (4.34), 238 (4.46), 262 (4.11), 300 (4.11)
nm; IR (film) νmax 3405, 2880, 1610 cm-1 13C and 1H NMR data, see
;
Table 1; HR-FABMS m/z 362.1743 [M - H]- (calcd for C23H24NO3,
362.1762).
Oridamycin B (2): pale yellow solid; [R]20D +110 (c 0.02, MeOH);
UV (MeOH) λmax (log ε) 216 (4.70), 238 (4.78), 261 (4.45), 300 (4.43)

700 Journal of Natural Products, 2010, Vol. 73, No. 4
Takada et al.
Table 1. NMR Spectroscopic Data (500 MHz, CD3OD) of Oridamycins A (1) and B (2)
oridamycin A (1)
oridamycin B (2)
δH (J in Hz)
no.
δC
δH (J in Hz)
HMBCa
ROESY
δC
1R
1ꢀ
2R
2ꢀ
3
40.0
2.57, dt (13.6, 3.6)
1.58, dt (4.1, 13.6)
2.30, dq (3.6, 13.6)
1.90, dq (13.6, 3.6)
3.22, dd (12.2, 4.6)
3, 5
18
3, 15
15
1ꢀ, 2R, 2ꢀ, 3, 14, 18
1R, 2ꢀ, 3, 5
39.7
2.60, dt (13.0, 3.5)
1.59, m
2.41, dq (4.1, 13.0)
1.95, m
30.3
1R, 2ꢀ, 18
29.8
1R, 1ꢀ, 2R, 3
1ꢀ, 2ꢀ, 5, 17
79.1
48.7
54.1
22.5
16, 17
73.3
55.5b
46.3
22.1
3.73, dd (12.4, 4.8)
4
5
1.51, dd (12.2, 2.3)
2.09, dt (5.4, 12.7)
2.23, m
3.06, ddd (16.3, 5.4, 2.3)
2.94, ddd (16.7, 12.7, 2.3)
3, 4, 6, 7, 15, 16
5, 7, 15
5, 7, 7a, 15
5, 6, 7a, 8, 14a
6, 7a, 14a
1ꢀ, 3, 6ꢀ, 7ꢀ, 17
6ꢀ, 7R, 18
5, 6R, 7ꢀ, 17
6R, 7ꢀ, 8
5, 6ꢀ, 7R
1.92, dd (12.2, 2.3)
2.08, m
2.17, m
6R
6ꢀ
7R
7ꢀ
7a
8
34.0
33.3
3.04, dd (10.3, 4.1)
134.5
111.4
140.1
134.5
110.5
140.0
7.03, s
7, 13b
7R, 7ꢀ
7.05, s
8a
9
9a
10
11
12
13
13a
13b
14
14a
15
16
17R
17ꢀ
18
142.0
126.1
110.7
119.3
120.6
124.6
123.2
117.5
140.3
39.6
141.9
125.9
111.3
119.2
120.4
124.5
123.2
117.2
140.5
39.2
7.32, d (8.1)
12, 13a
9a, 13
13a
7.33, d (7.9)
7.25, dt (1.4, 8.1)
7.05, dt (1.4, 8.1)
7.93, d (8.1)
7.27, dt (1.4, 7.9)
7.06, dt (1.4, 7.9)
7.95, d (7.9)
9a, 12
7.93, s
7a, 8a, 15
1R, 18
7.95, s
181.0
24.8
179.2b
64.4
1.48, s
1.26, s
3, 4, 5, 16
3, 6ꢀ
3.92, d (11.0)
4.09, d (11.0)
1.31, s
24.6
1, 5, 14a, 15
1R, 2R, 6R, 14
25.0
a HMBC correlations are from protons stated to the indicated carbon. b Chemical shifts were assigned from HMBC data.
nm; IR (film) νmax 3385, 2900, 1635 cm-1; H and 13C NMR data, see
Table 1; HMBC H-1R/C-3, and C-5, H-3/C-16, H-5/C-4, C-6, C-7, C-15,
C-16, and C-18, H-7/C-5, C-7a, C-8, and C-14a, H-8/C-7, C-13b, and
C-14a, H-10/C-12 and C-13a, H-11/C-9a and C-12, H-12/C-11, C-13a,
H-14/C-7a, C-8a, C-13b, and C-15, H-17R/C-3, C-4, C-5, and C-16, H-17ꢀ/
C-3 and C-5, H-18/C-1, C-5, C-14a, and C-15; ROESY H-1R/H-1ꢀ, H-2R,
H-2ꢀ, H-14, and H-18, H-1ꢀ/H-1R, H-2ꢀ, H-3, and H-5, H-2R/H-1R, H-2ꢀ,
and H-18, H-2ꢀ/H-1R, H-1ꢀ, H-2R, and H-3, H-3/H-1ꢀ, H-2ꢀ, H-5, H-17R,
and H-17ꢀ, H-5/H-1ꢀ, H-3, H-6ꢀ, H-7, H-17R, and H-17ꢀ, H-6R/H-6ꢀ,
H-7, and H-18, H-6ꢀ/H-5, H-6R, H-7, H-17R, and H-17ꢀ, H-8/H-7, H-14/
H-1R and H-18, H-17R/H-3, H-5, H-6ꢀ, and H-17ꢀ, H-17ꢀ/H-3, H-5,
H-6ꢀ, and H-17R, H-18/H-1R, H-2R, H-6R, and H-14; HR-FABMS m/z
378.1729 [M - H]- (calcd for C23H25NO4, 378.1711).
Anti-Phoma sp. Assay. The phytopathogenic fungus Phoma sp. was
isolated from leaves collected at Ritsumeikan University. The taxonomy
of the strain determined by a 18 rDNA analysis showed 99% similarity
to the fungus Phoma sp. CCF3818 (accession no. FJ430776). The
fungus was cultured in Sabouraud agar media (40 g maltose, 10 g
peptone, 1 L distilled H2O, pH 6.0). A piece of the grown agar medium
was cut and homogenized to form a mycelial suspension. The method
of the anti-Phoma sp. assay was the same as that employed with the
anti-S. parasitica assay apart from the medium (Sabouraud medium)
and incubation temperature (30 °C). A solution of cycloheximide (25
µg/mL) was used as a positive control.
Anti-Saccharomyces cereWisiae Assay. S. cereVisiae was kindly
provided by Dr. B. Ono, Ritsumeikan University. A cell suspension of
S. cereVisiae in distilled water (2.0 × 104 cells/mL, 100 µL) was added
to a YPD medium (10 g yeast extract, 20 g peptone, 20 g glucose, pH
6.5, 50 µL) and a sample solution (8% MeOH, 50 µL) and incubated
at 30 °C for 24 h. Anti-S. cereVisiae activity was estimated by cell
counts.
1
Preparation of MTPA Esters. A 1.0 mg portion of 1 was treated
with (S)-(+)-MTPACl in pyridine (100 µL) at room temperature for
2 h, and the reaction mixture was partitioned between H2O and CH2Cl2.
The organic layer was purified by reversed-phase HPLC to yield the
(R)-(+)-MTPA ester 3. The (S)-(-)-MTPA ester 4 was prepared in
the same manner as that of 3 except with (R)-(-)-MTPACl.
1
Acknowledgment. We thank Prof. T. Eguchi and Dr. E. Nango,
Tokyo Institute of Technology, for measuring HRFABMS spectra.
3: H NMR (CD3OD) 7.96 (H-14), 7.95 (H-13), 7.33 (H-10), 7.27
(H-11), 7.06 (H-8), 7.06 (H-12), 4.80 (H-3), 3.10 (H-7R), 3.03 (H-
7ꢀ), 2.81 (H-2R), 2.72 (H-1R), 2.21 (H-6ꢀ), 2.12 (H-2ꢀ), 1.95 (H-
6R), 1.77 (H-1ꢀ), 1.71 (H-5), 1.21 (H-17), 1.32 (H-18); ESIMS 580
[M + H]+.
Supporting Information Available: 1H, 13C, and 2D NMR spectra
for oridamycins A (1) and B (2). This material is available free of charge
via the Internet at http://pubs.acs.org.
1
4: H NMR (CD3OD) 7.95 (H-14), 7.95 (H-13), 7.32 (H-10), 7.27
(H-11), 7.06 (H-8), 7.06 (H-12), 4.89 (H-3), 3.12 (H-7R), 3.04 (H-
7ꢀ), 2.75 (H-2R), 2.70 (H-1R), 2.27 (H-6ꢀ), 1.98 (H-2ꢀ), 1.98 (H-
6R), 1.77 (H-1ꢀ), 1.73 (H-5), 1.37 (H-17), 1.31 (H-18); ESIMS 580
[M + H]+.
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Anti-Saprolegnia parasitica Indolosesquiterpenes
Journal of Natural Products, 2010, Vol. 73, No. 4 701
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NP1000522