Ulleungamides A and B, Modified α,β-Dehydropipecolic Acid Containing Cyclic Depsipeptides from Streptomyces sp. KCB13F003

Article abstract of DOI:10.1021/acs.orglett.5b01969

Two novel cyclic depsipeptides, ulleungamides A (1) and B (2), were isolated from cultures of terrestrial Streptomyces sp. Their structures were determined by analyses of spectroscopic data and various chemical transformations, including modified Mosher's method, advanced Marfey's method, PGME, GITC derivatizations, and Snatzke's method. Ulleungamides were determined to be a new class of peptides bearing unprecedented units, such as 5-hydroxy-6-methyl-2,3-dehydropipecolic acid, 4,5-dihydroxy-6-methyl-2,3-dehydropipecolic acid, and amino-linked 2-isopropylsuccinic acid. Ulleungamide A displayed growth inhibitory activity against Staphylococcus aureus and Salmonella typhimurium without cytotoxicity.

Full text of DOI:10.1021/acs.orglett.5b01969

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Ulleungamides A and B, Modified α,β-Dehydropipecolic Acid
Containing Cyclic Depsipeptides from Streptomyces sp. KCB13F003
Sangkeun Son,†,‡ Sung-Kyun Ko,†,‡ Mina Jang,†,‡ Jae Kyoung Lee,† In-Ja Ryoo,† Jung-Sook Lee,§
Kyung Ho Lee,∥ Nak-Kyun Soung,∥,‡ Hyuncheol Oh,⊥ Young-Soo Hong,†,‡ Bo Yeon Kim,∥,‡
Jae-Hyuk Jang,*,†,‡ and Jong Seog Ahn*,†,‡
∥
†Chemical Biology Research Center and Incurable Diseases Therapeutics Research Center (WCI), Korea Research Institute of
Bioscience and Biotechnology, Cheongju 363-883, Korea
‡Department of Biomolecular Science, University of Science and Technology, Daejeon 305-333, Korea
§Microbial Resources Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 306-809, Korea
⊥College of Pharmacy, Wonkwang University, Iksan 570-749, Korea
S
* Supporting Information
ABSTRACT: Two novel cyclic depsipeptides, ulleungamides A (1) and B (2), were isolated
from cultures of terrestrial Streptomyces sp. Their structures were determined by analyses of
spectroscopic data and various chemical transformations, including modified Mosher’s
method, advanced Marfey’s method, PGME, GITC derivatizations, and Snatzke’s method.
Ulleungamides were determined to be a new class of peptides bearing unprecedented units,
such as 5-hydroxy-6-methyl-2,3-dehydropipecolic acid, 4,5-dihydroxy-6-methyl-2,3-dehydropi-
pecolic acid, and amino-linked 2-isopropylsuccinic acid. Ulleungamide A displayed growth
inhibitory activity against Staphylococcus aureus and Salmonella typhimurium without
cytotoxicity.
tructurally unique and diverse secondary metabolites from
Sactinomycetes have been an invaluable source of drug leads
and molecular probes over the decades.1 However, discovering
novel structural scaffolds is getting more difficult due to the high
rediscovery rate of known compounds.2 To overcome this
difficulty, we have focused our attention on exploration of
actinomycetes from chemically less studied sites, which are
potentially prolific sources of novel chemistry.3 Although Ulleung
Island, a small volcanic island located 150 km off the coast of the
Korean Peninsula, has been reported as a biodiversity hot spot
which harbors a variety of microorganisms together with many
endemic and endangered plant species,4 secondary metabolites of
microorganisms derived from this island have not been
investigated. Attracted by its probability of harboring promising
strains, we isolated 208 actinomycetes from soil samples collected
at Ulleung Island and screened their secondary metabolites. The
Streptomyces sp. KCB13F003 was cultured in GLY medium (30
× 250 mL) for 6 days at 28 °C, and then the metabolites were
collected by the acetone extract of cells and Amberlite XAD-7
preliminary chemical screening of the EtOAc extracts by LC−MS
data suggested that Streptomyces sp. KCB13F003 produced
unusual metabolites, of which UV and MS data are rare in public
and in-house databases. These compounds were identified by
scale-up isolation and structure elucidation as two new branched
cyclic depsipeptides, ulleungamides A (1) and B (2). These novel
peptides possess unprecedented residues, modified α,β-dehy-
dropipecolic acid and amino-linked 2-isopropylsuccinic acid. The
isolation, structure elucidation, and biological activity of these
two new peptides are described below.
resin extract of the fermentation broth. The resulting crude
extract was purified by sequential solvent partitioning, ODS
vacuum flash chromatography, and reversed-phase HPLC to
afford ulleungamides A (1) and B (2).
Ulleungamide A (1) was isolated as a white powder. The
molecular formula C51H67N7O13 was determined by HRESIMS
analysis (m/z 986.4861 [M + H]+, calcd for C51H68N7O13,
Received: July 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01969
Org. Lett. XXXX, XXX, XXX−XXX

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986.4875) in combination with NMR data, indicating 22 degrees
of unsaturation. Despite many proton and carbon signals having
overlapping chemical shifts due to the presence of the minor
conformer (about 50% of main conformer), each amino acid unit
was identified and assembled by use of high-field NMR
spectrometers (900 MHz) and nonuniform sampling (NUS)
NMR processing.5 Amide proton signals at δH 7.7−8.9 and α-
amino methines at δH 4.3−5.6 in the HSQC-DEPT spectrum,
together with amide and ester carbonyl carbons at δC 162.3−
170.9 in the 13C NMR spectrum, suggested a peptide nature of 1.
A comprehensive analysis of 2D NMR data (i.e., HSQC-DEPT,
COSY, TOCSY, and HMBC) clearly established the presence of
glycine (Gly), threonine (Thr), phenylalanine (Phe), N-
methylphenylalanine (N-Me-Phe), and pipecolic acid (Pip). Of
note, Phe and N-Me-Phe residues were especially established by
HSQC-TOCSY data due to severely overlapped cross-peaks of
numerous aromatic protons in the region of 7.15−7.35 ppm in
COSY and TOCSY spectra (Figure 1). The proton spin system
Moreover, the connectivity between HMDPA and Pip was
confirmed by the HMBC correlation from H-6 (δH 3.93) of
HMDPA to the carbonyl C-8 (δC 170.6) of Pip. The ester linkage
between the β-carbon C-33 of Thr and the carbonyl carbon C-1
of HMDPA was established by the HMBC correlation from the
β-proton H-33 (δH 5.48) of Thr to C-1 (δC 162.3). In addition,
HMBC correlations of H3-44 (δH 2.94) and H-36 (δH 5.57) of N-
Me-Phe to theamide carbonyl C-45 (δC 172.0) of IPSAlinkedthe
IPSA to N-Me-Phe. Upon these spectroscopic data, the gross
structure of 1 was characterized as a 19-membered cyclic
depsipeptide incorporating six amino acids including unusual
residues and a branched chain terminated by the amino-linked
IPSA.
The stereochemistries of 10 stereogenic centers of 1 were
established by applying various chemical and spectroscopic
methods based on the chemical properties of chiral functional
groups. The absolute configurations of two secondary carbinol
centers, C-5 in HMDPA and C-26 in γ-OH-Pip, were determined
by the modified Mosher’s method.6 First, carboxylic acid was
methylated by exhaustive treatment of 1 with TMS-CHN2 to give
a methyl ester (1b), which was subsequently converted to S- and
R-α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA)
esters (1c and 1d) by treatment with R- and S-MTPA-Cl. The
distribution of the signs of the ΔδH values (ΔδH = δS − δR) of bis-
S- and bis-R-MTPA esters (1c and 1d) allowed us to assign the 5R
and 26R configurations (Figure 2). The absolute configuration of
Figure 1. Key 2D NMR correlations of 1.
from the methine proton H-24 (δH 4.29) to the methylene
protons H2-28 (H-24/H2-25/H-26/26-OH/H2-27/H2-28) ob-
served in the COSY spectrum and HMBC correlations from H-
24 to C-23 (δC 170.8) and C-28 (δC 34.1), together with the
downfield shift of C-26 (δC 61.9), revealed the presence of an
unusual amino acid 4-hydroxypipecolic acid (γ-OH-Pip) (Figure
1). Moreover, the cross-peaks among H-3/H2-4/H-5/5-OH/H-
6/H3-7 were observed in COSY and TOCSY spectra, which
allowed the establishment of another spin system from the
olefinic carbon C-3 (δC 120.2) to the methyl carbon C-7 (δC
14.5). Key HMBC correlations from the olefinic proton H-3 (δH
5.98) to the sp2 quaternary carbon C-2 (δC 129.4) and the
carbonyl carbon C-1 (δC 162.3) and from the downfield methine
proton H-6 (δH 3.93) to C-2 determined the presence of
unreported amino acid 5-hydroxy-6-methyl-2,3-dehydropipe-
colic acid (HMDPA). Furthermore, COSY correlations revealed
the spin system from the methylene protons H2-46 (δH 2.52 and
2.10) to the geminal dimethyl groups H3-49 (δH 0.78) and H3-50
(δH 0.76). This spin system was extended to the carbonyl carbons
C-45 (172.0) and C-51 (δC 175.6) by HMBC correlations from
H-47 (δH 2.48) to C-45 and C-51 and from H-48 (δH 1.73) to C-
51. The presence of carboxylic acid functionality (C-51, δc 175.6)
was suggested by the observation of a very broad singlet at δH
11.87 in the 1H NMR spectrum (Figure S3, Supporting
Information). In light of these data, the presence of 2-
isopropylsuccinic acid (IPSA) was established.
Figure 2. ΔδS‑R values obtained for bis-S- and bis-R-MTPA esters (1c
and 1d): (a) 4-hydroxypipecolic acid; (b) 5-hydroxy-6-methyl-2,3-
dehydropipecolic acid.
3
C-24 could be defined by JHH coupling constants and ROESY
experiment of 1c. In the 1H NMR spectrum of 1c, the oxymethine
proton H-26 (δH 5.25) appeared as a quintet with a coupling of
4.5 Hz, indicating an equatorial position of H-26. The methine
proton H-24 (δH 4.33) was then suggested to be present at the
equatorial position on the basis of its triplet signal with a coupling
of 4.5 Hz, which was consistent with the presence of ROESY
cross-peaks of H-24 with the adjacent methylene H2-25 and the
lack of correlations with H2-28. These established the S
configuration at C-24, thus indicating the presence of (2S, 4R)-
4-hydroxypipecolic acid.
The absolute configuration of C-6 was also determined by a
3
combination of extensive ROESY analysis and JHH couplings.
Even though broad and overlapping 1H signals in various solvents
(DMSO-d6, CDCl3, pyridine-d5, and CD3OD) prevented the
determination of coupling constants of HMDPA, they could be
obtained from resolved cross-peak multiplets in DQF-COSY.7
An equatorial position for H-5 was established on the basis of
ROESY correlations of H-5 with H2-4, H-6, and H3-7 (Figure 3).
In addition, the small vicinal coupling constant between H-5 and
H-6 (3.2 Hz) indicated an pseudoequatorial position of H-6, and
the ROESY correlation between H3-7 and H-4a revealed the
dipseudoaxial relationship of H3-7 and H-4a, confirming a half-
chair conformation of HMDPA. The absolute configuration of C-
6 was therefore assigned as S. The stereochemistry of the α-
The HMBC correlations from α-protons to amide carbonyls of
adjacent amino acids led us to the establishment of the amino acid
sequence of Pip-Phe-γ-OH-Pip-Gly-Thr-N-Me-Phe (Figure 1).
B
DOI: 10.1021/acs.orglett.5b01969
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observed correlations (H-5/H-4, H-6, H3-7 and H-4/H3-7)
suggested an equatorial orientation of H-5 and a dipseudoaxial
relationship of H3-7 and H-4. This observation was consistent
with the couplings of 3J(H-4, H-5) = 5.3 Hz and 3J(H-5, H-6) =
3.2 Hz, indicating the relative configuration of the stereogenic
centers in DHMDPA as 4R*,5S*,6S*. Then, the absolute
configuration of DHMDPA was assigned by applying the
Snatzke’s method using the in situ complex of dimolybdenum
tetraacetate [Mo2(OAc)4].11 The Mo2 complex with the 1,2-diol
moiety shows the diagnostic bands in the induced CD (ICD)
spectrum, which represent the chirality of the 1,2-diol moiety
expressed by the sign of the O−C−C−O dihedral angle. The
positive Cotton effect at 323 nm (Δε, + 5.0) and negative Cotton
effect at 282 nm (Δε, − 8.6) of cottonogenic derivative of 2
indicated the positive O−C−C−O dihedral angle (Figure 5).
Figure 3. ROESY correlations and 3JHH coupling constants of 5-hydroxy-
6-methyl-2,3-dehydropipecolic acid in 1.
carbons of Pip, Phe, Thr, and N-Me-Phe was assigned by
advanced Marfey’s analysis.8 HPLC comparison of L- and D-
FDLA (1-fluoro-2,4-dinitrophenyl-5-leucinamide) derivatives of
the acid hydrolysate of 1 indicated the presence of L-Pip, D-Phe,
and N-Me-D-Phe and established the absolute configuration of
the α-carbon in Thr as S. Moreover, the same retention time of
FDLA derivatives of commercial (2S, 4R)-4-hydroxypipecolic
acid with those of γ-OH-Pip in 1 further confirmed the absolute
configuration of C-24 as S.
To determine the absolute configuration of the β-carbon at C-
33 in Thr, we performed the derivatization of acid hydrolysate of
1 with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate
(GITC).9 By comparison of chromatograms with GITC
derivatives of authentic standards L-Thr and L-allo-Thr, the R
configuration of the β-carbon in Thr was established,
demonstrating that 1 contained L-Thr. Finally, the absolute
configuration of C-47 was determined by applying the phenyl-
glycine methyl ester (PGME) method.10 The ΔδH values (ΔδH =
δS − δR) obtained from the S- and R-PGME amides (1e and 1f)
assigned the S configuration of C-47 (Figure 4).
Figure 5. Determination of absolute configuration of 4,5-diol in 2 by
Snatzke’s method. (a) Time evolution of ICD spectra of 2 in solution of
dimolybdenum tetraacetate in DMSO. (b) The sign of the O−C−C-O
dihedral angle in the cottonogenic derivative.
These results determined the absolute configuration of
DHMDPA to be 4R,5S,6S. When we performed the same
experiment using 1, it did not exhibit any diagnostic bands,
demonstrating that Cotton effects of 2 in a solution of
Mo2(OAc)4 in DMSO are clearly due to the Mo2 complex with
4,5-diol (Figure S35, Supporting Information). Consequently, it
is concluded that the same stereochemistry is present in the
common stereogenic centers of 1 and 2. This result was further
supported by comparable optical rotation values and CD spectra
of 1 and 2 (Figures S39 and S40, Supporting Information).
Structurally, the presence of two sets of signals observed in 1D
NMR data of 1 and 2 could be explained by the cis/trans amide
bond conformation or by the inversion of the piperidine ring of
pipecolic acid units.12 The major differences of chemical shifts
between conformers were observed dominantly in branched
units, N-Me-D-Phe and IPSA, and groups that are close to them in
space (C-3 and C-33). Extensive ROESY analysis revealed that
the major and minor conformers adopted trans and cis
conformations of the amide bond between N-Me-Phe and
IPSA, respectively, suggesting that cis/trans isomerization would
be responsible for the conformational equilibrium of 1 and 2
(Figure S36, Supporting Information).
Figure 4. ΔδS‑R values around C-47 of 2-isopropylsuccinic acid obtained
for S- and R-PGME amides (1e and 1f).
Ulleungamide B (2) was isolated as a white powder, and the
HRESIMS analysis showed an ion peak at m/z 1024.4642 [M +
Na]+ (C51H67N7O14, calcd for C51H67N7O14Na, 1024.4644). The
1H and 13C NMR spectra similar to those of 1, together with an
additional 16 amu, suggested that 2 is likely the hydroxy
derivative of 1. The 2D NMR analysis clearly revealed that the
methylene group C-4 was replaced by the oxygenated methine
group (δC 62.9, δH 4.16), indicating the presence of 4,5-
dihydroxy-6-methyl-2,3-dehydropipecolic acid (DHMDPA).
The absolute configurations in L-Pip, D-Phe, N-Me-D-Phe, and
L-Thr in 2 were determined by using Marfey’s analysis and GITC
derivatization with the same manner as 1. The absolute
configurations of C-24 and C-26 in γ-OH-Pip of 2 were suggested
to be S and R configurations, respectively, on the basis of the
chemical shifts, ROESY correlations, and the retention time of
the FDLA derivatives being virtually identical to those of γ-OH-
Pip of 1. In addition, a PGME method assigned the S
configuration of C-47 (Figure S34, Supporting Information).
To determine the stereochemistry of DHMDPA, we conducted
ROESY analysis and Snatzke’s method. In the ROESY spectrum,
Compounds 1 and 2 were tested for their growth inhibitory
activity against cancer (HeLa, MCF-7, and PC-3) and normal
(NRK, MRC-5, and 267B1) cell lines, but none of them exhibited
pronounced activities up to 50 μM. Ulleungamides were also
evaluated for antibacterial and antifungal activities against various
pathogenic microbes by a disk diffusion assay. Compound 1
C
DOI: 10.1021/acs.orglett.5b01969
Org. Lett. XXXX, XXX, XXX−XXX

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Notes
showed inhibition zones only against Staphylococcus aureus (1; 14
mm at 25 μg/disk, kanamycin; 15 mm at 25 μg/disk) and
Salmonella typhimurium (1; 9 mm at 50 μg/disk, chloramphe-
nicol; 17 mm at 50 μg/disk), while 2 was inactive against all tested
organisms up to a concentration of 100 μg/disk, suggesting that
ulleungamide A (1) has a selective antibacterial activity and the
presence of a hydroxy group at position C-4 severely reduces the
activity.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support by a grant from the Global
R&D Center (GRDC, NRF-2010-00719) programs of the
National Research Foundation of Korea (NRF) funded by the
Ministry of Science, ICT, and Future Planning of Korea
(MSIFP). This research was also supported by grants from the
Chungcheongbuk-do, WCI, and KRIBB Research Initiative
Program. We acknowledge the Korea Basic Science Institute,
Ochang, Korea, for providing NMR (700, 800, and 900 MHz),
HRESIMS, and CD data. We also wish to thank Mr. Daehwan
Kim (WCI, KRIBB) for valuable assistance in collecting soil
samples from Ulleung Island.
Ulleungamides A (1) and B (2) are a new class of cyclic
depsipeptides featuring several unique structural features. They
contain multiple pipecolic acid-derived residues, including Pip, γ-
OH-Pip, HMDPA, and DHMDPA. Pipecolic acid, cyclic
nonproteogenic amino acid, is a key constituent of numerous
pharmaceutically important secondary metabolites, such as
rapamycin and FK506.13 Sandramycin, quinaldopeptin, and
petriellin A also have been reported to possess multiple pipecolic
acids,14 but ulleungamides are the first example of having three
residues of Pip and Pip derivatives. The peptide metabolites that
contain the γ-OH-Pip residue are quite rare with only two
examples, which were found in virginiamycin S5 and MBJ-0110.15
Moreover, the presence of HMDPA and DHMDPA was not
reported. On the basis of chemical structures, they are likely to be
formed via modification of a pipecolic acid by C-methylation,
hydroxylation, and desaturation during or after nonribosomal
peptide chain elongation. HMDPA and DHMDPA represent
new examples of natural α,β-dehydroamino acids, which have
been shown to contribute to conformational properties and
undergo chemical reactions that can influence the bioactivity of
peptide molecules.16 The significant differences in antimicrobial
activity between 1 and 2 imply that chemical properties of these
modified α,β-dehydroamino acids contribute significantly to the
activity of ulleungamides. Owing to their structural and
functional characteristics, pipecolic acid derivatives have been
used for scaffolds to design bioactive compounds, e.g., a HIV
inhibitor Palinavir and a thrombin inhibitor argatroban.17 Further
studies on identification of the gene cluster of HMDPA and
DHMDPA might provide a route to the combinatorial
biosynthesis of highly modified pipecolic acids to generate
compounds with interesting bioactivity. In addition, the presence
of an IPSA unit is also unprecedented. It could be originated from
2-isopropyl malate, which is an intermediate of leucine
biosynthesis,18 but its origin should be further investigated.
The discovery of ulleungamides is another example supporting
the potential of microorganisms from previously uninvestigated
sites and especially those which represent unique biodiversity to
produce novel secondary metabolites. Further investigation on
the other actinomyces derived from Ulleung Island based on
bioactivity and structural novelty is currently underway.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(18) Cole, F. E.; Kalyanpur, M. G.; Stevens, C. M. Biochemistry 1973,
12, 3346−3350.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01969.
Experimental procedures and spectral data of 1 and 2
(NMR, HRESIMS, and CD spectroscopic data) (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jangjh@kribb.re.kr.
*E-mail: jsahn@kribb.re.kr.
D
DOI: 10.1021/acs.orglett.5b01969
Org. Lett. XXXX, XXX, XXX−XXX