Revised structure of cyclolithistide a, a cyclic depsipeptide from the marine sponge discodermia japonica

Article abstract of DOI:10.1021/np400668k

A cyclic peptide was isolated from the deep-sea marine sponge Discodermia japonica, and its NMR spectroscopic data were identical to those reported for cyclolithistide A, a known antifungal depsipeptide. However, the interresidue HMBC correlations suggested that the amino acid sequence was different from that of the original structure. Moreover, chiral-phase GC-MS, combined with Marfey's analysis, indicated that the absolute configurations of three amino acids were also antipodal. Here, we propose the revised structure of cyclolithistide A and address the configuration of the previously unassigned 4-amino-3,5- dihydroxyhexanoic acid (Adha) moiety.

Full text of DOI:10.1021/np400668k

Note
pubs.acs.org/jnp
Revised Structure of Cyclolithistide A, a Cyclic Depsipeptide from the
Marine Sponge Discodermia japonica
Hiroki Tajima,† Toshiyuki Wakimoto,*,† Kentaro Takada,‡ Yuji Ise,§ and Ikuro Abe*,†
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
§Misaki Marine Biological Station, Graduate School of Science, The University of Tokyo, Miura, Kanagawa, 238-0225, Japan
S
* Supporting Information
ABSTRACT: A cyclic peptide was isolated from the deep-sea
marine sponge Discodermia japonica, and its NMR spectroscopic
data were identical to those reported for cyclolithistide A, a
known antifungal depsipeptide. However, the interresidue
HMBC correlations suggested that the amino acid sequence
was different from that of the original structure. Moreover,
chiral-phase GC-MS, combined with Marfey’s analysis, indicated
that the absolute configurations of three amino acids were also
antipodal. Here, we propose the revised structure of cyclo-
lithistide A and address the configuration of the previously
unassigned 4-amino-3,5-dihydroxyhexanoic acid (Adha) moiety.
tructurally complicated secondary metabolites having a
revealed the amino acid composition, including Ala, Phe, Thr,
Svariety of biological activities are often isolated from the Gln, norvaline (norVal), Gly, and two Leu residues. An intense
HMBC correlation between an N-methyl singlet (δH 3.05) and
an α-carbon of Leu (δC 65.2) suggested that one of the two
leucines was N-methylated (N-MeLeu). The other Leu turned
out to be N-formylated (fyl-Leu), because of mutual HMBC
correlations between the formyl proton (δH 8.16) and the
second α-carbon of Leu (δC 52.7) and between the
corresponding α-proton of Leu (δH 4.62) and the formyl
carbon (δC 163.6). The 4-amino-3,5-dihydroxyhexanoic acid
(Adha) moiety was established by simultaneous analysis of the
COSY and HMBC spectra. A downfield quartet (H-45, δH
5.31) showed COSY and HMBC correlations with the adjacent
CH3-46 (δH 1.27, δC 19.4) and COSY correlations with H-44
(δH 3.98), which in turn was COSY-correlated with an amide
proton (δH 8.52). The H-45 quartet also showed an HMBC
correlation to the deshielded 13C resonance of oxymethine CH-
43 (δC 72.4, δH 4.48). This proton showed COSY correlations
with the methylene protons (H2-42, δH 2.58/2.15), which had
HMBC correlations to a carbonyl carbon (C-41, δC 175.6). As
the presence of a chlorine atom in 1 was inferred from the
isotopic pattern of the pseudomolecular ion in the FABMS
spectrum, the remaining amino acid residue therefore contains
a chlorine atom. On the basis of the COSY and HMBC
correlations of δH 0.99/δC 10.2 and δH 1.51/δC 23.4, this amino
acid possessed an isoleucine-like structure, in which the γ-
position (δH 4.53/δC 59.2) is substituted with a chlorine atom.
Here, the rare amino acid chloroisoleucine (Cl-Ile) was
established.
lithistid sponges, particularly from the Theonella and Dis-
codermia genera. These compounds include polyketides such as
the swinholides1 from Theonella sp. and discodermolide2 from
Discodermia dissoluta and polypeptides such as the theonella-
mides3 from Theonella sp. and the discodermins4 from
Discodermia kiiensis. We recently reported two cytotoxic cyclic
peptides, calyxamides A and B,5 from Discodermia calyx. Their
structures were closely related to those of the keramamides
isolated from the Theonella genus.6 The structural resemblance
between the secondary metabolites from Theonella and
Discodermia sponges has been reported for cyclic peptides
and polyketides.7 Likewise, in this study, the chemical
investigation of Japanese Discodermia japonica revealed that
the major metabolite of the sponge was a depsipeptide, which
was originally isolated from the Indonesian Theonella swinhoei.
However, we discovered inconsistencies between the NMR
data and the original structure reported in 1998.8 We now
present a reinvestigation of the structure of cyclolithistide A.
The sponge D. japonica was collected at a depth of 200 m in
Sagami Bay, Japan. The MeOH extract of the sponge (200 g,
wet weight) was partitioned between EtOAc and H2O, and the
organic layer was subjected to chromatography on a silica gel
column to yield 1 as an amorphous, white solid (160.1 mg,
0.080% wet weight).
The molecular formula was established as C54H86ClN11O15
by positive ion HRFABMS. The 1H NMR spectrum in CD3OD
showed α-protons between 3.5 and 4.5 ppm, as well as amide
protons between 7.0 and 9.0 ppm, which were detectable for
several hours even in CD3OD. Interpretation of the 1D and 2D
NMR data including COSY, HMQC, and HMBC in CD3OD
Received: August 16, 2013
Published: December 13, 2013
© 2013 American Chemical Society and
American Society of Pharmacognosy
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Journal of Natural Products
Note
Cl-Ile should be reassigned to those of N-MeLeu, Gly, Cl-Ile,
and Adha, respectively. Furthermore, the amide proton of Phe
(δH 7.96) showed an HMBC correlation to the carbonyl carbon
at δC 172.7 (allo-Thr), which is also overlapped with that of N-
MeLeu. Considering that the dipeptide fragment Phe-N-MeLeu
has already been established, allo-Thr should precede Phe.
Finally, the ring closure by placing the remaining Gln residue
between the N-terminus of allo-Thr and the C-terminus of
norVal satisfied the molecular formula. This was supported by
the ROESY correlation between δH 8.54 (allo-Thr NH) and δH
4.59 (Gln). Thus, the new structure 1 was established as shown
in Figure 1.
Figure 1. Key 2D NMR correlations for 1.
With the revised structure of cyclolithistide A (1) in place,
we turned our attention to the MS/MS data of 1′ reported in
the original paper.8 Surprisingly, all of the MS/MS
fragmentation patterns were in full agreement with the revised
sequence (Figure S14). The fragment ions are as follows: loss
of Phe-Thr (m/z 916), loss of Phe-Thr-Gln (788), loss of Phe-
Thr-Gln-norVal-Gly (632), loss of Phe-Thr-Gln-norVal-Gly and
the formyl group (604), loss of Phe-Thr-Gln-norVal-Gly and
fyl-Leu (490), and loss of Phe-Thr-Gln-norVal-Gly/fyl-Leu-
Adha (346). All of these results corroborated our proposed
structure, but were still insufficient to preclude the reported
one.
For this reason, 1 was subjected to partial hydrolysis with 4
M HCl, which yielded a tripeptide 2, Thr-Phe-N-MeLeu (m/z
394, see Figures 2 and S15 and Table S2). This sequence was
not present in the original structure, but composed a segment
of the revised structure (Figure 2). Furthermore, we measured
the ESIMS/MS data of the linearized peptide 3, which was
prepared by methanolysis. As a result, four diagnostic MS/MS
fragments were detected, which validated the revised sequence
without exception (Figures 2 and S16).
Phoriospongins A (4) and B (5), analogues of cyclolithistide
A, were reported by Capon and co-workers in 2002.9
Phoriospongins possess the same amino acid composition as
1′, except that Asn is substituted for Gln. However, the absolute
configurations of three amino acids (norVal, allo-Thr, Ala) were
reportedly antipodal to those of 1′. To clarify the discrepancies
in the stereochemical assignments between cyclolithistide A
and the phoriospongins, we reinvestigated the absolute
configurations of the amino acids of 1.
The absolute configurations of most of the component
amino acids were established by a chiral-phase GC analysis of
the N-trifluoroacetyl/methyl ester derivatives of the hydrolysate
of 1 (Figures S17 and S18). This approach successfully
identified the existence of D-Leu, D-norVal, L-Gln, D-allo-Thr, L-
Eventually, the molecular weight together with 1D and 2D
NMR spectroscopy revealed that the isolated compound was
identical to cyclolithistide A (1′), a known antifungal
cyclodepsipeptide isolated from the sponge Theonella swinhoei,
reported by Crews and co-workers in 1998.8 While their
assignment was mainly accomplished by the interpretation of
2D NMR spectroscopic data in DMSO-d6,8 our assignment of
the data in DMSO-d6 was hampered by the presence of the
surplus signals observed in the COSY spectrum, probably due
to rotamers (Figure S6).
The amino acid sequence and the position of the macrocyclic
ring junction were confirmed by the interresidue HMBC and
NOESY cross-peaks. First, the tetrapeptide sequence norVal-
Gly-Adha-fylLeu was confirmed on the basis of HMBC
correlations, δH 8.06 (norVal NH)/δC 173.3 (Gly), δH 3.87,
3.67 (Gly)/δC 175.6 (Adha), and δH 8.52 (Adha NH)/δC 175.2
(fylLeu). The ester linkage between the δ-hydroxy group of
Adha and the C-terminus of Cl-Ile, in place of norVal in the
original structure, was deduced from the HMBC correlation
between δH 5.31 (Adha) and δC 173.4 (Cl-Ile). The amide
proton of Cl-Ile (δH 7.76) was correlated to a carbonyl carbon
at δC 174.6 (Ala), which overlaps with that of Phe. In spite of
this overlap, the presence of a NOESY cross-peak between the
α-proton of Phe and N-Me protons corroborated that the
assignment originally reported to be δH 3.05 (N-MeLeu)/δC
174.6 (Ala) should be revised to δH 3.05 (N-MeLeu)/δC 174.6
(Phe). Along with these correlations, the HMBC cross-peak
between δH 7.32 (Ala NH) and δC 172.7 (N-MeLeu) provided
evidence that the tetrapeptide sequence Phe-N-MeLeu-Ala-Cl-
Ile should be present in the revised structure. At this point, it
became apparent that the original 13C chemical-shift assign-
ments of four carbonyl carbons of Gly, Adha, N-MeLeu, and
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Journal of Natural Products
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Figure 2. Summary of the partial hydrolysis and MS/MS experiments.
Phe, and D-Ala (Table 1). On the other hand, although
authentic standards of N-MeLeu were synthesized from Leu10
Table 1. Absolute Configurations of Amino Acids of 1, 1′,
and 5
cyclolithistide A
phoriospongin B
amino acid
revised (1)
original (1′)8
59
(fyl-)Leu
norVal
Gln
D
D
L
D
L
L
L
L
L
L
D
D
L (Asn)
allo-Thr
Phe
D
L
D
L
Ala
D
L
D
L
N-MeLeu
and analyzed by the same procedure, the configuration could
not be elucidated, due to the overlapped retention times of the
enantiomers. Instead, Marfey’s analysis of the acid hydrolysate
and standards revealed that it had the L-configuration.11
Overall, the absolute configurations of Leu, N-Me Leu, Gln,
and Phe matched those of 1′, but those of norVal, allo-Thr, and
Ala were in full accordance with 5, rather than 1′. Given that
the absolute configuration of 1′ was originally elucidated by
chiral-phase TLC methods,8 our result is more reliable because
of the higher resolution of GC and HPLC.
Finally, the absolute configuration of the 4-amino-3,5-
dihydroxyhexanoic acid moiety, which remained unassigned
in the original report, was elucidated by chemical trans-
formation in conjunction with the modified Mosher’s method.
At first, the 1,3-diol portion of the methyl ester 3 was converted
to the acetonide, thus forming 43,45-O-isopropylidene-3. The
geminal dimethyl groups resonated at diagnostic 13C chemical
shifts (δC 18.8 and 29.0) for the chair conformation of a syn-
1,3-diol acetonide.12 This was confirmed by the NOESY
correlations between the axial methyl protons (δH 1.49) and the
two downfield oxymethines at H-43 (δH 4.53) and H-45 (δH
4.23). Thus, these two protons are axial (Figure 3).13
Furthermore, the coupling constant between oxymethine H-
43 (δH 4.53) and amidomethine H-44 (δH 3.71) was 2.0 Hz,
indicating that the amide substituent is also axial (Figure 3).
Thus, the relative configuration of this moiety was considered
to be either (43S,44R,45R) or (43R,44S,45S). The absolute
configuration was conclusively determined to be the former, by
Figure 3. Assignment of the absolute configuration of the Adha
residue. Δδ = δ(R-bis-MPA ester) − δ(S-bis-MPA ester).
the modified Mosher’s method (Figure 3 and Table S4) with
the bis-MPA (methoxyphenylacetic acid) ester of 1,14 which
implied that this PKS/NRPS hybrid portion could be derived
from L-Thr.
In summary, the revised structure (1) differs from the
original (1′) in the amino acid sequence and the absolute
configurations of norVal, allo-Thr, and Ala. Compound 1 and
the phoriospongins are unique macrocyclic depsipeptides
containing the nonproteinogenic amino acids norvaline
(norVal) and chloroisoleucine (Cl-Ile) as well as a 4-amino-
3,5-dihydroxyhexanoic acid in their structures. We successfully
determined the absolute configuration of Adha, while that of
Cl-Ile is still unassigned. Given that the component amino acids
of the phoriospongins were almost the same as 1, their
structures are also worthy of reconsideration.
EXPERIMENTAL SECTION
General Experimental Procedures. Optical rotations were
measured on a JASCO DIP-1000 digital polarimeter. The UV
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Journal of Natural Products
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1
spectrum was obtained by a Gene Spec III UV/vis spectrometer. H
and 13C NMR spectra were recorded on a JEOL ECX-500
D-Thr (7.8), L-allo-Thr (10.5), D-allo-Thr (11.5), L-Gln (17.6), D-Gln
(18.6), L-Phe (18.9), and D-Phe (19.5) (Figures S17 and S18). Thus,
the presence of D-Ala, Gly, D-norVal, D-Leu, D-allo-Thr, L-Gln, and L-
Phe was confirmed. The remaining peaks that were not mentioned
above should include those of the Cl-Ile and Adha moieties. The
absolute configuration of N-Me-Leu could not be elucidated from this
experiment.
1
spectrometer in CD3OD and CD3OH. H and 13C NMR chemical
shifts were reported in parts per million and referenced to solvent
peaks: δH = 3.29 and δC = 47.8 for both CD3OD and CD3OH.
HRFABMS data were obtained from a JEOL JMS-700T spectrometer,
using m-nitrobenzyl alcohol as the matrix. MS/MS experiments were
performed on a Bruker amaZon SL spectrometer. GC/MS experi-
ments were performed on a Shimadzu GCMS-QP2010 spectrometer.
Animal Material. The sponge Discodermia japonica was collected
off Jogashima, Sagami Bay, Japan, 35°6.172′ N, 139°34.257′ E, 364−
158 m depth, by dredging of R/V Rinkai-maru of Misaki Marine
Biological Station, the University of Tokyo, on January 13, 2012.
Sponge description: two thick branches ramified on the base; each
trunk having a hollow on its summit with several small oscules; color
beige; consistency stony hard. Ectosomal skeleton made of
phyllotriaene and a few discotriaene, with long diactinal spicules
traversing the choanosome. Choanosomal skeleton consisted of dense
articulation of tetraclone desma. Microscleres acanthoxea and
microstrongyle. Phyllotriaene spatulate with short rhabd, 781 (630−
890) μm in longest diameter. Discotriaene oval, some with slightly
incised margins, 372 (260−470) μm in longest diameter. Tetraclone
desmas, smooth on shaft, 118 (113−130) μm in thickness. Acanthoxea
almost uniform in shape and size, fusiform, straight or slightly bent at
midpoint of the spicule, sharply pointed at both extremities, 70 (55.0−
77.5) μm in length, 3.6 (3.0−3.8) in width. Micostrongyle almost
uniform in shape and size, straight, with rough surface, 13.1 (11.3−
16.3) μm in length, 3.7 (3.0−5.0) μm in width. The sponge is most
Synthesis of N-MeLeu. Sodium hydride (15.6 mg, 10 equiv) was
added to 15 mg (64.9 μmol) of Boc-L-Leu dissolved in THF (200 μL)
at 0 °C. After stirring for 1 h, iodomethane (40 μL, 10 equiv) was
added at 0 °C. The reaction mixture was then stirred at 0 °C for 2 h
and held at rt for 12 h before it was quenched with H2O. The reaction
mixture was acidified by HCl (pH 1−2) and extracted with EtOAc
twice. The combined organic layer was dried over sodium sulfate,
concentrated under reduced pressure, and treated with TFA (500 μL)
at rt for 1 h. The reaction mixture was then freeze-dried. N-Me-L-Leu
was obtained as a white solid (8.5 mg). N-Me-D-Leu was synthesized
by the same scheme (7.7 mg).
Determination of the Configuration of N-MeLeu. Due to the
overlapped retention times of the L and D isomers of N-MeLeu on GC-
MS, the absolute configuration of this residue was determined by
Marfey’s analysis. To 150 μg of the acid hydrolysate of the peptide and
authentic amino acid standards of N-MeLeu was added 75 μL of 1-
FDAA (10 mg/mL) in acetone, and 150 μL of 1 M NaHCO3(aq), and
the mixture was incubated at 50 °C for 1 h. Subsequently, 75 μL of 2
M HC1 and 300 μL of MeOH were added. The solution was subjected
to reversed-phase HPLC on ODS (Cosmosil MS-II column ϕ 4.6 ×
250 mm; flow rate 0.8 mL/min; 10−50% CH3CN/H2O containing
0.05% TFA over 20 min; UV detection at 340 nm; oven 40 °C). The
retention times (min) were as follows: hydrolysate (28.5), N-Me-L-Leu
(28.5), and N-Me-D-Leu (29.7) (Figure S19). Thus, the configuration
of N-MeLeu was established as the L form.
Determination of the Configuration of 4-Amino-3,5-dihy-
droxyhexanoic Acid. The relative configuration was elucidated as
follows: K2CO3 (1 mg, 0.8 equiv) was added to a solution of 1 (10
mg) in MeOH (1.5 mL). After stirring at rt for 4 h, the reaction
mixture was extracted with EtOAc, dried with sodium sulfate, and
concentrated under reduced pressure. The mixture, in 1,4-dioxane (1.5
mL), was treated with pyridinium p-toluenesulfonate (4.3 mg, 2 equiv)
and 2,2-dimethoxypropane (20 μL, 20 equiv) and was stirred at 40 °C
for 2 h. The resulting solution was purified by reversed-phase HPLC
on ODS (Cosmosil MS-II column ϕ 10 × 250 mm; flow rate 3 mL/
min; 75% MeOH/H2O; UV detection at 200 nm) to afford 43,45-O-
isopropylidene-5 (Table S3, Figure S21). The coupling constants and
the NOESY correlations of 43,45-O-isopropylidene-3 revealed the
relative configuration to be either (43S,44R,45R) or (43R,44S,45S)
(Figure S22). The absolute configuration was determined as follows:
To a solution of 1 (1 mg) in CH2Cl2 (200 μL) were added DCC (1
mg, 5.7 equiv), DMAP (10 μg, 0.1 equiv), and either S- or R-MPA
(800 μg, 5.6 equiv). After stirring for 4 h, the reaction mixture was
purified by reversed-phase HPLC on ODS (Cosmosil MS-II column ϕ
10 × 250 mm; flow rate 3.0 mL/min; 80−100% MeOH/H2O
containing 0.05% TFA over 15 min; UV detection at 200 nm; oven 40
°C) to yield the S/R-MPA esters of 1 (FABMS m/z 1460 [M + H]+).
According to the chemical shift difference (δR  δS), the absolute
configuration was determined to be (43S,44R,45R) (Table S4).
likely D. japonica (Doderline, 1884) according to Tanita and Hoshino
̈
(1989),15 because external morphology and spicule composition are
similar and the type locality of D. japonica is very close to the sampling
locality. The sample was identified by Y.I. The specimen used for
identification (NSMT-Po2451) is deposited at the National Museum
of Nature and Science, Tokyo.
Isolation. The MeOH (0.5 L × 3) extract of the sponge D. japonica
(200 g, wet weight) was partitioned between EtOAc (350 mL × 2)
and H2O (350 mL). The EtOAc-soluble material (1.2 g) was subjected
to open chromatography on a silica gel column, eluted with a stepwise
gradient of MeOH (0−40%) and H2O (0−10%) in CHCl3, to afford
cyclolithistide A (1, 160.1 mg, 0.080% wet weight).
Cyclolithistide A (1): white, amorphous solid; [α]24D −51.5 (c 0.12,
MeOH); [α] −29.3 (c 0.015, MeOH, in the original report);8 UV
(MeOH) λmax 256 nm; 1H and 13C NMR (Table S2); HRFABMS m/z
1186.5875 [M + Na]+ (calcd for C54H86ClN11NaO15, 1186. 5891).
Partial Hydrolysis of Cyclolithistide A. 1 (5 mg) was hydrolyzed
with 4 M HCl (2 mL) at 100 °C for 1 h. The reaction mixture was
purified by reversed-phase HPLC on ODS (Cosmosil MS-II column ϕ
10 × 250 mm; flow rate 3 mL/min; 10−100% MeOH/H2O
containing 0.05% TFA over 30 min; UV detection at 200 nm) to
afford tripeptide 2 (Table S2 and Figure S15).
MS/MS Fragment Analysis. A solution of 1 (1 mg) and K2CO3
(0.1 mg, 0.8 equiv) in MeOH (200 μL) was stirred at room
temperature (rt) for 4 h. The reaction mixture was purified by
reversed-phase HPLC on ODS (Cosmosil MS-II column ϕ 10 × 250
mm; flow rate 3 mL/min; 80% MeOH/H2O containing 0.05% TFA;
UV detection at 200 nm) to afford 3. The MS/MS fragments thus
obtained are m/z 946.7, 801.6, 636.4, and 553.4 (Figure S16).
Amino Acid Analysis by Chiral-Phase GC. 1 (200 μg) was
hydrolyzed with 6 M HCl (500 μL) at 110 °C for 24 h. The reaction
mixture was treated with 5−10% HCl/MeOH (500 μL) at 100 °C for
30 min, followed by a treatment with trifluoroacetic anhydride
(TFAA)/CH2Cl2 (1:1, 500 μL) at 100 °C for 5 min. The chiral-phase
GC analysis of the N-trifluoroacetyl (TFA)/methyl ester derivatives
was performed using a CP-Chirasil-D-Val column (Alltech, 0.25 mm ×
25 m; N2 as the carrier gas; program rate 50−200 at 4 °C/min) and
showed peaks at tR = 5.5, 7.3, 7.5, 9.1, 11.3, 11.5, 17.6, and 18.7 min.
Standard amino acids were also converted to the TFA/Me derivatives
by the same procedure. Retention times (min) were as follows: L-Ala
(4.3), D-Ala (5.2), Gly (6.9), N-Me-L-Leu (7.5), N-Me-D-Leu (7.5) L-
norVal (8.1), D-norVal (9.1), L-Leu (10.0), D-Leu (11.3), L-Thr (6.9),
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental Section, 1D and 2D NMR spectra, and chiral-
phase GC analytical data for 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: wakimoto@mol.f.u-tokyo.ac.jp; abei@mol.f.u-tokyo.ac.
jp.
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Note
*Phone: +81-3-5841-4740. Fax: +81-3-5841-4744. E-mail:
abei@mol.f.u-tokyo.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. P. Crews, University of California, Santa Cruz,
for valuable discussions. This work was partly supported by a
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
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