Dotofide, a guanidine-interrupted terpenoid from the marine slug doto pinnatifida (Gastropoda, Nudibranchia)

Article abstract of DOI:10.1002/ejoc.201100347

An unusual natural product (dotofide, 1), in which the terpenoid skeleton is interrupted by a guanidine moiety was obtained from the marine slug Doto pinnatifida. The absolute configuration of compound 1 was deduced by ozonolysis and subsequent CD spectro

Full text of DOI:10.1002/ejoc.201100347

FULL PAPER
DOI: 10.1002/ejoc.201100347
Dotofide, a Guanidine-Interrupted Terpenoid from the Marine Slug Doto
pinnatifida (Gastropoda, Nudibranchia)
Annika Putz,[a,b] Stefan Kehraus, Guillermo Díaz-Agras, Heike Wägele, and
[a]
[c]
[b]
Gabriele M. König*[
a]
Keywords: Natural products / Terpenoids / Chemical defence / Structure elucidation / Nudibranchia
An unusual natural product (dotofide, 1), in which the terpe- perform the biosynthesis of the metabolite by itself. D. pin-
noid skeleton is interrupted by a guanidine moiety was ob-
tained from the marine slug Doto pinnatifida. The absolute
configuration of compound 1 was deduced by ozonolysis and
subsequent CD spectroscopy. D. pinnatifida subsists on the
hydrozoan Nemertesia antennina (Cnidaria), which however
does not contain dotofide, suggesting that the snail is able to
natifida is grouped into the chemically hardly investigated
taxon Cladobranchia (Opisthobranchia, Gastropoda). All
members of this taxon completely lack a shell and are
thought to employ toxic secondary metabolites or alterna-
tively cnidocysts sequestered from their cnidarian prey or-
ganism as defence strategy.
Introduction
Cladobranchia are an opisthobranch clade, which mostly
feed on cnidarians, i.e. Anthozoa (hexa- and octocorals)
and hydrozoans, whereas some members consume bryozo-
ans. There is a tremendous wealth of information on the
presence of secondary metabolites in opisthobranch groups
Marine snails without a protective shell are vulnerable
soft-bodied animals and often employ toxic chemicals taken
up from their food or synthesized by the animal itself as
chemical defence. This sequestration of secondary metabo-
lites from the prey, or the de novo synthesis is considered
as a major driving force for speciation within Opisthobran-
closely related to the Cladobranchia, the so-called Antho-
[1,10,11]
branchia.
In contrast, the natural product chemistry
and ecology of the Cladobranchia has hardly been investi-
[
1,2]
chia.
Investigation of defence strategies within marine
[7]
gated (see review in ref. ).
Opisthobranchia will thus aid to understand the evolution
of this group of animals.
Members of the cladobranch family Dotidae have been
[12]
reported to exclusively feed on hydrozoans.
With nearly
In marine gastropods, reduction or a complete loss of
the shell is realized in the Opisthobranchia, potentially fa-
cilitating the occupation of new ecological niches and there-
fore supporting speciation within this group.[ However, ab-
sence of a protective shell necessitates alternative defensive
mechanisms. The most important defence strategies which
ensure protection against predators involve cryptic appear-
ance by mimicking colouration and shape of the food or-
7
0 described species, this extremely species-rich family with
the only genus Doto Oken 1815 appears to be evolutionary
very successful. Doto is characterized by the presence of
one row of dorsal cerata, which very often are tuberculate
3]
(Figure 1). Underneath these tubercles, glandular cells are
[13–15]
located.
Many of the species can only be distinguished
by the shape and colour of the marks on the body and
[4]
ganism (see, for example, ref. ), formation of spicules in
[
5]
epidermal tissue, uptake and use of nematocysts (stinging
cells) from cnidarian food sources (found in Aeolido-
[
6,7]
idea),
countered in many opisthobranch species (see, for example,
and the uptake or synthesis of biochemicals en-
ref.[
8–11]
).
[
a] Institute for Pharmaceutical Biology, University of Bonn,
Nussallee 6, 53115 Bonn, Germany
Fax: +49-228-733250
E-mail: g.koenig@uni-bonn.de
[
[
b] Zoologisches Forschungsmuseum Alexander Koenig,
Adenauerallee 160, 53113 Bonn, Germany
c] Estación de Bioloxía Mariña da Graña, Universidade de
Santiago de Compostela,
Rúa da Ribeira 1–4, 15590, A Graña, Ferrol, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100347.
Figure 1. Doto pinnatifida individual on its prey, the hydrozoan
Nemertesia antennina.
Eur. J. Org. Chem. 2011, 3733–3737
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3733

A. Putz, S. Kehraus, G. Díaz-Agras, H. Wägele, G. M. König
FULL PAPER
cerata. Defensive strategies within this genus do neither in- CH-6 via C-5. HMBC correlations between 7-H2 and
clude the formation of spicules in epidermal tissue nor the C-1, C-2 and C-6 established exo-methylene group Δ1 and
,7
uptake and use of nematocysts from cnidarian food connected CH -2 to CH-6 via C-1, thus completing a cyclo-
2
[
16]
sources.
Despite the small size of these animals (usually hexane ring, respectively. 11Ј-H had correlations to C-2Ј,
3
around 5 to 10 mm), it seems unlikely that Dotidae exclu- C-3Ј and C4Ј establishing the connectivities between CH -
3
sively rely on cryptic appearance as a single defence strat- 11Ј and C-3Ј and between Δ3 and CH -2Ј. The linkage
Ј,4Ј
2
egy. It therefore appears plausible that species of this family between carbonyl atom C-5Ј and C-4Ј was proven by a cor-
protect themselves by predator-deterrent chemicals. How- relation between 4Ј-H and C-5Ј. Finally, a (CH ) C=CH–
3
2
ever, the natural product chemistry has not been described CO-fragment could be delineated by correlations between
for any member of this cladobranch family.
both 10Ј-H and 12Ј-H and C-7Ј, C-8Ј and C-9Ј, and 8Ј-H
3 3
and both C-7Ј and C-9Ј. Still remaining to be assigned were
three nitrogen, one carbon and three hydrogen atoms. The
1
3
Results and Discussion
characteristic C NMR chemical shift of C-6Ј (δ =
C
[
17]
160.8)
evidenced the presence of a guanidine moiety
which was placed between C-5Ј and C-7Ј due to the
13
Chemical Investigation of Doto pinnatifida
C
NMR chemical shifts (δC = 175.8 and δC = 175.5, respec-
tively) of these carbon atoms, thus completing the planar
structure of compound 1.
D. pinnatifida (64 individual animals) collected in Span-
ish waters was extracted with methanol and the extract sep-
arated by vacuum liquid chromatography (VLC). The polar
fractions contained compounds such as the known metabo-
lites homarine, trigonelline, and purine derivatives such as
adenine. The novel terpenoid 1 (Figure 2) was present in a
non-polar VLC fraction eluting with 100% methanol from
RP-18 material. After further purification on Sephadex
LH-20 stationary phase, 2.1 mg of the pure compound were
obtained as yellowish oil. On average each animal thus con-
tains 0.033 mg of 1.
The geometry of the double bond Δ3 was assigned on
Ј,4Ј
the basis of a correlation in the NOESY spectrum between
2
Ј-H and 4Ј-H to be E. To establish the absolute configura-
2
tion of 1 an ozonolysis was conducted resulting in diketone
(Figure 3). The absolute configuration of 2 was deter-
2
mined to be S by comparing the CD spectrum of 2 (positive
Cotton effect at 292 nm; see Supporting Information Figure
[
18]
S9) with literature data, also indicating the absolute con-
figuration of 1 to be S. We propose the trivial name dotof-
ide for compound 1.
Figure 2. Structure of the unprecedented terpenoid 1 isolated from
Doto pinnatifida.
Figure 3. Structure of ozonolysis product 2.
The molecular formula of compound 1 was deduced by
accurate mass measurement to be C H N O and showed Chemical Investigation of Nemertesia antennina
2
1
33
3
2
it to have seven elements of unsaturation. A sharp IR ab-
The food source of D. pinnatifida, the hydrozoan N.
antennina was extracted in the same way. The polar frac-
tions obtained by VLC contained compounds such as the
known metabolites homarine and trigonelline as found in
D. pinnatifida. However, the new terpenoid 1 isolated from
D. pinnatifida was not detectable via NMR- and LC-MS
spectroscopical analyses in the crude extract or in any of
the VLC fractions.
–
1
sorption at 3334 cm evidenced the presence of an amino
–
1
group and additional absorptions at 1620 cm
1
and
C
–
1
13
689 cm were indicative for carbonyl functions. The
NMR spectroscopic data contained a total of 21 resonances
attributable to five methyl, six methylene, and three methine
groups, as well as seven quaternary carbons, as indicated by
a dept 135 spectrum. These data also revealed the presence
of six double bonds (3ϫ C=C, one of which is an exo-
methylene group, 1ϫ C=N; 2ϫ C=O); 1 was thus monocy-
clic. After assignment of all protons to their directly bonded
carbon atoms via a HSQC measurement, it was possible to
deduce minor fragments of the molecule from the results of
Discussion
Cladobranchia are marine slugs which have completely
1
1
a H- H COSY measurement. Thus, analysis of the COSY lost their protective shell during evolution, suggesting that
spectrum of 1 gave evidence for connectivities from CH -2 they developed other strategies of defence. Only a very few
2
13
1
to CH -4 and from CH-6 to CH -2Ј, respectively. A H- C members of the Cladobranchia, particularly specimens of
2
2
HMBC measurement permitted the planar structure of 1 to those families which forage on octocorals, have been studied
be further elaborated. Correlations from 8-H and 9-H to in detail concerning their secondary metabolites (e.g., Tri-
3
3
C-4, C-5 and C-6 showed that methyl groups CH -8 and toniidae, Tethydidae, Facelinidae). A recent review by Putz
3
[
7]
CH -9 both are attached to C-5 and connected CH -4 to et al. summarizes all results on these few groups that usu-
3
2
3734
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3733–3737

Guanidine-Interrupted Terpenoid from a Marine Slug
ally sequester compounds from their prey. However, mem- ity to triophamine 6, the authors concluded that limaciam-
bers of the cladobranch family Tethydidae have been shown ine 7 likewise is produced de novo by L. clavigera.[
to produce deterrent compounds de novo, i.e. Melibe leo-
32]
nina was reported to acquire an odoriferous substance, 2,6-
dimethyl-5-heptenal via de novo biosynthesis.[
19,20]
Chemi-
cal studies of the Mediterranean Tethys fimbria (Tethydi-
dae) led to the characterization of many prostaglandin-
1
,15-lactones which also have been shown to be produced
[
21–24]
de novo.
During the current study, aiming to decipher defence
strategies within Cladobranchia and to understand the evo-
lutionary success (i.e. radiation) of subgroups within this
taxon, the unprecedented terpenoid 1 was obtained from
the Mediterranean slug D. pinnatifida, belonging to the
hitherto not studied family Dotidae. The structure of dotof-
ide (1) has a novel architecture, consisting of a sesquiter- from the dorid nudibranch Archidoris montereyensi, and terpenoid
penoid part including a substituted hexane ring similar to metabolites 4 and 5 known from green alga of the genus Cau-
the one present in carotenoids (i.e. β- and α-ionon ring) and
Figure 4. Structure of monocyclofarnesic acid glyceride 3 obtained
lerpa.[
25–28]
a hemiterpene unit, with both parts being interrupted by a
guanidine moiety.
No traces of the new D. pinnatifida-derived terpenoid 1
were detectable in the prey of this marine slug, Nemertesia
antennina. The latter, a member of the hydrozoan family
Aglaopheniidae is reliably reported as the exclusive food
source of D. pinnatifida. Likewise, the slugs investigated
here were collected directly from this hydrozoan. Aglao-
pheniidae are very well protected by large nematocysts
(stinging cells) which render them rather painful even for
human skin. Nevertheless, D. pinnatifida is able to consume
the polyps of N. antennina without any adverse reaction.
But in contrast to many other cladobranch relatives, which
sequester these stinging cells and use them for their de-
Figure 5. Structure of triophamine 6 and limaciamine 7 derived
[
6,16]
[13,16]
fence,
D. pinnatifida is not able to do so,
probably from the dorid nudibranchs Triopha catalinae and Limacia clavig-
era, respectively.[
29–32]
because the animal relies on chemical defence.
Distantly related compounds are known from dorid nu-
dibranchs (Anthobranchia), some of which display feeding
deterrent or ichthyotoxic properties. Thus, a structure show-
ing similarities with respect to the terpene part of com-
pound 1 is the monocyclofarnesic acid glyceride 3 which
Conclusions
The new terpenoid dotofide (1) was not detectable in the
was isolated from the dorid nudibranch Archidoris montere- slug‘s food source N. antennina. Based on the structural
yensis (Anthobranchia, Doridina) (Figure 4).[ Several do- similarity of the new terpenoid to compounds known from
rid nudibranchs, amongst others A. montereyensis, have animals of the sea slug clade Doridina, which have been
25]
been shown to be capable of de novo biosynthesis of ter- proven to synthesize toxic compounds de novo (e.g.[ ), it
31]
penoic acid glycerides.[
25,26]
Various structurally similar ter- is tempting to speculate that D. pinnatifida produces the
penoid metabolites, e.g. 4 and 5 (Figure 4), known from new terpenoid de novo as well. Other examples also illus-
green alga of the genus Caulerpa[ are assumed to be se- trate that nudibranchs have well developed biosynthetic
27]
[
9,26]
questered by the sacoglossan Tridachia crispata as defensive capabilities for generating terpenoids.
The lack of ade-
[
28]
agents. Other compounds resemble the new compound 1 quate compounds for sequestration in the prey N. antennina
with respect to the guanidine moiety. Triophamine 6 (Fig- could potentially have forced the slug to produce toxic com-
ure 5) which contains a rare diacylguanidine functionality pounds itself for protection against predators. Dotidae,
was derived from the bryozoan eating dorid Triopha catali- however are not closely related with Doridina, hence there
Graziani and An- is no evidence that the ability for de novo synthesis of these
dersen could show that the acyl residues of triophamine related structures may have evolved only once in a common
6) are formed de novo from five intact acetate units. Unfor- stemline. Rather, the structural similarities of the com-
[29,30]
nae (Anthobranchia, Doridina).
[
31]
(
tunately, feeding deterrency or toxicity of the compound pounds (see Figures 1, 4, and 5) may be due to constraints
has not been tested. The structurally similar compound lim- relating to the metabolic availability of precursors for bio-
aciamine 7 (Figure 5) was later found in a related species, synthesis. Thus, terpenoid units – in the case of 1 farnesyl-
Limacia clavigera (Doridina). Due to its structural similar- and dimethylallyl-pyrophosphate – as well as a guanidine
Eur. J. Org. Chem. 2011, 3733–3737
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3735

A. Putz, S. Kehraus, G. Díaz-Agras, H. Wägele, G. M. König
FULL PAPER
moiety may be available through the general terpenoid and each on the following day. All together, 64 D. pinnatifida individuals
equalling 1.13 g wet weight yielded 365 mg of extract. The D. pin-
natifida extract was submitted to vacuum liquid chromatography
amino acid (i.e. arginine) metabolism. It could also be en-
visaged that dotofide is produced by the oxidative cleavage
of a precursor terpenoid, e.g. a carotenoid-type compound
as known for retinal (Vit. A aldehyde). Further studies will
address the biosynthetic origin and the ecological role of
dotofide.
(VLC; RP18 5ϫ3 cm, water/methanol). The new terpenoid 1 was
found in the non-polar fraction that was eluted with 100% meth-
anol. This fraction was further purified by liquid chromatography
on Sephadex LH-20 medium (column 1.5ϫ11 cm) with 100%
methanol as eluent to yield 2.1 mg of the pure terpenoid 1.
The same extraction procedure was applied to the slug’s food, N.
antennina. The material (2.28 g wet weight) was extracted as de-
scribed above for the D. pinnatifida samples. A total of 877 mg of
extract was obtained. 432 mg of this extract was separated on VLC
under the same conditions as for the D. pinnatifida extract.
4
Experimental Section
General Experimental Procedures: Optical rotation was measured
at room temperature in MeOH on a Jasco DIP 140 polarimeter.
UV and IR spectra were obtained employing a Perkin–Elmer Spec-
Compound 1: Yellowish oil (2.1 mg; 0.19%). [α]2
= –3.6 (c = 0.14,
D
trum BX instrument. CD spectra were recorded in CHCl
temperature using a JASCO J-810–150S spectropolarimeter. All
NMR spectra were recorded in MeOD employing a Bruker Avance
3
at room
MeOH). UV (MeOH): λmax = 241 (ε = 16609), 276 nm (ε = 25951).
IR (ATR) ν˜ max = 3334, 2927, 2863, 1689, 1620, 1523, 1441, 1358,
–
1
1
13
1267, 1220, 1137, 1087 cm . H and C NMR spectroscopic data
–
300 DPX spectrometer. Spectra were referenced to residual solvent
see Table 1. LR-ESI-MS: m/z 358.3 (M – H) . HR-ESI-MS: calcd.
34 3 2
H N O
[M + H]+ m/z 360.2646, found 360.2659.
signals with resonances at δH/C 3.35/49.0. LC-ESIMS was per-
formed using an Agilent 1100 system with an API 2000 Triple Qua-
drupole LC/MS/MS with ESI source (Applied Biosystems/MDS
Sciex) and a DAD. HRESIMS were recorded on a Finnigan MAT
for C21
Compound 2: Colourless film (0.2 mg). CD (c = 0.2 mg/mL,
1
CHCl
3
): λ (Δε) = 292 (+1.23). H NMR (CDCl
, s), 1.09 (8Ј-H , s).
3
): δ = 2.12 (11Ј-
H
3
, s), 0.78 (9-H
3
3
95 spectrometer.
Ozonolysis: Compound 1 (1.5 mg) was dissolved in 2 mL of
Sample Collection: Samples of both Doto pinnatifida and its exclus-
ive food source, the hydrozoan Nemertesia antennina, were sampled
in Ferrol, Spain in April 2009. Specimen were collected via SCUBA
diving and subsequently stored in 70% ethanol. Extraction and
purification of the crude extract was performed in the laboratory
in Bonn.
CH OH and allowed to react with O for 20 min at –78 °C. Di-
3
3
methyl sulfide (5 drops) was then added and the solution was
stirred for additional 45 min. The solvent was evaporated under
reduced pressure to obtain 0.7 mg of a crude product which was
purified by chromatography over a 3 mL silica solid-phase extrac-
tion column (J. T. Baker) yielding 2 as a colourless film (0.2 mg).
Extraction and Purification: The ethanol in which Doto pinnatifida
samples were stored was evaporated and gave the first extract. The
remaining material was extracted exhaustively in methanol over-
night. Extraction was repeated twice with fresh methanol for 1 h
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data and other relevant information are in-
cluded for compounds 1 and 2. This material is available on the
WWW under http://www.eurjoc.org or from the author.
Table 1. NMR spectroscopic data obtained for the new terpenoid 1.
C, mult.[a,b,e]
δ
H
[a,b]
(J in Hz)
COSY[a,c]
HMBC[a,d]
NOESY[a,c]
δ
1
2
3
4
150.3, C
33.3, CH
24.8, CH
37.1, CH
2
2
2
2.10, m
1.59, m
a: 1.28, m
b: 1.58, m
3, 4a, 4b, 7b
2, 4a, 4b
a: 2, 3, 4b, 6
b: 2, 3, 4a
1, 3, 4, 7
1, 4, 5
a: 5, 6, 8
b: 2, 3, 6, 8, 9
a: 4b, 8
b: 4a, 9
5
6
7
35.8, C
54.9, CH
110.1, CH
1.80, dd (3.0, 11.4)
a: 4.63, d (2.4)
b: 4.85, br. s
0.98, s
0.91, s
a: 1.65, m
b: 1.72, m
a: 1.99, m
b: 2.17, m
4a, 7a, 1Ј, 2Ј
a: 6, 7b
b: 2, 7a
1, 4, 5, 7, 1Ј, 2Ј
a: 1, 2, 6
b: 2, 6
4, 5, 6, 9
4, 5, 6, 8
4, 5, 6, 2Ј
2, 8, 9
a: 6, 7b, 11Ј
b: 2, 7a,
2
8
9
1
28.8, CH
26.9, CH
25.6, CH
3
3
2
Ј
Ј
6, 2Ј
6, 1Ј
2
40.9, CH
2
3Ј, 4Ј, 11Ј
4Ј
2Ј
3
4
5
6
7
8
9
1
1
1
Ј
Ј
Ј
Ј
Ј
Ј
Ј
0Ј
1Ј
2Ј
161.1, C
121.8, CH
175.8, C
160.8, C
175.5, C
121.4, CH
157.1, C
27.7, CH
19.3, CH
20.4, CH
5.87, br. s
11Ј
2Ј, 3Ј, 5Ј, 11Ј
5.87, br. s
10Ј, 12Ј
7Ј, 10Ј, 12Ј
10Ј, 12Ј (w)
8Ј, 12Ј
3
3
3
1.95, d (0.9)
2.21, d (1.0)
2.23, d (1.0)
8Ј, 12Ј
2Ј, 4Ј
8Ј, 10Ј
7Ј, 8Ј, 9Ј, 12Ј
2Ј, 3Ј, 4Ј, 5Ј
7Ј, 8Ј, 9Ј, 10Ј
8Ј (w), 10Ј
4
[a] [D ]MeOH, 300/75.5 MHz. [b] Assignments are based on extensive 1D and 2D NMR experiments (HMBC, HSQC, COSY). [c]
Numbers refer to proton resonances. [d] Numbers refer to carbon resonances. [e] Implied multiplicities determined by DEPT.
3736
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3733–3737

Guanidine-Interrupted Terpenoid from a Marine Slug
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Published Online: April 28, 2011
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