Biochemical Systematics and Ecology 49 (2013) 101–106

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Biochemical Systematics and Ecology

journal homepage: www.elsevier.com/locate/biochemsyseco

Isomalabaricane triterpenes with potent protein-tyrosine

phosphatase 1B (PTP1B) inhibition from the Hainan sponge
Stelletta sp.
Duo-Qing Xue a, Shui-Chun Mao b, **, Xiao-Qing Yu b, Yue-Wei Guo a, *
a
State key laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
b
School of Pharmacy, Nanchang University, Nanchang 330006, PR China

a r t i c l e i n f o a b s t r a c t

Article history: A new isomalabaricane triterpene, stellettin N (1), has been isolated together with five
Received 1 November 2012 known analogues, stellettin H (2), rhabdastrellic acid A (3), stellettin G (4), stellettin D (5),
Accepted 9 March 2013 and 22,23-dihydrostellettin D (6), from the Hainan sponge Stelletta sp. The structure of 1
Available online 13 April 2013
was elucidated on the basis of detailed spectroscopic analysis of its methyl ester (7) and by
comparison of NMR data of 7 with those of related known compounds. Compounds 3–8
Keywords:
were evaluated for their inhibitory activity against hPTP1B and the result showed com-
Sponge
pound 4 had a strong hPTP1B inhibitory activity with IC50 value of 4.1
0.9 mM. Compound
Stelletta sp.
Isomalabaricane triterpenes
4 also exhibited weak cytotoxicity against A549 and HL-60 cells at a concentration of 10 mM.
Cytotoxicity Furthermore, the chemotaxonomic significance of these compounds was also summarized.
PTP1B inhibitor Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Marine sponges of the genus Stelletta, belonging to the family Ancorinidae (order Astrophorida, class Demospongiae, and
phylum Porifera), are reported to contain various sterols (Lin et al., 2007; Li et al., 1994), alkaloids (El-Naggar et al., 2008;
Matsunaga et al., 1999), isomalabaricane-type triterpenes (Lin et al., 2007; McCormick et al., 1996; Su et al., 1994), fatty acids
(Lee et al., 2003; Bergquist et al., 1984), dimeric macrolide glycosides (Erickson et al., 2002), polymethoxydienes (Rao and
Faulkner, 2002), phosphorus-containing clavosines (Fu et al., 1998), depsipeptides (Lu et al., 2011), porphyrin analogues,
swinholide polyketides, carotenoids, and diketopiperazines (Wegerski et al., 2004). Of these secondary metabolites, numerous
isomalabaricane-type triterpenoids have been found to have significant cytotoxic activity towards tumour cell lines.
As part of our ongoing programme focused towards the isolation of biologically active compounds from Chinese marine
invertebrates (Mao et al., 2007a, 2007b, 2006; Huang et al., 2004), we carried out a chemical investigation on the sponge
Stelletta sp. Careful chromatographic separation of the Et2O-soluble portion of acetone extract of the sponge resulted in the
isolation of a new isomalabaricane triterpene, stellettin N (1), together with five known analogues, stellettin H (2), rhab-
dastrellic acid A (3), stellettin G (4), stellettin D (5), and 22,23-dihydrostellettin D (6). The structure of 1 was elucidated on the
basis of detailed spectroscopic analysis of its methyl ester (7) and by comparison of NMR data of 7 with those of related known
compounds. Compounds 3–8 were evaluated in vitro for their cytotoxic and hPTP1B inhibitory activities. This paper deals with
the isolation and structure elucidation of the new compound 1 based on spectroscopic analysis of its methyl ester (7), and the
biological evaluation of all the compounds isolated.Fig. 1

* Corresponding author. Tel.: þ86 21 50805813; fax: þ86 21 50807088.

** Corresponding author. Tel./fax: þ86 21 6361839.
E-mail addresses: maoshuichun@ncu.edu.cn (S.-C. Mao), ywguo@mail.shcnc.ac.cn, yw_guo58@yahoo.com.cn (Y.-W. Guo).

0305-1978/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bse.2013.03.001
102 D.-Q. Xue et al. / Biochemical Systematics and Ecology 49 (2013) 101–106

Fig. 1. Chemical structures of compounds 1–9.

2. Materials and methods

2.1. General experimental procedures

Optical rotations were measured with a Perkin–Elmer 241 MC polarimeter. UV spectra were recorded on a Varian Cary 300
Bio spectrophotometer. IR spectra were recorded on a Nicolet-Magna FT-IR 750 spectrometer. NMR spectra were recorded on
a Bruker DRX-400 spectrometer with the residual CDCl3 (dH 7.26 ppm, dC 77.6 ppm) as an internal standard. ESI-MS and HR-
ESI-MS spectra were recorded on a Q-TOF Micro LC-MS-MS mass spectrometer. Reversed-phase HPLC {Agilent 1100 series
liquid chromatography using a VWD G1314A detector at 210 nm and a semi-preparative ODS-HG-5 [5 mm, 10 mm
(i.d.)  25 cm] column} was also employed. Commercial Si gel (Qing Dao Hai Yang Chemical Group Co., 200–300 and 400–600
mesh) was used for CC, and precoated Si gel plates (Yan Tai Zi Fu Chemical Group Co., G60 F-254) were used for analytical TLC.

2.2. Animal material

Specimens of Stelletta sp., identified by Prof. J.-H. Li at Institute of Oceanology, Chinese Academy of Sciences, were collected
off Lingshui Bay, Hainan Province, China, in November 2003, and were frozen immediately after collection. A voucher sample
(YAL-37) is available for inspection at the Herbarium of Shanghai Institute of Materia Medica, CAS.

2.3. Extraction and isolation

Frozen specimens of the sponge (65 g, dry weight) were triturated and exhaustively extracted with acetone (1 L  3) at
room temperature. The extract was concentrated in vacuo, and the resulting residue (2.2 g) was partitioned between Et2O and
H2O. The Et2O-soluble portion (1.6 g) was chromatographed on a silica gel column using light petroleum ether with increasing
amount of EtOAc as eluent to give eight fractions (I–VIII) on the basis of TLC analysis. Fraction III, eluted with petroleum ether/
EtOAc (8:2), was further purified by Si gel CC eluting with CHCl3/MeOH (95:5) to afford compounds 5 (5.7 mg) and 6 (8.2 mg).
Fraction VI, eluted with petroleum ether/EtOAc (6:4), was further chromatographed on Si gel CC using a stepped gradient
(CHCl3/CH3OH, 9:1–7.5:2.5) to obtain pure compounds 3 (5.7 mg) and 4 (18.2 mg) as well as a mixture of 1 and 2 (30.0 mg),
which was separated after methylation with diazomethane by RP-HPLC [semipreparative ODS-HG-5 (5 mm, 250  10 mm),
CH3OH/H2O (4:6), 2.0 mL/min] to afford the methyl esters 7 (4.2 mg) and 8 (5.1 mg), derived from 1 and 2, respectively.

2.4. Spectroscopic data of compound 7

Methyl ester of stellettin N (7): yellow oil; [a]25D 68.0 (c ¼ 0.20, CHCl3); UV (CHCl3) lmax (logε): 410 (4.65), 392 (4.66),
294 (3.55); IR (KBr) nmax: 3360 (broad), 1731, 1709, 1691, 1675 cm1; 1H and 13C NMR see Table 1; HR-ESI-MS: m/z 545.3242
[M þ Na]þ (calcd for C33H46O5Na, 545.3240).

2.5. Cytotoxic bioassay

The cytotoxic activities of the isolated compounds were assessed using the MTT method. The cells were grown in DMEM
media supplemented with 10% fetal bovine serum in a humidified atmosphere of 5% CO2 and 95% air. The cells were incubated
with varying concentrations of each compound, and cell survival was detected at 37  C by MTT method. Cell suspensions were
plated in 96-well plates at a density of 2  104 cells mL1. 10 mL of the test compound solutions (in DMSO) at various
 D.-Q. Xue et al. / Biochemical Systematics and Ecology 49 (2013) 101–106 103

Table 1
1
H and 13C NMR spectral data of compound 7a and 9b.

Position 7 9

dH (mult., J in Hz) dC (muit.) dH (mult., J in Hz) dC (muit.)

1 1.42 (m) 33.0 (t) 2.15 (m) 31.3 (t)
1.60 (m) 1.49 (m)
2 1. 64 (m) 25.1 (t) 2.71 (ddd, 16.1, 12.2, 5.9) 33.5 (t)
1.82 (m) 2.38 (m)
3 4.57 (m) 80.7 (d) 219.2 (s)
4 38.1 (s) 46.8 (s)
5 1.78 (m) 46.7 (d) 2.39 (dd, 13.2, 2.4) 45.4 (d)
6 1.45 (m) 18.4 (t) 1.50 (m) 19.8 (t)
1.70 (m) 1.58 (m)
7 2.15 (m) 39.5 (t) 2.16 (m) 38.5 (t)
8 44.7 (s) 45.0 (s)
9 1.83 (m) 49.9 (d) 1.85 (t, 10.6) 47.8 (d)
10 35.4 (s) 34.8 (s)
11 2.20 (m) 36.6 (t) 2.20 (br d, 10.6) 36.7 (t)
12 207.6 (s) 207.0 (s)
13 147.2 (s) 146.2 (s)
14 141.3 (s) 142.0 (s)
15 6.67 (d, 15.0) 133.9 (d) 6.67 (d, 15.1) 133.7 (d)
16 7.03 (dd, 11.7, 15.0) 131.9 (d) 7.03 (dd, 15.1, 11.6) 132.2 (d)
17 6.34 (d, 11.7) 134.2 (d) 6.34 (d, 11.6) 134.1 (d)
18 2.32 (s) 14.4 (q) 2.32 (s) 14.5 (q)
19 0.92 (s) 22.3 (q) 0.84 (s) 23.5 (q)
20 139.1 (s) 139.4 (s)
21 2.03 (s) 13.2 (q) 2.00 (s) 13.2 (q)
22 6.43 (d, 15.0) 142.8 (d) 6.43 (d, 15.1) 142.6 (d)
23 7.50 (dd, 11.4, 15.0) 127.0 (d) 7.50 (dd, 15.1, 11.2) 127.2 (d)
24 6.51 (d, 11.4) 141.2 (d) 6.51 (d, 11.2) 141.0 (d)
25 126.0 (s) 126.2 (s)
26 2.01 (s) 21.0 (q) 2.02 (s) 21.0 (q)
27 168.0 (s) 167.9 (s)
28 1.02 (s) 29.0 (q) 1.10 (s) 29.2 (q)
29 0.89 (s) 17.0 (q) 1.03 (s) 19.4 (q)
30 1.40 (s) 25.9 (q) 1.41 (s) 25.9 (q)
OCOCH3 2.07 (s) 21.3 (q)
OCOCH3 171.1 (s)
OCH3 3.78 (s) 51.5 (s) 3.77 (s) 51.5 (s)
a
Spectra were recorded at 400 MHz for 1H and 100 MHz for 13C in CD3OD. d Values referenced to CH3OH (dH ¼ 3.33, dC ¼ 49.0).
b
Data measured in CDCl3 reported in reference 2 (McCormick et al., 1996).

concentrations were added to each well and the culture was incubated for 72 h at 37  C in a 5% CO2 incubator. After the
treatment 20 mL of the MTT solution (5 mg/mL) was added to each well and cells were incubated at 37  C in 5% CO2. After
incubation for 3 h, the medium was removed and add 100 mL DMSO. The absorbance was measured at 550 nm. Dose response
curves were generated and the concentration of each compound required to inhibit cell proliferation by 50% (IC50) was
calculated from the linear portion of the log dose response curves.

2.6. PTP1B bioassay

PTP1B (human, recombinant) was purchased from BIOMOLÒ International LP (USA) and the enzyme activity was measured
using pNPP as described previously (Oh et al., 2004). To each well of a 96-well plate (final volume: 200 mL) was added 2 mM
pNPP and PTP1B (0.05–0.1 mg) in a buffer containing 50 mM citrate (PH 6.0), 0.1 M NaCl, 1 mM EDTA and 1 mM dithiothreitol
(DTT) with or without test compounds. Following incubation at 37  C for 30 min, the reaction was terminated with 10 N
NaOH. The amount of produced p-nitrophenol was estimated by measuring the absorbance at 405 nm. The non-enzymatic
hydrolysis of 2 mM pNPP was corrected for by measuring the increase in absorbance at 405 nm obtained in the absence of
PTP1B enzyme.

3. Results and discussion

The structures of the known compounds were readily determined as stellettin H (2) (Tasdemir et al., 2002), rhabdastrellic
acid A (3) (Rao et al., 1997), stellettin G (4) (McCormick et al., 1996), stellettin D (5) (McCormick et al., 1996), and 22,23-
dihydrostellettin D (6) (Tang et al., 2005) by extensive spectroscopic analysis combined with careful comparisons with the
reported spectroscopic data.
The mixture of compounds 1 and 2 proved very difficult to be separated. Exhaustive efforts to separate the mixture using
column chromatography and HPLC employing different stationary and mobile phase were unsuccessful in even partially
104 D.-Q. Xue et al. / Biochemical Systematics and Ecology 49 (2013) 101–106

Fig. 2. Selected 1H–1H COSY and HMBC correlations of compound 7.

resolving the geometric isomers. Treatment of the mixture with diazomethane allowed purification of the methyl esters 7 and
8, derived from 1 and 2, respectively. Literature checking revealed that 1 is a new isomalabaricane, namely stellettin N.
Compound 7 was obtained as a yellow oil. Its molecular formula, C33H46O5, was determined by HR-ESI-MS at m/z 545.3242
[M þ Na]þ (calcd 545.3240), in combination with 13C NMR (DEPT) experiments, suggesting the presence of 11 degrees of
unsaturation. The IR spectrum showed absorption peaks at 1731, 1709 and 1691 cm–1, indicating the presence of three car-
bonyls, while the UV bands at 410, 392 and 294 nm indicated the presence of a highly conjugated polyene system, as seen for
the side chain of isomalabaricane triterpenoids. The 1H NMR spectrum (Table 1) exhibited six olefinic protons at dH 7.50 (dd,
J ¼ 11.4, 15.0 Hz), 7.03 (dd, J ¼ 11.7, 15.0 Hz), 6.67 (d, J ¼ 15.0 Hz), 6.51 (d, J ¼ 11.4 Hz), 6.43 (d, J ¼ 15.0 Hz), and 6.34 (d,
J ¼ 11.7 Hz), seven methyl singlets at dH 0.89, 0.92, 1.02, 1.40, 2.01, 2.03, and 2.32, with the latter three signals attributed to
olefinic methyls and the remaining four methyls to sp3 quaternary carbons, an oxygenated methine at dH 4.57 (m), a methoxy
group at dH 3.78 (3H, s), as well as an acetyl at dH 2.07 (3H, s).
Inspection of the 13C NMR spectrum data (Table 1) for 7 revealed the presence of five double bonds (10 sp2 resonances
between dC 120–150), two ester carbonyls (dC 168.0 and 171.1), a ketone (dC 207.6), an oxymethine carbon (dC 80.7), a methoxy
group (dC 51.5), ten sp3 resonances (five CH2, two CH, and three quaternary carbons), and seven methyl groups. These NMR
features, together with the IR and UV absorption spectra, implied that 7 is an isomalabaricane triterpenoid possessing one
COOCH3 and an extra acetyl functionalities.
The NMR spectra mentioned above of 7 were strongly reminiscent of those of 9, a synthetic product derived from
methylation of stellettin F (McCormick et al., 1996). A comparison of the NMR data of 7 and 9 revealed that the only difference
between them resided in replacement of the ketone in 9 by an acetoxy group, in agreement with a mass difference of 44 Da,
while the rest of the structure of 7 is the same as in 9. This was supported by the disappearance of the ketone carbonyl
resonance at dC 216.4 (C-3) in the 13C NMR spectrum of 7 and the emergence of new NMR signals at dH 4.57 and 2.07 (1H) and
dC 80.7, 21.3, and 171.1 (13C) in 7. The acetoxy group attached to C-3 (dC 80.7) was determined by the HMBC cross-peaks (Fig. 2)
between H-3 and CH3-28, CH3-29, and an acetoxy carbonyl. Additionally, the HMBC correlations traced from CH3-26 to C-24,
C-25, and COOCH3 carbonyl (C-27) further confirmed that 7 possessed a polyene side chain with the terminal COOCH3 moiety.
The relative stereochemistry of 7 was substantiated by scalar coupling constants and NOESY experiments (Fig. 3). As for the
ring junctions of the tricyclic core, key NOESY cross-peaks between the pairs H-5/H3-28, H-5/H3-30, H-9/H3-19, as well as
H3-19/H3-29 suggested a trans-syn-trans stereochemistry, consistent with an isomalabaricane skeleton in which ring B adopts
a twist-boat conformation (McCabe et al., 1982). The chemical shift of H-3 (d 4.57, m) showed the equatorial (b) orientation of
the acetoxy group (Meragelman et al., 2001; Oku et al., 2000; McCormick et al., 1996; Ryu et al., 1996). This stereochemistry
was confirmed by NOE correlations between H-3/H-5 and H-3/H3-28. The J value of 15.0 Hz between H-15/H-16 and H-22/H-
23, together with ROESY effects observed for H3-18/H-16, H-16/H3-21, H3-21/H-23, H-15/H-17, H-22/H-24, and H-24/H3-26,
firmly secured the (E)-configuration of the double bonds D13(14), D15(16), D17(20), and D22(23) and the (Z)-configuration at D24(25)
on the pentaene side chain. Detailed analysis of its 2D NMR (1H–1H COSY, HMQC, HMBC, and NOESY) allowed unambiguous
assignments of 1H and 13C NMR data of 7 (Table 1). Therefore, the structure of 7 was elucidated as methyl ester of stellettin N.
The crude Et2O-soluble extract of the sponge exhibited significant PTP1B inhibitory activity. To trace the responsible
compound, compounds 3–8 were evaluated the inhibitory activity against hPTP1B immediately after isolation, and the result

Fig. 3. Selected NOEs observed in the NOESY spectrum of 7.

 D.-Q. Xue et al. / Biochemical Systematics and Ecology 49 (2013) 101–106 105

showed that stellettin G (4) had a strong PTP1B inhibitory activity with IC50 value of 4.1
0.9 mM. The known PTP1B inhibitor
ursolic acid (IC50 ¼ 3.6
0.2 mM) were used as positive control in this assay. In addition, the cytotoxicity against A549 and
HL-60 cell lines was also tested for all the compounds isolated, however, the result was disappointing as only compound 4
exhibited weak cytotoxicity against A549 and HL-60 cells with 64.0% and 86.8% inhibition at a concentration of 10 mM,
respectively.

4. Chemotaxonomic significance

The present study reported the isolation and identification of six isomalabaricane-type triterpenoids (1–6) from the
sponge Stelletta sp. Among them, compound 1 was identified as a new metabolite, while compound 6 is reported from the
Stelletta genus for the first time.
Isomalabaricanes are a class of trans-syn-trans 6,6,5-tricyclic triterpenoid natural products previously reported only in
marine sponges of the four genera, comprising Stelletta (Lin et al., 2007; McCormick et al., 1996; Su et al., 1994), Jaspis (family
Ancorinidae) (Meragelman et al., 2001; Kobayashi et al., 1996), Geodia (family Geodiidae) (Zhang and Che, 2001), and
Rhabdastrella (family Ancorinidae) (Li et al., 2012; Clement et al., 2006; Bourguet-Kondracki et al., 2000), which belong to the
same order Astrophorida. Their molecular structures are characterized by the presence of a highly conjugated polyene system
as a side chain attached to C-13, while a ketone functionality is always located at C-12 of the tricyclic core. Interestingly, in the
present study, we found a new minor isomalabaricane-type triterpenoid, stellettin N (1), from Stelletta sp. The occurrence of
compound 1 might have some chemotaxonomic implications. In previous study, compounds 2–6 were isolated from other
species of the order Astrophorida. To the best of our knowledge, compound 6 was characterized for the first time from the
genus Stelletta but has only been reported from an unidentified sponge of the genus Jaspis (Tang et al., 2005), which supports
that there are taxonomic relationships between the two genera, and the occurrence of 6 could have some chemotaxonomic
implications. This is the third time that compound 4 has been found in nature, and it was only recorded from the Stelletta
genus (Mckee et al., 1997; McCormick et al., 1996). Therefore, compound 4 may possibly be utilized for useful taxonomic
markers of the genus Stelletta. Compounds 2, 3, and 5 were all reported from three genera Stelletta, Jaspis, and Rhabdastrella
(Li et al., 2010; Tasdemir et al., 2002; Mckee et al., 1997; Rao et al., 1997; McCormick et al., 1996), indicating a close
chemotaxonomic relationship between the three genera.
According to the above results, the existence of six isomalabaricane-type triterpenoids in the Stelletta genus could partly
provide the chemotaxonomic evidence. Further investigations on isomalabaricane-type triterpenoids of the species of Stel-
letta as well as other marine sponges should be conducted to confirm the chemotaxonomic significance of isomalabaricane-
type triterpenoids in the genus Stelletta.

Acknowledgements

This research work was financially supported by the National Marine 863 Project (No. 2013AA092902), the Natural Science
Foundation of China (Nos. 81273430, 21021063, 21162016, 30730108, and 20862013). We are indebted to Dr. Ernesto Mollo of
ICB-CNR, Italy, for the collection of the animal material. We are also grateful to Prof. Jia Li of SIMM-CAS, for the biological
assays.

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