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Brominated polyunsaturated lipids with protein tyrosine phosphatase-1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria ab

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b

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Wen-Fei He , Lin-Fu Liang , You-Sheng Cai , Li-Xin Gao , Yu-Fen b

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Li , Jia Li , Hai-Li Liu & Yue-Wei Guo a

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China

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State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Published online: 01 Apr 2015.

To cite this article: Wen-Fei He, Lin-Fu Liang, You-Sheng Cai, Li-Xin Gao, Yu-Fen Li, Jia Li, Hai-Li Liu & Yue-Wei Guo (2015): Brominated polyunsaturated lipids with protein tyrosine phosphatase-1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria, Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2015.1026334 To link to this article: http://dx.doi.org/10.1080/10286020.2015.1026334

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Journal of Asian Natural Products Research, 2015 http://dx.doi.org/10.1080/10286020.2015.1026334

Brominated polyunsaturated lipids with protein tyrosine phosphatase1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria Wen-Fei Hea,b1, Lin-Fu Liangb1, You-Sheng Caib, Li-Xin Gaob, Yu-Fen Lib, Jia Lib, Hai-Li Liub* and Yue-Wei Guob*

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School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; bState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China (Received 24 December 2014; final version received 3 March 2015) A new brominated polyunsaturated lipid, methyl (E,E)-14,14-dibromo-4,6,13tetradecatrienoate (1), along with three known related analogues (2 – 4), were isolated from the Et2O-soluble portion of the acetone extract of Chinese marine sponge Xestospongia testudinaria treated with diazomethane. The structure of the new compound was elucidated by detailed spectroscopic analysis and by comparison with literature data. Compound 3 exhibited significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), a key target for the treatment of type II diabetes and obesity, with an IC50 value of 5.30 ^ 0.61 mM, when compared to the positive control oleanolic acid (IC50 ¼ 2.39 ^ 0.26 mM). Keywords: brominated polyunsaturated lipid; sponge; Xestospongia testudinaria; PTP1B inhibitory activity

1.

Introduction

Tremendous experimental data have proved that protein tyrosine phosphatase 1B (PTP1B) is a promising drug target for the treatment of type II diabetes and obesity because of its negative regulation of both insulin and leptin signalling [1 –3]. Great efforts in the search for new PTP1B inhibitors as drug candidates from natural sources have resulted in the discovery of numerous bioactive compounds, including phenolic compounds, terpenes, steroids, N- or S-containing compounds, etc., of which, only a few are marine natural products [4,5]. Sponges of the genus Xestospongia (class Demospongia, order Haplosclerida, family Petrosiidae), known as barrel sponges, are a rich source of brominated polyunsaturated lipids with intriguing

structural features characterized by containing the various numbers of bromines, lengths of alkyl chains, patterns of substitutions, degrees of oxidations, and positions of enynic bonds. This type of secondary metabolites not only displays a remarkable chemical diversity, but also exhibited various biological activities ranging from antitumoral, antibacterial, antifungal, to inhibiting pancreatic lipase, HIV-1 integrase [6,7]. The complex and unique structures of brominated polyacetylenes have also attracted the attention of synthetic chemists for their total synthesis [8]. In the course of our ongoing project searching for PTP1B inhibitors from Chinese marine organisms [9], we recently collected the sponge Xestospongia testudinaria off the Weizhou Island, Guangxi Autonomous Region, China. The animals

*Corresponding author. Email: [email protected]; [email protected] q 2015 Taylor & Francis

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have been well recognized for the production of various secondary metabolites, such as brominated polyunsaturated lipids [10 – 17], steroids [16,18], sterol esters [19], etc. Previous chemical investigation on the species carried out by our group had resulted in the isolation and structure elucidation of eight new brominated polyacetylenic compounds, named xestonarienes A –H, as a new class of pancreatic lipase inhibitors [7]. Our continuing investigation of the minor acetylenic components of the sponge extract has led to the isolation of a new brominated polyunsaturated lipid, namely methyl (E, E)-14,14-dibromo-4,6,13-tetradecatrienoate (1), and three known analogues (2 –4) (Figure 1). The structure of the new compound was elucidated by detailed spectroscopic analysis and by comparison with reported data. In addition, all the isolates were evaluated in vitro for PTP1B and pancreatic lipase inhibitory activities. In this paper, we report the isolation, structure elucidation,

2.

activity

Br

11

9

Freshly collected animals were immediately put at 2 208C and kept frozen until used. The frozen material (4.0 kg, dry weight) was extracted exhaustively with acetone (16 £ 3.0 l) at room temperature. The Et2O-soluble portion of the acetone extract was treated with diazomethane and then repeatedly subjected to silica gel column chromatography to afford four brominated polyunsaturated lipids (1– 4). The three known compounds 2–4 were readily identified as methyl (Z, E)-14,14dibromo-4,6,13-tetradecatrienoate (2) [20], methyl 18-bromo-(17Z)-octadeca-l7-ene5,7,15-triynoate (3) [12], and methyl 18bromo-(13Z,17E)-octadeca-13,17-diene5,7,15-triynoate (4) [21], respectively, on the basis of detailed spectroscopic analysis and by comparison with reported data. Furthermore, 13C NMR spectral data of compounds 3 and 4 were totally assigned

7

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3 1

14

12

10

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O

Br 1 4E 2 4Z O O

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3 Br

O O 4

Figure 1. Structures of compounds 1 –4.

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Results and discussion

O 13

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Br 14

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Br 11

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Figure 2.

1

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O

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O

a

H 2 1H COSY and selected HMBC correlations of compound 1.

since these data had not yet been reported in their corresponding literatures. Compound 1 was isolated as colorless oil. Its molecular formula was determined to be C15H22O2Br2 by HREIMS (m/z 391.9982 [M]þ, calcd 391.9987), which corresponded to four degrees of unsaturation. The LREIMS of 1 displayed a series of characteristic triple peaks, such as at m/z 392, 394, and 396, corresponding to the [M]þ isotopic peaks, with relative intensities of approximately 1:2:1 ratio, indicating the presence of two bromine atoms in the molecule. The 13C NMR spectral data of 1 showed the presence of seven sp2 carbon atoms (1 £ CvO, 1 £ CvCH, 2 £ CHvCH) at lower field and eight sp3 carbon atoms at higher field (1 £ OCH3, 7 £ CH2), accounting for four degrees of unsaturation. There are no remaining degrees of unsaturation indicating an acyclic skeleton for compound 1. Analogous to co-occurring 2, the characteristic absorptions in the UV spectrum at lmax (log 1) 230 (4.33) nm indicated the presence of a conjugated diene moiety in 1 [20]. This observation was in agreement with the signals in its 1H and 13C NMR spectra (dH 5.55 [1H, dt, J ¼ 14.5, 7.6 Hz, H-4], 6.03 [1H, dd, J ¼ 14.5, 10.5 Hz, H-5], 5.99 [1H, dd, J ¼ 14.6, 10.5 Hz, H-6], 5.58 [1H, dt, J ¼ 14.6, 7.2 Hz, H-7], and dC 129.6 [d, C4], 131.4 [d, C-5], 130.1 [d, C-6], 133.2 [d, C-7]). The location of the conjugated diene at C-4 to C-7 in 1 could be deduced from the correlations of H2-2/H2-3/H-4/H-5/H6/H-7 as shown in 1H – 1H COSY spectrum (Figure 2). The 4E,6E configurations for the conjugated double bonds in 1 were inferred from the 1H NMR coupling

constants (J4,5 ¼ 14.5 Hz; J6,7 ¼ 14.6 Hz) of the olefinic protons [20,22,23]. Due to the change in the orientation of the D4 double bond, the signal of H-4 was shifted downfield significantly (from dH 5.26 in 2 to 5.55 in 1) [11]. The remaining double bond (dC 138.8 [d, C-13], 88.5 [s, C-14]) was assigned to a v, v-dibromovinylidene group [20]. Partial structures a and b (Figure 2), which were located at the two terminals of the molecule, were identified by the analysis of the 1H NMR data of 1 in comparison with those of 2. The proton sequence from H-7 to H-13 as established by the 1H – 1H COSY experiment and HMBC correlations of H-7 to C-8/C-9 and H-13 to C-11/C-12 (Figure 2) fully supported that 1 is the D4 isomer of 2. It is well known that brominated polyunsaturated lipids are widely distributed in sponge of genus Xestospongia. However, polyethylene lipids with C14 carbon chain lengths containing a v, vdibromovinylidene group are uncommon for the species. Literature survey revealed that the known compound 2 [20] is the first example of the aforementioned structural type. And herein reported new compound 1 is the second case of polyacetylene bearing a v, v-dibromovinylidene terminal found from the sponge genus Xestospongia. Compounds 1 –4 have been evaluated for their inhibitory activity against PTP1B enzyme, a key target for the treatment of type II diabetes and obesity [4], and pancreatic lipase inhibitory effects. The bioassay results showed that only 3 exhibited significant PTP1B inhibitory activity with an IC 50 value of 5.30 ^ 0.61 mM, and when compared to

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the positive control oleanolic acid (IC50 ¼ 2.39 ^ 0.26 mM), all tested compounds did not show pancreatic lipase inhibitory activity at a concentration of 50 mM. 3.

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3.1

Experimental General experimental procedures

UV spectrum was recorded on a Varian Cary 300 Bio spectrophotometer (Varian, USA). IR spectrum was recorded on a Nicolet Magna FT-IR 750 spectrometer (Thermo, USA). NMR spectra were measured on a Bruker DRX-400 (400 MHz for 1H and 100 MHz for 13C) spectrometer (Bruker Biospin AG, Fa¨llanden, Germany), in ppm with the residual CDCl3 (dH 7.26 and dC 77.0) as internal standard, J in Hz. The EIMS and HRESIMS data were recorded on a FinniganMAT-95 mass spectrometer (FinniganMAT, San Jose, CA, USA). Commercial silica gel (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China, 200 – 300 and 400 – 600 mesh) was used for column chromatography, and precoated silica gel plates (Yan Tai Zi Fu Chemical Group Co., Yantai, China, G60 F-254) were used for analytical TLC. 3.2

Biological material

The specimens of X. testudinaria, identified by Dr Nicole J. de Voogd (National Museum of Natural History, The Netherlands), were collected by scuba at Weizhou Island, Guangxi Autonomous Region, China, in September 2011, at a depth of 215 m. A voucher specimen (No. 11WZ-2) is available for inspection at the Shanghai Institute of Materia Medica, CAS. 3.3

Extraction and isolation

The frozen animals (4.0 kg, dry weight) were cut into pieces and extracted exhaustively with acetone at room temperature (16 £ 3.0 l). The organic extract was evaporated

to give a brown residue, which was partitioned between Et2O and H2O. The Et2O solution was concentrated under reduced pressure to give a dark brown residue (109.5 g), which was fractionated by silica gel column chromatography (CC) eluting with a step gradient (0–100% ethyl acetate (EA) in petroleum ether (PE)), yielding nine fractions (Fr. A – I). Fr. F (5.6 g), which consisted of brominated polyunsaturated lipids as detected by 1H NMR technique, was treated with diazomethane and then fractionated by gradient silica gel CC (1–100% EA in PE) to afford 10 sub-fractions (Fr. F1–F10). The subfraction Fr. F2 (417.5 mg) was purified by 400–600 mesh silica gel (PE:EA [40:1]), yielding compounds 1 (5.0 mg) and 2 (21.3 mg). Similarly, compound 3 (5.0 mg) was obtained from sub-fraction Fr. F3 (266.8 mg) when subjected to 400 – 600 mesh silica gel CC (PE:EA [35:1]). Repeated 400–600 mesh silica gel CC (PE: EA [30:1–25:1]) of sub-fraction Fr. F4 (325.2 mg) yielded compound 4 (13.4 mg).

3.3.1 Methyl (E,E)-14,14-dibromo4,6,13-tetradecatrienoate (1) Colorless oil; UV (MeOH) lmax (log 1) 230 (4.33) nm; IR (KBr) nmax 2857, 1741, 1635, 1435, 1170 cm21; for 1H and 13C NMR spectral data, see Table 1; EIMS: m/ z 392, 394, 396 ([M]þ, 1:2:1); HR-EI-MS: m/z 391.9982 [M] þ (calcd for C15H22O79 2 Br2, 391.9987).

3.3.2 Methyl 18-bromo-(17Z)-octadeca17-ene-5,7,15-triynoate (3) Colorless oil; 13C NMR (CDCl3, 100 MHz): d 173.4 (C-1, s), 32.7 (C-2, t), 23.5 (C-3, t), 18.7 (C-4, t), 76.0 (C-5, s), 66.2 (C-6, s), 65.2 (C-7, s), 77.8 (C-8, s), 19.1 (C-9, t), 28.1 (C-10, t), 28.3 (C-11, t), 28.2 (C-12, t), 28.2 (C-13, t), 19.6 (C-14, t), 99.0 (C-15, s), 76.7 (C-16, s), 116.1 (C-17, d), 116.1 (C-18, d), 51.6 (COOCH3, q);

Journal of Asian Natural Products Research Table 1. 1H and compound 1.

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C NMR spectral data for

dH

dC

2.38– 2.40, m 2.37– 2.39, m 5.55, dt (14.5, 7.6) 6.03, dd (14.5, 10.5) 5.99, dd (14.6, 10.5) 5.58, dt (14.6, 7.2), 2.05, q (7.0) 1.31– 1.33, m 1.36– 1.38, m 1.40– 1.42, m 2.08, q (7.3) 6.38, t (7.3)

173.5, C a 33.8, CH2 27.8, CH2 129.6, CH 131.4, CH 130.1, CH 133.2, CH 32.4, CH2 29.0, CH2 27.6, CH2 28.5, CH2 32.9, CH2 138.8, CH 88.5, C 51.6, CH3

Position 1 2 3 4 5 6 7 8 9 10 11 12 13 14 OCH3

13

3.67, s

a NMR data were measured in CDCl3 on a Bruker DRX 400 MHz spectrometer; chemical shifts (ppm) were referenced to CDCl3 (dH 7.26, dC 77.0). Proton coupling constants (J) in Hz are given in parentheses. The assignments were based on DEPT, 1H– 1H COSY, HMQC, and HMBC experiments.

ESI-MS (positive): m/z 385, 387 (1:1) [M þ Na] þ. 3.3.3 Methyl 18-bromo-(13Z,17E)octadeca-13,17-diene-5,7,15-triynoate (4)

5

generates product pNP ( p-nitrophenol) which was monitored at an absorbance of 405 nm by the EnVision multilabel plate reader (PerkinElmer Life Sciences, Boston, MA). In a typical 100 ml assay mixture containing 50 mmol/l 3-[N-morpholino] propanesulfonic acid (MOPs), pH 6.5, 2 mmol/l pNPP, and 30 nmol/l recombinant PTP1B activities were continuously monitored and the initial rate of the hydrolysis was determined using the early linear region of the enzymatic reaction kinetic curve. The IC50 was calculated with Prism 4 software (Graphpad, San Diego, CA) from the nonlinear curve fitting of the percentage of inhibition (% inhibition) versus the inhibitor concentration [I] by using the following equation: % Inhibition ¼ 1/(1 þ [IC50/ [I]] k), where k is the Hill coefficient. IC50 $ 50 mM was considered inactive. Disclosure statement No potential conflict of interest was reported by the authors.

Funding

Colorless oil; 13C NMR (CDCl 3, 100 MHz): d 173.4 (C-1, s), 32.7 (C-2, t), 23.5 (C-3, t), 18.6 (C-4, t), 76.1 (C-5, s), 66.1 (C-6, s), 65.3 (C-7, s), 77.5 (C-8, s), 18.9 (C-9, t), 27.6 (C-10, t), 27.7 (C-11, t), 29.8 (C-12, t), 144.3 (C-13, d), 109.1 (C14, d), 90.0 (C-15, s), 88.5 (C-16, s), 117.8 (C-17, d), 117.7 (C-18, d), 51.6 (COOCH3, q); ESIMS (positive): m/z 383, 385 (1:1) [M þ Na]þ.

This research work was financially supported by the Natural Science Foundation of China [grant numbers 81273430, 41306130, 81302692 and 41476063], the National Marine ‘863’ Project [grant numbers 2012AA092105 and 2013AA092902], the China Postdoctoral Science Foundation [grant numbers 2012M520956 and 2014T70443], the SKLDR/ SIMM Project [grant number 1501ZZ-03], NSFC-Shandong Joint Fund for Marine Science Research Centers [grant number U1406402] and was partially funded by the SCTSM Project [grant number 14431901100].

3.4

Note

PTP1B inhibitory activity assay

Recombinant PTP1B catalytic domain was expressed and purified according to a previous report [24]. The enzymatic activities of the PTP1B catalytic domain were determined at 308C by monitoring the hydrolysis of pNPP ( p-nitrophenyl palmitate). Dephosphorylation of pNPP

1.

These authors contributed to this work equally.

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Brominated polyunsaturated lipids with protein tyrosine phosphatase-1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria.

A new brominated polyunsaturated lipid, methyl (E,E)-14,14-dibromo-4,6,13-tetradecatrienoate (1), along with three known related analogues (2-4), were...
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