Meroterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory

DOI: 10.1021/acs.jnatprod.7b00435. Publication Date (Web): August 23, 2017. Copyright © 2017 The American Chemical Society and American Society of Ph...
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Meroterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory Activity from a Hyrtios sp. Marine Sponge Jie Wang,†,⊥ Feng-Rong Mu,‡,§,⊥ Wei-Hua Jiao,*,‡ Jian Huang,† Li-Li Hong,‡ Fan Yang,‡ Ying Xu,‡ Shu-Ping Wang,‡ Fan Sun,‡ and Hou-Wen Lin*,†,‡ †

School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China § Changzheng Hospital, Second Military Medical University, Shanghai 200003, People’s Republic of China ‡

S Supporting Information *

ABSTRACT: Three new meroterpenoids, hyrtiolacton A (1), nakijinol F (2), and nakijinol G (3), along with three known ones, nakijinol B (4), nakijinol E (5), and dactyloquinone A (6), were isolated and characterized from a Hyrtios sp. marine sponge collected from the South China Sea. The new structures were determined based on extensive analysis of HRESIMS and NMR data, and their absolute configurations were assigned by a combination of single-crystal X-ray diffraction and electronic circular dichroism analyses. Hyrtiolacton A (1) represents an unprecedented meroterpenoid featuring an unusual 2-pyrone attached to the sesquiterpene core, which is the first example of a pyrone-containing 4,9-friedodrimane-type sesquiterpene. These compounds were evaluated for their protein tyrosine phosphatase (PTP1B) inhibitory and cytotoxic activities. Nakijinol G (3) showed PTP1B inhibitory activity with an IC50 value of 4.8 μM but no cytotoxicity against four human cancer cell lines.

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ype 2 diabetes is a chronic disorder characterized by relative insulin deficiency due to pancreatic β-cell dysfunction and insulin resistance.1 In 2015, the International Diabetes Federation estimated that 415 million adults had diabetes, more than 90% of whom had type 2 diabetes, and the number will increase to 642 million by 2040.1,2 Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the insulin and leptin signaling pathway and, thus, is considered as a potential therapeutic target for the treatment of type 2 diabetes and obesity.3 Up to now, a number of natural products with PTP1B inhibitory activity have been reported, and many of them were isolated from marine organisms,4 including terpenoids,5−11 meroterpenoids,12−17 phenols/bromophenols,18−21 polyketides,22,23 and other types.24−26 In the course of our ongoing discovery of new PTP1B inhibitors from marine sponges,27−30 we found that the EtOH extract of the title sponge showed potent PTP1B inhibitory activity and was selected for detailed investigation. Bioactivityguided fractionation of this active extract resulted in the isolation of three new meroterpenoids, hyrtiolacton A (1), nakijinol F (2), and nakijinol G (3), and three known ones, nakijinol B (4), nakijinol E (5), and dactyloquinone A (6). Among them, hyrtiolacton A (1) possesses an unusual 6/6/5/ 6-fused tetracyclic scaffold. Herein, the isolation, structure elucidation, and bioactivities of these meroterpenoids are reported in detail. © 2017 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION Hyrtiolacton A (1), obtained as colorless crystals, has a molecular formula of C21H28O3 based on the HRESIMS ion peak at m/z 351.1938 [M + Na]+, corresponding to eight Received: May 18, 2017 Published: August 23, 2017 2509

DOI: 10.1021/acs.jnatprod.7b00435 J. Nat. Prod. 2017, 80, 2509−2514

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Table 1. 1H and 13C NMR Spectroscopic Data of Compounds 1−3 1a position 1α 1β 2α 2β 3α 3β 4 5 6α 6β 7α 7β 8 9 10 11 12 13 14 15α 15β 16 17 18 19 20 21 22 23 17-OH a1

δC 24.8, CH2 28.8, CH2 33.1, CH2 158.9, C 39.9, C 33.6, CH2 27.4, CH2 49.6, 47.3, 49.0, 104.0,

C C CH CH2

19.5, 24.4, 16.4, 43.9,

CH3 CH3 CH3 CH2

165.0, 116.2, 171.1, 87.3, 166.2, 55.9,

C C C CH C CH3

2b

δH, mult. (J in Hz) 1.47, 1.58, 1.23, 1.89, 2.12, 2.32,

1.34, 1.52, 1.57, 2.31,

1.10, 4.47, 4.52, 1.06, 1.04, 1.03, 2.51, 2.42,

br d (12.0) m m m br d (14.0) dt (14.0, 3.6)

ddd (13.5, 3.0) dt (13.5, 3.6) m m

dd (12.0, 2.4) s s s s s d (17.4) d (17.4)

5.37, s 3.83, s

δC

3c

δH, mult. (J in Hz)

23.5, CH2 28.9, CH2 33.1, CH2 160.5, C 40.6, C 36.6, CH2 28.2, CH2 37.6, 43.2, 49.6, 102.6,

CH C CH CH2

20.7, 18.4, 17.6, 34.8,

CH3 CH3 CH3 CH2

109.6, 144.6, 145.1, 99.4, 131.1, 145.9, 151.1, 56.6,

C C C CH C C CH CH3

2.27, 1.54, 1.26, 1.90, 2.04, 2.34,

br d (12.0) qd (12.5, 3.5) m m dd (14.0, 4.5) ddd (14.0, 5.5)

1.22, m 1.45, m 1.41, m 1.41, m 0.94, 4.34, 4.38, 1.07, 1.06, 0.94, 2.86, 2.95,

dd (12.0, 2.0) t (1.5) t (1.5) s d (6.5) s d (14.0) d (14.0)

7.11, s

7.92, s 3.95, s 5.98, s

δC 22.8, CH2 28.1, CH2 32.4, CH2 159.4, C 39.5, C 36.2, CH2 27.5, CH2 36.7, 42.2, 48.7, 102.9,

CH C CH CH2

20.2, CH3 18.4, CH3 17.5, CH3 34.2 108.8, 145.1, 142.6, 101.9, 131.5, 143.4, 160.8, 14.1,

C C C CH C C C CH3

δH, mult. (J in Hz) 2.22, 1.42, 1.16, 1.83, 1.99, 2.26,

m m m m m m

1.10, m 1.33, m 1.35, m 1.35, m 0.82, 4.29, 4.35, 1.01, 1.02, 0.87, 2.70, 2.77,

d (11.6) s s s s s d (14.0) d (14.0)

6.83, s

2.45, s

H (600 MHz) and 13C (150 MHz) in CDCl3. b1H (500 MHz) and 13C (125 MHz) in CDCl3. c1H (400 MHz) and 13C (100 MHz) in DMSO-d6.

Figure 1. Key COSY, HMBC, and NOESY correlations of 1.

aforementioned data accounted for four out of eight degrees of unsaturation, indicative of a tetracyclic core in 1. The structure of 1 was elucidated by a combination of 2D NMR analysis (Figure 1). The COSY correlations of H-10/H21/H2-2/H2-3 indicated the existence of the spin system C10− C1−C2−C3. The HMBC correlations of H2-11/C-3, C-4, and C-5, H3-12/C-4, C-5, and C-10, and H-10/C-2 and C-5 established a six-numbered ring A. Meanwhile the COSY correlation of H2-6/H2-7 coupled with the HMBC correlations of H3-12/C-6 and C-10, H3-13/C-7, C-8, and C-9, and H3-14/ C-9 and C-10 allowed for the linkage of ring B. Thus, a bicyclic moiety was revealed with one exomethylene (CH2-11) at C-4 and three methyl groups (CH3-12, CH3-13, and CH3-14) attached at C-5, C-8, and C-9, respectively. In addition, the HMBC correlations of H-19/C-17, C-18, and C-20 and H3-21/

degrees of unsaturation. The IR spectrum of 1 showed absorptions at 1731 and 1642 cm−1, suggesting the presence of carboxyl ester and olefinic functionalities. The 1H NMR spectrum of 1 (Table 1) displayed the resonances for three methyl singlets at δH 1.03 (H3-14), 1.04 (H3-13), and 1.06 (H312), one O-methyl group at δH 3.83 (H3-21), one exomethylene group at δH 4.47 and 4.52 (H2-11), and one olefinic singlet at δH 5.37 (H-19). Analysis of the 13C NMR, DEPT135, and HSQC spectra of 1 revealed the presence of 21 carbon signals (Table 1), including three methyls at δC 16.4, 19.5, and 24.4, one methoxy at δC 55.9, seven methylenes (one exomethylene at δC 104.0), two methines (one olefinic at δC 87.3), and eight nonprotonated carbons (one ester carbonyl at δC 166.2, four olefinic at δ C 116.2, 158.9, 165.0, and 171.1). The 2510

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C-18, coupled with their chemical shifts, implied the presence of an α-pyrone moiety with a methoxy group at C-18 (ring D). Furthermore, the HMBC correlations of H2-15/C-8, C-9, C-16 and C-17 supported the linkage of C-9 and C-16 via the methylene (CH2-15) between rings B and D. Moreover, the HMBC correlation of H3-13/C-17 connected rings B and D via another carbon−carbon bond, C8−C17, to form a new fivenumbered ring C (Figure 1). Thus, the planar structure of 1 was elucidated as depicted. The relative configuration of 1 was determined by analysis of the NOESY spectrum (Figure 1). The key correlations of H1β/H3-12, H3-13, and H3-14, H-1α/H-15α, and H-15α/H-10 suggested that the three methyl groups (H3-12, H3-13, and H314) were β-oriented, while H-10 was α-oriented. The absolute configuration of 1 was unambiguously determined as 5S,8R,9S,10R by single-crystal X-ray diffraction analysis using Cu Kα radiation [Flack parameter: −0.15(9)] (Figure 2).

Figure 3. Key COSY, HMBC, and NOESY correlations of 2 and 3.

determined the absolute configuration of nakijinol B as 5S,8S,9R,10S with Cu Kα radiation [Flack parameter: −0.1(2)] (Figure 4). Because the Cotton effects at 205 and

Figure 2. X-ray crystallographic structure of 1.

Nakijinol F (2), obtained as a pale yellow powder, exhibited a negative HRESIMS ion peak at m/z 368.2228 [M − H]−, indicating its molecular formula as C23H31NO3 (with nine degrees of unsaturation). The 1H and 13C NMR data of 2 (Table 1) were similar to those of nakijinol B (4),31 except for the presence of one methoxy group (δH 3.95/δC 56.6, C-23) at C-18 in 2, instead of a hydroxy group (HO-18) in nakijinol B,31 which was supported by the HMBC correlation of H3-23/C-18 (Figure 3). The relative configuration of 2 was established by analysis of the NOESY spectrum. The NOESY correlations of H-1β/H3-12, H3-13, and H3-14 and H-1α/H-10 indicated the three methyl groups (H3-12, H3-13, and H3-14) were βoriented, whereas H-10 was α-oriented, as shown in Figure 3. Nakijinol G (3), obtained as a pale yellow powder, showed the same molecular formula as that of 2 by the HRESIMS data. The 1H and 13C NMR data of 3 were similar to those of nakijinol B, expect for one additional methyl group (δH 2.45/δC 14.1, CH3-23) and the absence of H-22, which suggested the H-22 was substituted by a methyl group in 3. This assignment was supported by the HMBC correlation of H3-23/C-22. Additionally, the NOESY correlations of H-1β/H3-12, H3-13, and H3-14 and H-1α/H-10 revealed that 2 and 3 shared the same relative configuration as depicted in Figure 3. The structure of compound 4 was determined as nakijinol B by comparing its MS and NMR data with the literature data.31 The crystal of 4 was obtained from acetone/MeOH (1:1, v/v) at 4 °C. Subsequent single-crystal X-ray diffraction analysis

Figure 4. X-ray crystallographic structure of nakijinol B (4).

250 nm observed in the electronic circular dichroism (ECD) spectra of 2 and 3 were consistent with those of nakijinol B (Figure 5), both 2 and 3 should share the same absolute configuration as that of nakijinol B. The other two known compounds were identified as nakijinol E (5) and dactyloquinone A (6) by comparing their spectroscopic data with the literature data.32,33 A single-crystal X-ray diffraction analysis using Cu Kα radiation [Flack parameter: 0.02(7)] confirmed the absolute configuration of dactyloquinone A as 5R,8S,9R,10R (Figure 6). 2511

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EXPERIMENTAL SECTION

General Experimental Procedures. Melting points were measured on an SGW X-4B digital display micromelting apparatus and are uncorrected. Optical rotation measurements were recorded with an Autopol I polarimeter (no. 30575, Rudolph Research Analytical) and an Autopol VI polarimeter (no. 91003, Rudolph Research Analytical). UV spectra were recorded on a Hitachi U-3010 spectrophotometer. ECD spectra were recorded with a Jasco J-715 spectropolarimeter. IR spectra were measured on a Jasco FTIR-400 spectrometer. The NMR experiments were conducted on Bruker Avance DRX-600, Bruker AMX-500, and Bruker AMX-400 MHz NMR spectrometers in CDCl3 (δH 7.26, δC 77.16) or DMSO-d6 (δH 2.49, δC 39.5). ESIMS spectra were recorded on a Finnigan MAT 95 spectrometer. High-resolution ESIMS spectra were acquired with a Waters Q-Tof micro YA019 mass spectrometer. Column chromatographic separations were carried out using silica gel (200−300 mesh, Yantai) and ODS C18 (15 μm, Santai Technologies, Inc.). TLC was performed on silica gel HSGF254 plates (Yantai) and visualized by spraying with anisaldehyde reagent. RP HPLC was performed on a YMC-Pack Pro C18 column (250 × 10 mm, 5 μm) using a Waters 1525 binary HPLC pump with a Waters 2998 photodiode array detector. Sponge Material. The marine sponge was collected off Yongxing Island in the South China Sea in May 2013 and was identified by Prof. Jin-He Li (Institute of Oceanology, Chinese Academy of Sciences, People’s Republic of China) as a Hyrtios sp. The sponge was crusty in shape, measuring 17 × 10 and 1 cm thick. The color was light brown in life and dark brown in EtOH. The surface was uneven, and the oscules were slightly raised and scattered over the surface. The texture of the sponge was tough and compressible, and it was easy to tear. The fibers are striated and fasciculated. The spicules were small oxeas with many bulges (lengths of 0.5−1.5 mm and widths of 0.5−0.6 mm). The specimen is similar to those of H. communis (Carter, 1885) (order Dictyoceratida, family Thorectidae) but differs in the appearance and arrangements of fibers.34 The morphology of the skeleton is an important taxonomic characteristic, but insufficient for the current sponge samples. A voucher specimen (no. 1312) is deposited at Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Extraction and Isolation. The frozen Hyrtios sp. sponge (0.5 kg, wet weight) was soaked in 95% EtOH three times to obtain the EtOH extract. The extract was partitioned between petroleum ether and 90% aqueous MeOH (1:1). The 90% aqueous MeOH layer was diluted into 60% aqueous MeOH with H2O and partitioned with CH2Cl2 to yield a CH2Cl2 extract (1.3 g). The petroleum ether extract (1.6 g) with PTP1B inhibitory activity was subjected to column chromatography on silica gel with a gradient elution of acetone in petroleum ether to yield eight fractions (P1−P8). Fraction P3 (0.48 g) was next separated by MPLC (MeOH/H2O, 50−100%) to afford eight fractions (P3A− P3H). Subfraction P3B was further purified by RP HPLC (70% MeCN/H2O) to give dactyloquinone A (6, 12.0 mg). Subfraction P3C was subjected to RP HPLC (80% MeCN/H2O) to afford nakijinol B (4, 4.0 mg), nakijinol G (3, 2.0 mg), and hyrtiolacton A (1, 4.3 mg). Nakijinol E (5, 1.4 mg) and nakijinol F (2, 1.5 mg) were purified from subfraction P3D using an RP HPLC (85% MeOH/H2O). Hyrtiolacton A (1): colorless crystals; mp 187−190 °C; [α]25 D +39.3 (c 0.12, MeOH); UV (MeOH) λmax (log ε) 217 (4.48), 297 (4.98) nm; IR (KBr) νmax 3346, 2925, 2854, 1731, 1642, 1552, 1466, 1416, 1247, 1079 cm−1; 1H NMR (600 MHz, CDCl3) and 13C NMR (150 MHz, CDCl3) data, Table 1; HRESIMS m/z 351.1938 [M + Na]+ (calcd for C21H28O3Na, 351.1936). Nakijinol F (2): pale yellow powder; [α]25 D −16.2 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 234 (4.43), 293 (4.42) nm; ECD (0.3 mg/ mL, MeOH) λ (Δε) 202 (+3.63), 253 (−0.28) nm; IR (KBr) νmax 2958, 2925, 2855, 1623, 1461, 1424, 1360, 1240, 1094 cm−1; 1H NMR (500 MHz, CDCl3) and 13C NMR (125 MHz, CDCl3) data, Table 1; HRESIMS m/z 368.2228 [M − H]− (calcd for C23H30NO3, 368.2226).

Figure 5. ECD spectra (MeOH) of 2−4.

Figure 6. X-ray crystallographic structure of dactyloquinone A (6).

The PTP1B inhibitory activities of compounds 1, 3, 4, and 6 were evaluated in vitro. Among these compounds, compound 3 exhibited PTP1B inhibitory activity with an IC50 value of 4.8 μM, similar to the positive control, oleanolic acid, with an IC50 value of 2.0 μM, whereas the other compounds lacked significant inhibitory activity at the concentration of 30 μM. The cytotoxic activities of these four compounds against human cancer cell lines were evaluated as well; however, none of them showed significant cytotoxicity against four human cancer cell lines (RPMI-8226, HeLa, HepG2, and HL-60) at the concentration of 30 μM. The bioactivities of nakijinol G (3) and nakijinol B (4) were different, although the only difference between them is that the proton of CH-22 in 4 was substituted by a methyl group CH3-23 in 3. This finding clearly showed that the incorporation of a methyl group at the C-22 position in nakijinols could increase their PTP1B inhibitory activity, without impacting on their cytotoxicity. 2512

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Nakijinol G (3): pale yellow powder; [α]25 D −18.4 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 212 (4.50), 302 (4.16) nm; ECD (0.3 mg/ mL, MeOH) λ (Δε) 204 (+2.63), 248 (−0.34) nm; IR (KBr) νmax 3364, 2922, 2852, 1659, 1634, 1469, 1458, 976 cm−1; 1H NMR (400 MHz, DMSO-d6) and 13C NMR (100 MHz, DMSO-d6) data, Table 1; HRESIMS m/z 368.2228 [M − H]− (calcd for C23H30NO3, 368.2226). Nakijinol B (4): pale red crystals; mp 213−218 °C; [α]25 D −27.3 (c 31 ECD (0.3 mg/mL, 0.11, MeOH); lit. [α]25 D −6.7 (c 0.075, MeOH); MeOH) λ (Δε) 203 (+3.74), 251 (−0.31) nm. Dactyloquinone A (6): pale yellow crystals; mp 200−205 °C; [α]25 D 33 −56.7 (c 0.12, MeOH); lit. [α]25 D −28.3 (c 0.6, CHCl3). X-ray Crystallographic Analysis. Crystals of 1, 6, and 4 were obtained from MeOH and acetone/MeOH (1:1, v/v), respectively. The X-ray crystallographic data of 1, 4, and 6 were collected on a Bruker APEX-II CCD diffractometer using graphite-monochromated Cu Kα radiation (λ = 1.541 78 Å) at 130, 296, and 140(2) K, respectively. The structures were solved by direct methods using SHELXS-97 and refined with full-matrix least-squares on F2. Crystallographic data have been deposited with the Cambridge Crystallographic Data Center (CCDC) as supplementary publication nos. CCDC 1559797 for 1, CCDC 1559798 for 4, and CCDC 1559799 for 6. Copies of these data can be obtained free of charge from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [tel: (+44) 1223-336-408; fax: (+44) 1223-336-033; e-mail: deposit@ccdc. cam.ac.uk]. Crystallographic data for hyrtiolacton A (1): C21H28O3, M = 328.43, orthorhombic, space group P212121, a = 10.0210(10) Å, b = 13.4995(2) Å, c = 26.1852(4) Å, α = β = γ = 90°, V = 3542.29(8) Å3, T = 130 K, Z = 8, Dcalcd = 1.232 g/cm3, μ(Cu Kα) = 0.636 mm−1, F(000) = 1424, crystal size 0.2 × 0.15 × 0.12 mm3, 19 062 reflections measured, 6378 independent reflections (Rint = 0.0387). The final R1 = 0.0349 (I > 2σ(I)), wR2 = 0.0850 (I > 2σ(I)), R1 = 0.0374 (all data), wR2 = 0.0864 (all data), S = 1.065. The Flack parameter was −0.15(9). Crystallographic data for nakijinol B (4): C22H29NO3, M = 355.46, monoclinic, space group P1211, a = 16.6578(11) Å, b = 9.9005(7) Å, c = 12.3571(8) Å, α = 90°, β = 102.887(4)°, γ = 90°, V = 1986.6(2) Å3, T = 296 K, Z = 4, Dcalcd = 1.188 g/cm3, μ(Cu Kα) = 0.621 mm−1, F(000) = 768, crystal size 0.12 × 0.08 × 0.02 mm3, 13 940 reflections measured, 5934 independent reflections (Rint = 0.0348). The final R1 = 0.0652 (I > 2σ(I)), wR2 = 0.1823 (I > 2σ(I)), R1 = 0.0732 (all data), wR2 = 0.1920 (all data), S = 1.021. The Flack parameter was −0.1(2). Crystallographic data for dactyloquinone A (6): C22H28O4, M = 356.44, monoclinic, space group P21, a = 7.8670(10) Å, b = 11.4726(2) Å, c = 10.1815(10) Å, α = 90°, β = 93.641(10)°, γ = 90°, V = 917.08(2) Å3, T = 140(2) K, Z = 2, Dcalcd = 1.291 g/cm3, μ(Cu Kα) = 0.701 mm−1, F(000) = 384, crystal size 0.30 × 0.26 × 0.13 mm3, 7006 reflections measured, 3067 independent reflections (Rint = 0.0286). The final R1 = 0.0340 (I > 2σ(I)), wR2 = 0.0914 (I > 2σ(I)), R1 = 0.0341 (all data), wR2 = 0.0916 (all data), S = 1.050. The Flack parameter was 0.02(7). PTP1B Inhibitory Assay. PTP1B inhibitory activity was determined by measuring the activity of the enzyme by monitoring the rate of hydrolysis of pNPP (p-nitrophenyl phosphate) as described in a previous study.35 Briefly, 2 mM pNPP, 30 nM PTP1B, and 50 mM 3-[N-morpholino]propanesulfonic acid (MOPs) buffer (pH 6.5) were combined into each well of a 96-well plate with or without test compounds (100 μL for each well). The reaction was terminated with 1 M NaOH (10 μL) after incubation at 37 °C for 30 min. The amount of produced pNP was monitored at an absorbance of 405 nm. A known phosphatase inhibitor, oleanolic acid, was used as a positive control. The IC50 value was calculated on the basis of sigmoidal dose− response (variable slope) using the software Graphpad Prism 4. Cytotoxicity Assay. Cytotoxicity was determined using an MTT assay as described previously.36 Compounds were solubilized in DMSO with the working concentration of 30 μM. Cells were inoculated into 96-well plates. After incubation for 24 h, the cells were treated with test substances for 48 h and then were incubated with 20 μL of MTS at 37 °C for 2 h. The formazan dye product was measured by the absorbance at 490 nm on a Spectra Max 340 microplate reader.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00435. HRESIMS, IR, and NMR spectra of 1−3 and ECD spectra of 1−4 and 6 (PDF) Crystallographic data of 1 (CIF) Crystallographic data of 4 (CIF) Crystallographic data of 6 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel: +86-21-68383346. Fax: +86-21-58732594. E-mail: [email protected] (W. H. Jiao). *E-mail: [email protected] (H. W. Lin). Author Contributions ⊥

J. Wang and F.-R. Mu contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Prof. J.-H. Li (Institute of Oceanology, CAS) for identifying the marine sponge. This work was supported by the National Science Foundation of China (Nos. 41576130, 41476121, 81402844, 41406139, U1605221, 81502936, 81302691, and 81225023).

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REFERENCES

(1) Chatterjee, S.; Khunti, K.; Davies, M. J. Lancet 2017, 389, 2239− 2251. (2) Herman, W. H. In Diabetes Mellitus in Developing Countries and Underserved Communities; Dagogo-Jack, S., Ed.; Springer International Publishing: Cham, 2017; pp 1−5. (3) Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C.C.; Ramachandran, C.; Gresser, M. J.; Tremblay, M. L.; Kennedy, B. P. Science 1999, 283, 1544−1548. (4) Wang, L.-J.; Jiang, B.; Wu, N.; Wang, S.-Y.; Shi, D.-Y. RSC Adv. 2015, 5, 48822−48834. (5) Liang, L.-F.; Gao, L.-X.; Li, J.; Taglialatela-Scafati, O.; Guo, Y.-W. Bioorg. Med. Chem. 2013, 21, 5076−5080. (6) Xue, D.-Q.; Mao, S.-C.; Yu, X.-Q.; Guo, Y.-W. Biochem. Syst. Ecol. 2013, 49, 101−106. (7) Liang, L.-F.; Kurtán, T.; Mándi, A.; Gao, L.-X.; Li, J.; Zhang, W.; Guo, Y.-W. Eur. J. Org. Chem. 2014, 2014, 1841−1847. (8) Abdjul, D. B.; Yamazaki, H.; Takahashi, O.; Kirikoshi, R.; Mangindaan, R. E.; Namikoshi, M. Bioorg. Med. Chem. Lett. 2015, 25, 904−907. (9) Abdjul, D. B.; Kanno, S.; Yamazaki, H.; Ukai, K.; Namikoshi, M. Bioorg. Med. Chem. Lett. 2016, 26, 315−317. (10) Liang, L. F.; Chen, W. T.; Mollo, E.; Yao, L. G.; Wang, H. Y.; Xiao, W.; Guo, Y. W. Chem. Biodiversity 2017, 14, e1700079. (11) Liang, L.-F.; Kurtán, T.; Mándi, A.; Yao, L.-G.; Li, J.; Zhang, W.; Guo, Y.-W. Org. Lett. 2013, 15, 274−277. (12) Iguchi, K.; Shimada, Y.; Yamada, Y. J. Org. Chem. 1992, 57, 522−524. (13) Kate, A. S.; Aubry, I.; Tremblay, M. L.; Kerr, R. G. J. Nat. Prod. 2008, 71, 1977−1982. (14) Li, Y.; Zhang, Y.; Shen, X.; Guo, Y. W. Bioorg. Med. Chem. Lett. 2009, 19, 390−392. (15) Lee, J. S.; Abdjul, D. B.; Yamazaki, H.; Takahashi, O.; Kirikoshi, R.; Ukai, K.; Namikoshi, M. Bioorg. Med. Chem. Lett. 2015, 25, 3900− 3902. 2513

DOI: 10.1021/acs.jnatprod.7b00435 J. Nat. Prod. 2017, 80, 2509−2514

Journal of Natural Products

Article

(16) Yamazaki, H.; Nakayama, W.; Takahashi, O.; Kirikoshi, R.; Izumikawa, Y.; Iwasaki, K.; Toraiwa, K.; Ukai, K.; Rotinsulu, H.; Wewengkang, D. S.; Sumilat, D. A.; Mangindaan, R. E.; Namikoshi, M. Bioorg. Med. Chem. Lett. 2015, 25, 3087−3090. (17) Abdjul, D. B.; Yamazaki, H.; Takahashi, O.; Kirikoshi, R.; Ukai, K.; Namikoshi, M. J. Nat. Prod. 2016, 79, 1842−1847. (18) Shi, D.; Xu, F.; He, J.; Li, J.; Fan, X.; Han, L. Sci. Bull. 2008, 53, 2476−2479. (19) Seo, C.; Sohn, J. H.; Oh, H.; Kim, B. Y.; Ahn, J. S. Bioorg. Med. Chem. Lett. 2009, 19, 6095−6097. (20) Lee, D. S.; Jang, J. H.; Ko, W.; Kim, K. S.; Sohn, J. H.; Kang, M. S.; Ahn, J. S.; Kim, Y. C.; Oh, H. Mar. Drugs 2013, 11, 1409−1426. (21) Yamazaki, H.; Sumilat, D. A.; Kanno, S.; Ukai, K.; Rotinsulu, H.; Wewengkang, D. S.; Ishikawa, M.; Mangindaan, R. E.; Namikoshi, M. J. Nat. Med. 2013, 67, 730−735. (22) Seibert, S. F.; Eguereva, E.; Krick, A.; Kehraus, S.; Voloshina, E.; Raabe, G.; Fleischhauer, J.; Leistner, E.; Wiese, M.; Prinz, H.; Alexandrov, K.; Janning, P.; Waldmann, H.; Konig, G. M. Org. Biomol. Chem. 2006, 4, 2233−2240. (23) Imperatore, C.; Luciano, P.; Aiello, A.; Vitalone, R.; Irace, C.; Santamaria, R.; Li, J.; Guo, Y. W.; Menna, M. J. Nat. Prod. 2016, 79, 1144−1148. (24) Wang, L.; Chen, B.; Shen, X. R.; Zhou, Y. Y.; Jiang, D. W.; Li, J.; Kong, J. L. J. Asian Nat. Prod. Res. 2007, 9, 753−761. (25) He, W. F.; Liang, L. F.; Cai, Y. S.; Gao, L. X.; Li, Y. F.; Li, J.; Liu, H. L.; Guo, Y. W. J. Asian Nat. Prod. Res. 2015, 17, 861−866. (26) Abdjul, D. B.; Yamazaki, H.; Takahashi, O.; Kirikoshi, R.; Ukai, K.; Namikoshi, M. Chem. Pharm. Bull. 2016, 64, 733−736. (27) Piao, S. J.; Zhang, H. J.; Lu, H. Y.; Yang, F.; Jiao, W. H.; Yi, Y. H.; Chen, W. S.; Lin, H. W. J. Nat. Prod. 2011, 74, 1248−1254. (28) Piao, S. J.; Jiao, W. H.; Yang, F.; Yi, Y. H.; Di, Y. T.; Han, B. N.; Lin, H. W. Mar. Drugs 2014, 12, 4096−4109. (29) Jiao, W.; Huang, X.; Yang, J.; Yang, F.; Piao, S.; Gao, H.; Li, J.; Ye, W.; Yao, X.; Chen, W.; Lin, H. Org. Lett. 2012, 14, 202−205. (30) Yu, H. B.; Liu, X. F.; Xu, Y.; Gan, J. H.; Jiao, W. H.; Shen, Y.; Lin, H. W. Mar. Drugs 2012, 10, 1027−1036. (31) Ovenden, S. P. B.; Nielson, J. L.; Liptrot, C. H.; Willis, R. H.; Tapiolas, D. M.; Wright, A. D.; Motti, C. A. J. Nat. Prod. 2011, 74, 65− 68. (32) Hwang, I. H.; Oh, J.; Zhou, W.; Park, S.; Kim, J.-H.; Chittiboyina, A. G.; Ferreira, D.; Song, G. Y.; Oh, S.; Na, M.; Hamann, M. T. J. Nat. Prod. 2015, 78, 453−461. (33) Mitome, H.; Nagasawa, T.; Miyaoka, H.; Yamada, Y.; van Soest, R. W. M. J. Nat. Prod. 2001, 64, 1506−1508. (34) Li, J.; Du, L.; Kelly, M.; Zhou, Y. D.; Nagle, D. G. J. Nat. Prod. 2013, 76, 1492−1497. (35) Cui, L.; Na, M.; Oh, H.; Bae, E. Y.; Jeong, D. G.; Ryu, S. E.; Kim, S.; Kim, B. Y.; Oh, W. K.; Ahn, J. S. Bioorg. Med. Chem. Lett. 2006, 16, 1426−1429. (36) Jiao, W. H.; Shi, G. H.; Xu, T. T.; Chen, G. D.; Gu, B. B.; Wang, Z.; Peng, S.; Wang, S. P.; Li, J.; Han, B. N.; Zhang, W.; Lin, H. W. J. Nat. Prod. 2016, 79, 406−411.

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