Azaphilone and Diphenyl Ether Derivatives from a Gorgonian-Derived

Aug 20, 2015 - College of Science, Northwest A&F University, Yangling 712100, ..... established by the U.S. Navy program as an efficacy level for natu...
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Azaphilone and Diphenyl Ether Derivatives from a GorgonianDerived Strain of the Fungus Penicillium pinophilum Dong-Lin Zhao,† Chang-Lun Shao,† Qiang Zhang,‡ Kai-Ling Wang,† Fei-Fei Guan,† Ting Shi,† and Chang-Yun Wang*,†,§ †

Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, and §Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, People’s Republic of China ‡ College of Science, Northwest A&F University, Yangling 712100, People’s Republic of China S Supporting Information *

ABSTRACT: Three new azaphilone derivatives, pinophilins D−F (1−3), and one new diphenyl ether derivative, hydroxypenicillide (10), together with nine known compounds (4−9, 11−13), were isolated from the gorgonian-derived fungus Penicillium pinophilum XS-20090E18. Their structures including absolute configurations were determined by spectroscopic data, chemical conversions, the ECD exciton chirality method, and ECD calculations. Compounds 10−13 exhibited inhibitory activity against the larval settlement of the barnacle Balanus amphitrite at nontoxic concentrations. Compounds 10 and 11 showed cytotoxicity against Hep-2, RD, and HeLa cell lines.

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arine fungi have been increasingly investigated to discover new potential bioactive compounds during the past decades.1,2 Among them, the genus Penicillium, which represents half of the marine-derived fungal species, has become one of the most well-known genera for the discovery of bioactive compounds.1 The secondary metabolites isolated from marine-derived Penicillium spp. have exhibited potential bioactivities, such as antitumor, antibacterial, antiviral, antifouling, and enzyme inhibitory activities.2 In the course of our ongoing investigation on new bioactive secondary metabolites from marine-derived fungi in the South China Sea,3 a gorgonian-derived fungal strain, Penicillium pinophilum XS20090E18, collected from the Xisha Islands coral reef, attracted our attention because the extract of the fungal culture showed moderate cytotoxic activity. Chemical investigation of the EtOAc extract led to the isolation of four new compounds, including three azaphilone derivatives, pinophilins D−F (1−3), and one diphenyl ether derivative, hydroxypenicillide (10), together with six known azaphilone derivatives, Sch 1385568 (4),4 pinophilin B (5),5a Sch 725680 (6),5 (−)-mitorubrin (7),6 (−)-mitorubrinol (8),6 and (−)-mitorubrinic acid (9),6 and three known diphenyl ether derivatives, penicillide (11),7 isopenicillide (12), and purpactin A (13).7 Herein we report the isolation, structure elucidation, and biological activities of these compounds. Pinophilin D (1) was obtained as a yellow, amorphous powder, possessing a molecular formula of C21H22O8 with 11 degrees of unsaturation. The IR spectrum indicated the presence of hydroxy (3451 cm−1) and conjugated carbonyl (1703 cm−1) groups. The 1H and 13C NMR spectra (Table 1) © XXXX American Chemical Society and American Society of Pharmacognosy

suggested the presence of azaphilone and orsellinic acid partial structures for 1, which closely resembled those of pinophilin A (14), an azaphilone derivative isolated from the culture of a strain of the fungus P. pinophilum derived from a seaweed Received: June 29, 2015

A

DOI: 10.1021/acs.jnatprod.5b00575 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Table 1. 1H NMR Data (500 MHz, Acetone-d6, δ in ppm, J in Hz) and 13C NMR Data (125 MHz, Acetone-d6, δ in ppm) for 1− 3 1

2

3

position

δC, type

δH (J in Hz)

δC, type

δH (J in Hz)

δC, type

1

68.7, CH2

3.82, dd (13.0, 10.5) 4.78, dd (10.5, 5.5)

69.0, CH2

3.85, dd (13.5, 10.5) 4.48, dd (10.5, 5.0)

64.5, CH2

3 4 4a 5

159.2, 103.5, 149.6, 116.9,

C CH C CH

6 7 8 8a 9

191.8, 85.4, 74.2, 37.8, 122.4,

C C CH CH CH

10 11 7-CH3 1′ 2′ 3′ 4′ 5′ 6′ 7′ 7′-CH3 3′-OH

136.6, 61.2, 17.5, 169.9, 143.7, 164.8, 100.7, 162.5, 111.5, 104.8, 23.8,

CH CH2 CH3 C C C CH C CH C CH3

5.76, brs

165.8, 102.9, 151.0, 115.9,

C CH C CH

3.72, d (9.5) 3.22, m 6.19, d (15.5)

195.0, 74.5, 76.5, 35.4, 45.2,

C C CH CH CH2

65.5, 23.6, 19.9, 171.5, 145.1, 166.2, 101.7, 163.8, 112.7, 104.7, 24.8,

CH CH3 CH3 C C C CH C CH C CH3

5.74, brs

6.46, dt (15.5, 4.5) 4.22, d (4.5) 1.67, s

6.21, d (2.0) 6.28, d (2.0) 2.51, s 11.01, s

5.69, brs 5.66, brs

5.28, 3.45, 2.29, 2.40, 4.04, 1.16, 1.30,

d (10.0) m dd (14.0, 5.5) dd (14.0, 7.0) m d (6.5) s

6.29, d (2.0) 6.36, d (2.0) 2.62, s 11.35, s

157.2, 111.9, 147.4, 35.1,

C CH C CH2

68.1, 87.9, 192.2, 119.1, 137.2,

CH C C C CH

123.2, 167.0, 16.4, 170.8, 105.8, 165.9, 101.4, 163.2, 112.3, 144.7, 24.3,

CH C CH3 C C C CH C CH C CH3

δH (J in Hz) 5.01, d (15.0) 4.87, d (15.0) 6.01, s 2.80, dd (18.0, 6.0) 2.66, dd (18.0, 10.5) 5.09, dd (10.5, 6.0)

7.12, d (15.5) 6.34, d (15.5) 1.54, s

6.22, d (1.5) 6.31, d (1.5) 2.53, s 11.20, s

at C-3 in 2 instead of a propenyl group [−CHCHCH3] in 6. The observed COSY correlations of H-9/H-10/H-11 and the HMBC correlations from H-9 to C-3, from H-10 to C-3, and from H-11 to C-9 and C-10 (Figure S47) confirmed the above deduction. The relative configuration of 2 was established by interpretation of 1H−1H coupling constants and 1D NOE difference spectra. The doublet H-8 showed ax/ax coupling (J = 10.0 Hz) to H-8a, suggesting a trans relationship of these two stereogenic centers (C-8 and C-8a). The syn relationship of H8/7-CH3 was determined by the NOE correlation of H-8 with 7-CH3. Attempts were made to determine the absolute configuration at C-10 of 2 by the modified Mosher’s method;10 however, the reaction failed to yield the corresponding acylation products. Hydrogen bonding between 10-OH and O-2 may have prevented the formation of the MTPA ester. Thus, the absolute configuration at C-10 remained undetermined. As for 1, the ECD exciton chirality method established the 7S,8S,8aS absolute configuration for 2 (Figure S43). Pinophilin F (3) was attained as an orange gum with a molecular formula of C21H20O9, requiring 12 degrees of unsaturation. The general features of its 1H and 13C NMR data (Table 1) suggested that 3 was also an azaphilone derivative. The skeleton with azaphilone and orsellinic acid moieties was the same as that of rubiginosin B (15), an azaphilone derivative obtained from the inedible mushroom Hypoxylon rubiginosum, collected from the bark and wood of Fraxinus excelsior at the Neandertal in Haan-Gruiten, North Rhine Westphalia, Germany.11 The side chain at C-3 was determined as an acrylic acid group, which was confirmed by the COSY correlations of H-9/H-10 and HMBC correlations from H-9 to C-4 and C-11 and from H-10 to C-3 (Figure S47).

collected along the coast of Kasai Marine Park, Edogawaku, Tokyo, Japan.5a However, the methyl at δH 1.86; δC 15.4 in 14 was absent in 1. Instead, the signals for an oxymethylene (δH 4.22; δC 61.2) were observed in the 1H and 13C NMR spectra of 1. This difference indicated that there was a hydroxymethyl group in 1 rather than a methyl group as in 14, which was confirmed by the COSY cross-peaks of H-9/H-10/H-11 and the HMBC correlations from H-11 to C-9 and C-10 (Figure S47). The relative configuration of 1 was determined by 1 H−1H coupling constants and 1D NOE correlations. The anti relationship of H-8/H-8a was deduced from the ax/ax coupling constant (J8,8a = 9.5 Hz). In the NOE difference spectrum, irradiation of H-8 and H-8a enhanced the resonance of 7-CH3 and 7′-CH3, respectively, indicating a syn relationship of H-8 and 7-CH3. The absolute configuration of 1 was determined by the ECD exciton chirality method.5a,8 The ECD spectrum of 1 showed the negative first Cotton effect at 328 nm (Δε −16.77) and positive second Cotton effect at 299 nm (Δε +9.58) (Figure S42), which is consistent with a 7S configuration, as was determined for pinophilin A.5a,9 Thus, the absolute configuration of 1 was determined as 7S,8S,8aS. Pinophilin E (2) was also isolated as a yellow, amorphous powder. Its molecular formula was determined to be C21H24O8 based on its HRESIMS, requiring 10 degrees of unsaturation. The structure elucidation of 2 was straightforward due to its close relationship with Sch 725680 (6).5b Analysis of their 1H and 13C NMR spectra indicated that the only difference between 2 and 6 was the side chain at C-3. The disappearance of the trans olefin unit and the presence of an additional oxymethine and methylene in the NMR spectra of 2 suggested that there was a 2-hydroxypropyl [−CH2CH(OH)CH3] moiety B

DOI: 10.1021/acs.jnatprod.5b00575 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Table 2. 1H NMR Data (500 MHz, δ in ppm, J in Hz) and 13 C NMR Data (125 MHz, δ in ppm) for 10 and 12

The geometry of the double bond at C-9 and C-10 was assigned as E on the basis of the coupling constant (J9,10 = 15.5 Hz). The relative configuration of the ax/ax coupling constant (J6,5α = 10.5 Hz) of H-6/H-5α and the NOE correlation of 7CH3 with H-5α were observed, indicating the trans relationship of C-6 and C-7. Thus, 3 and 15 had similar skeletons, but with different relative configurations. The absolute configuration of 3 was determined by the ECD exciton chirality method.5a,8 The ECD spectrum of 3 exhibited Cotton effects at 346 and 298 nm (Δε −0.58 and +4.70), indicating the S configuration at C-7. Therefore, the 6R,7S configuration for 3 was assigned. An ECD calculation using TDDFT was applied to verify the absolute configuration of 3. Conformational analyses were carried out in the MMFF94S molecular mechanics force field in Conflex 6.712 to acquire meaningful conformers for 6R,7S-3, followed by DFT optimizations at the B3LYP/6-31+G(d,p) level in MeOH by the Gaussian 09 program.13 The ECD spectrum was calculated by the TDDFT methodology with a larger basis set at the CAM-B3LYP/TZVP level and simulated using SpecDis 1.6214 according to Boltzmann distributions. The theoretical ECD spectrum for 6S,7R-3 was obtained by directly reversing the spectrum of 6R,7S-3. The experimental ECD spectrum of 3 matched very well with the theoretical ECD spectrum for 6R,7S-3 (Figure 1), confirming the absolute structure of 3.

10a position

δC, type

1 2 3 4 4a 5 7

118.5, 131.8, 139.2, 154.9, 120.7, 167.8, 69.6,

CH CH C C C C CH2

7a 8 9 10 11 12 12a 1′

128.0, 118.6, 140.3, 116.4, 149.4, 143.6, 152.2, 65.8,

C CH C CH C C C CH

2′

49.0, CH2

3′ 4′ 5′ 4-OCH3 1″

25.6, 23.9, 22.1, 62.7, 63.8,

a

CH CH3 CH3 CH3 CH2

δH (J in Hz) 7.02, d (8.5) 7.73, d (8.5)

5.20, d (15.0) 5.16, d (15.0) 6.65, brs 7.03, brs

5.11, dd (9.0, 3.5) 1.61, m 1.43, m 1.85, m 0.92, d (6.5) 0.97, d (6.5) 3.94, s 4.51, s

12b δC, type 117.8, 130.9, 136.3, 153.5, 119.1, 168.1, 69.2,

CHc CH C C C C CH2

125.6, 120.5, 134.9, 117.8, 147.6, 141.3, 151.2, 66.0,

C CH C CHc C C C CH

δH (J in Hz) 6.85, d (8.5) 7.61, d (8.5)

5.07, m

6.33, brs 6.84, brs

49.1, CH2

5.36, dd (9.5, 2.0) 1.74, m

72.1, C 27.5, CH3 32.0, CH3 62.3 CH3 20.8, CH3

1.45, 1.27, 3.95, 2.22,

s s s s

In acetone-d6. bIn CDCl3. cOverlapping signals.

were confirmed by comparison of their ECD spectra (Figures S43 and S45) with those of the reported compounds in the literature.5a,15 The absolute configurations at C-1′ of 11 and 12 were determined as S by comparison of the ECD spectra of their corresponding acetylated derivatives 17 and 18 with the ECD spectrum of purpactin A (13) (Figure S46). This is also the first time the NMR data and the absolute configuration of 12 were reported, although one commercial source sample has been reported. All of the isolated compounds were evaluated for their antifouling, cytotoxic, and topoisomerase I (Topo I) inhibitory activities. None of the isolated azaphilone derivatives were active in any of bioassays performed. The isolated diphenyl ether derivatives 10−13 displayed inhibitory activity against the larval settlement of the barnacle Balanus amphitrite with EC50 values at 6.0, 2.6, 20, and 10 μg/mL (LC50/EC50 > 50), respectively, which were lower than the standard requirement of an EC50 of 25 μg/mL established by the U.S. Navy program as an efficacy level for natural antifouling agents. Compound 10 exhibited cytotoxic activity against the human cervical carcinoma (HeLa) cell line with an IC50 value of 6.1 μM. Compound 11 showed cytotoxic activity against the human laryngeal carcinoma (Hep-2) cells and human rhabdomyosarcoma (RD) cells with IC50 values of 6.7 and 7.8 μM, respectively. In conclusion, 13 compounds, including nine azaphilones derivatives (1−9) and four diphenyl ether derivatives (10−13), were isolated from the gorgonian-derived fungus Penicillium pinophilum XS-20090E18, among which four were new compounds (1−3, 10). Their absolute configurations were determined by using the ECD exciton chirality method and ECD calculations. The absolute configurations of two known

Figure 1. Experimental and calculated ECD spectra for 6R,7S-3.

Hydroxypenicillide (10) was isolated as a colorless gum. The molecular formula was established to be C21H24O7 on the basis of the HRESIMS, indicating 10 degrees of unsaturation. The 1 H and 13C NMR spectra of 10 (Table 2) were similar to those of penicillide (11),7 except for the appearance of one more oxymethylene (δH 4.51, δC 63.8) and the disappearance of the methyl group on the benzene ring in 10. Detailed inspection of the HMBC correlations from H-1″ to C-8, C-9, and C-10 (Figure S47) confirmed the above deduction. To determine the absolute configuration at C-1′, 10 was acetylated by acetic anhydride and pyridine to obtain the acetylated derivative of 10 (16). The negative first, positive second, and negative third Cotton effects in the ECD spectrum of 16 (Figure S46) were consistent with those of purpactin A (13), previously reported as a naturally occurring acetylated product isolated from P. simplicissimum,7 indicating the 1′S configuration in 10. The known compounds 4−9 and 11−13 were identified on the basis of their spectroscopic data by comparison with those in the literature. The absolute configuration of 4 was determined for the first time by the ECD exciton chirality method (Figure S44).5a,8 The absolute configurations of 5−9 C

DOI: 10.1021/acs.jnatprod.5b00575 J. Nat. Prod. XXXX, XXX, XXX−XXX

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compounds, 4 and 12, were determined for the first time. All of the isolated diphenyl ether derivatives (10−13) displayed inhibitory activity against the larval settlement of the barnacle B. amphitrite at nontoxic concentrations. Compounds 10 and 11 showed cytotoxic activities against Hep-2, RD, and HeLa cell lines.

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Pinophilin E (2): yellow, amorphous powder; [α]20D +63.5 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 268 (3.69), 317 (3.82) nm; ECD (1.24 mM, MeOH) λmax (Δε) 206 (+3.14), 236 (−3.13), 268 (+5.50), 298 (−2.85), 356 (+3.15) nm; IR (KBr) νmax 3334, 2927, 1703, 1653, 1258, 1170 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 403.1391 [M − H]− (calcd for C21H23O8, 403.1387). Pinophilin F (3): orange gum; [α]20D +12.4 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 217 (4.72), 265 (4.32), 305 (4.01), 384 (4.16) nm; ECD (0.79 mM, MeOH) λmax (Δε) 212 (−7.00), 298 (+4.70), 346 (−0.58) nm; IR (KBr) νmax 3452, 2927, 1703, 1653, 1591, 1259, 1170 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 415.1032 [M − H]− (calcd for C21H19O9, 415.1024). Sch 1385568 (4): yellow, amorphous powder; [α]20D +155.2 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 218 (4.58), 268 (4.16), 306 (4.00), 364 (4.13) nm; ECD (0.26 mM, MeOH) λmax (Δε) 208 (+19.37), 222 (−14.39), 256 (+4.13), 278 (−29.39), 366 (+10.72) nm; IR (KBr) νmax 3409, 2926, 1703, 1621, 1542, 1256, 1168 cm−1; 1H and 13C NMR and MS data were consistent with the reported values.4 Hydroxypenicillide (10): colorless gum; [α]20D +13.0 (c 0.23, MeOH); UV (MeOH) λmax (log ε) 212 (4.38), 282 (3.72) nm; IR (KBr) νmax 3377, 2955, 2369, 1737, 1597, 1473, 1381, 1291, 1136, 1049 cm−1; 1H and 13C NMR data, Table 2; HRESIMS m/z 389.1604 [M + H]+ (calcd for C21H25O7, 389.1595). Isopenicillide (12): colorless gum; [α]20D +25.0 (c 0.15, MeOH); UV (MeOH) λmax (log ε) 214 (4.36), 282 (3.68) nm; IR (KBr) νmax 3350, 2925, 1737, 1597, 1472, 1381, 1293, 1050 cm−1; 1H and 13C NMR data, Table 2; ESIMS m/z 411.2 [M + Na]+. Antifouling Assays. The antifouling activity against the larval settlement of the barnacle was determined using cyprids of Balanus amphitrite Darwin according to literature procedures.16 SeaNine 211 (EC50 = 1.2 μg/mL, LC50/EC50 = 20.3), a new type of nontoxic antifouling agent developed by Rohm & Haas, was used as a positive control. Cytotoxicity Assays. The cytotoxicity against human laryngeal carcinoma (Hep-2), human rhabdomyosarcoma (RD), and human cervical carcinoma (HeLa) cell lines were evaluated using the Neutral Red method.17 Adriamycin (IC50: Hep-2, 1.5 μM; RD, 2.0 μM; and HeLa 1.0 μM) was used as a positive control.

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a JASCO P-1020 digital polarimeter. UV spectra were recorded on a Beckman DU 640 spectrophotometer. ECD spectra were recorded on a Jasco J-815−150S circular dichroism spectrometer. IR spectra were recorded on a Nicolet-Nexus-470 spectrometer using KBr pellets. NMR spectra were recorded on an Agilent DD2 500 MHz NMR spectrometer (500 MHz for 1H and 125 MHz for 13C), using TMS as an internal standard. ESIMS and HRESIMS spectra were obtained from a Micromass Q-TOF spectrometer and a Thermo Scientific LTQ Orbitrap XL spectrometer. Semipreparative HPLC was performed on a Waters 1525 system using a C18 (Kromasil, 5 μm, 10 × 250 mm) column coupled with a Waters 2996 photodiode array detector. Silica gel (Qing Dao Hai Yang Chemical Group Co.; 200− 300 mesh), octadecylsilyl silica gel (Unicorn; 45−60 μm), and Sephadex LH-20 (Amersham Biosciences) were used for column chromatography. Precoated silica gel plates (Yan Tai Zi Fu Chemical Group Co.; G60, F-254) were used for thin-layer chromatography. Fungal Material. The fungal strain Penicillium pinophilum XS20090E18 was isolated from a piece of fresh tissue from the inner part of an unidentified Gorgonian (XS-200909), which was collected from the Xisha Islands coral reef in the South China Sea in December 2009. The strain was deposited in the Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, PR China, with the GenBank (NCBI) accession number KP901304. Extraction and Isolation. Eighty Erlenmeyer flasks of the fungal strain were cultivated in rice medium (3.6 g of natural sea salt (from Yangkou saltern, China), 80 g of rice, 120 mL of H2O in each Erlenmeyer flask) for 40 days at room temperature (rt). The fermented rice substrate was extracted repeatedly with EtOAc (400 mL for each flask), and the solvent was combined and concentrated in vacuo to afford a residue (23 g), which was subjected to silica gel column chromatography (CC) using a step gradient elution with EtOAc−petroleum ether (0−100%) and then with EtOAc−MeOH (0−100%) to provide five fractions (Fr.1−Fr.5). Fr.2 was separated on a Sephadex LH-20 column with a mixture of petroleum ether− CH2Cl2−MeOH (v/v/v, 2:1:1) to provide 13 (25.4 mg). Fr.3 was separated under the same chromatography conditions as for Fr.2 to give 11 (183.0 mg). Fr.4 was subjected to Sephadex LH-20 CC eluting with a mixture of CH2Cl2−MeOH (v/v, 1:1) to give subfractions Fr.41 and Fr.4-2. Fr.4-1 was further purified by semipreparative HPLC eluting with 55% MeOH−H2O to give 12 (11.7 mg) and Fr.4-2 with 45% MeOH−H2O to afford 4 (9.6 mg), 6 (15.3 mg), and 7 (40.0 mg). Fr.5 was subjected to silica gel CC using gradient elution with petroleum ether−EtOAc to afford three subfractions (Fr.5-1−Fr.5-3). Fr.5-2 was subjected to an ODS column eluting with 50% MeOH− H2O and finally purified by semipreparative HPLC eluting with 40% MeOH−H2O to give 1 (9.0 mg) and 10 (11.0 mg). Fr.5-3 was chromatographed on Sephadex LH-20 (CH2Cl2−MeOH (v/v, 1:1)) and then purified by semipreparative HPLC eluting with 35% CH3CN−(H2O + 0.1% TFA) to afford subfraction Fr.5-3-1 and compounds 5 (7.9 mg) and 9 (6.0 mg). Fr. 5-3-1 was further separated by semipreparative HPLC eluting with MeOH−H2O (55:45 + 0.1% TFA) to yield 2 (4.0 mg), 3 (50.1 mg), and 8 (9.7 mg). Pinophilin D (1): yellow, amorphous powder; [α]20D −24.3 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 265 (4.21), 313 (4.11), 339 (4.05) nm; ECD (1.24 mM, MeOH) λmax (Δε) 299 (+9.58), 328 (−16.77) nm; IR (KBr) νmax 3451, 2927, 1703, 1652, 1258, 1170 cm−1; 1H and 13 C NMR data, Table 1; HRESIMS m/z 401.1239 [M − H]− (calcd for C21H21O8, 401.1231).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.5b00575. 1 H NMR, 13C NMR, HMQC, COSY, HMBC, and MS spectra of 1−3 and 10; 1D NOE spectra of 1−3; 1H NMR, 13C NMR, and MS spectra of 12; 1H NMR and MS spectra of 16 and 18; ECD spectra of 1, 2, 4−9, 13, and 16−18; preparation as well as the spectroscopic, mass, and other physical data of the acetylated derivatives 16−18; topoisomerase I inhibitory assays (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel/Fax: 86-532-82031536. E-mail: [email protected] (C.-Y. Wang). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (Nos. 41130858; 41322037; 81172977; 41176121) and NSFC-Shandong Joint Fund for Marine Science Research Centers (No. U1406402). D

DOI: 10.1021/acs.jnatprod.5b00575 J. Nat. Prod. XXXX, XXX, XXX−XXX

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REFERENCES

(1) Vanstellandt, M.; Roullier, C.; Blanchet, E.; Guitton, Y.; Pouchus, Y. F.; Ruiz, N.; Grovel, O. Outstanding Marine Molecules; Barre, S. L; Kornprobst, J. M., Eds.; Wiley: New York, 2014; pp 45−83. (2) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Nat. Prod. Rep. 2015, 32, 116−211. (3) (a) Zhao, D. L.; Shao, C. L.; Gan, L. S.; Wang, M.; Wang, C. Y. J. Nat. Prod. 2015, 78, 286−293. (b) Chen, M.; Shao, C. L.; Meng, H.; She, Z. G.; Wang, C. Y. J. Nat. Prod. 2014, 77, 2720−2724. (c) Shao, C. L.; Xu, R. F.; Wei, M. Y.; She, Z. G.; Wang, C. Y. J. Nat. Prod. 2013, 76, 779−782. (4) Yang, S. W.; Chan, T. M.; Terracciano, J.; Loebenberg, D.; Patel, M.; Gullo, V.; Chu, M. J. Antibiot. 2009, 62, 401−403. (5) (a) Myobatake, Y.; Takeuchi, T.; Kuramochi, K.; Kuriyama, I.; Ishido, T.; Hirano, K.; Sugawara, F.; Yoshida, H.; Mizushina, Y. J. Nat. Prod. 2012, 75, 135−141. (b) Yang, S. W.; Chan, T. M.; Terracciano, J.; Patel, R.; Patel, M.; Gullo, V.; Chu, M. J. Antibiot. 2006, 59, 720− 723. (6) Zhu, J. L.; Porco, J. A., Jr. Org. Lett. 2006, 8, 5169−5171. (7) Komai, S.; Hosoe, T.; Itabashi, T.; Nozawa, K.; Yaguchi, T.; Fukushima, K.; Kawai, K. J. Nat. Med. 2006, 60, 185−190. (8) Koreeda, M.; Harada, N.; Nakanishi, K. J. Am. Chem. Soc. 1974, 96, 266−268. (9) Itabashi, T.; Ogasawara, N.; Nozawa, K.; Kawai, K. Chem. Pharm. Bull. 1996, 44, 2213−2217. (10) Kusumi, T.; Fujita, Y.; Ohtani, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2923−2926. (11) Quang, D. N.; Hashimoto, T.; Stadler, M.; Asakawa, Y. J. Nat. Prod. 2004, 67, 1152−1155. (12) Conflex 6.7; Conflex Corp.: Tokyo Yokohama, Japan, 2010. (13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. GAUSSIAN 09 revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (14) Bruhn, T.; Schaumloeffel, A.; Hemberger, Y.; Bringmann, G. Chirality 2013, 25, 243−249. (15) Wang, H.; Wang, Y.; Wang, W.; Fu, P.; Liu, P. P.; Zhu, W. M. J. Nat. Prod. 2011, 74, 2014−2018. (16) Thiyagarajan, V.; Harder, T.; Qiu, J. W.; Qian, P. Y. Mar. Biol. (Heidelberg, Ger.) 2003, 143, 543−554. (17) Repetto, G.; del Peso, A.; Zurita, J. L. Nat. Protoc. 2008, 3, 1125−1131.

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DOI: 10.1021/acs.jnatprod.5b00575 J. Nat. Prod. XXXX, XXX, XXX−XXX