Sulawesins A–C, Furanosesterterpene Tetronic Acids That Inhibit

Jun 16, 2017 - USP7, a deubiquitinating enzyme, is an emergent target of cancer therapy, and the isolated compounds inhibited USP7 with IC50 values in...
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Sulawesins A−C, Furanosesterterpene Tetronic Acids That Inhibit USP7, from a Psammocinia sp. Marine Sponge Ahmed H. Afifi,†,‡,§ Ippei Kagiyama,†,§ Ahmed H. El-Desoky,†,‡ Hikaru Kato,† Remy E. P. Mangindaan,⊥ Nicole J. de Voogd,∥ Nagwa M. Ammar,‡ Mohammed S. Hifnawy,▽ and Sachiko Tsukamoto*,† †

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan Division of Pharmaceutical Industries, Department of Pharmacognosy, National Research Centre, P.O. 12622, 33 El Bohouth Street (Former El Tahrir Street), Dokki, Giza, Egypt ⊥ Faculty of Fisheries and Marine Science, Sam Ratulangi University, Kampus Bahu, Manado 95115, Indonesia ∥ Naturalis Biodiversity Center, P.O. Box 9517, 2300 RA Leiden, The Netherlands ▽ Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr-el-Aini Street, 11562 Cairo, Egypt ‡

S Supporting Information *

ABSTRACT: Three new furanosesterterpene tetronic acids, sulawesins A−C (1−3), were isolated from a Psammocinia sp. marine sponge, along with the known compounds ircinins-1 (4) and -2 (5). Although ircinins-1 and -2 were previously isolated as (+)- or (−)-enantiomers from marine sponges, we isolated them as enantiomeric mixtures. Sulawesins A and B possess a new carbon skeleton with a 5-(furan-3-yl)-4hydroxycyclopent-2-enone moiety and were also found to be diastereomeric mixtures of four isomers by an HPLC analysis with a chiral-phase column. Sulawesin C has a dimeric structure of ircinin-1 and is the first dimer in this family. USP7, a deubiquitinating enzyme, is an emergent target of cancer therapy, and the isolated compounds inhibited USP7 with IC50 values in the range of 2.7−4.6 μM.

F

90% MeOH fraction was subjected to column chromatography followed by ODS HPLC to afford 1−5. The specific rotations of 4 and 5 ([α]D +8.0 (c 0.050, MeOH) and −24 (c 0.050, MeOH), respectively) clearly indicated that they were enantiomeric mixtures, e.g., (+)-18R-4, [α]D +32.3 (c 0.05, MeOH) and (+)-18R-5, [α]D +34.8 (c 0.06, MeOH);5 (−)-18S-4, [α]D −34.12 (MeOH) and (−)-18S-5, [α]D −40.20 (MeOH).13 In order to clarify the enantiomeric excess, 4 was purified by HPLC with a chiral-phase column to afford (+)-18R- and (−)-18S-4 in a ratio of 5:4 ([α]D +36 (c 0.050, MeOH) and −27 (c 0.055, MeOH), respectively) (Figure 1), which revealed that natural 4, isolated in this study, was an enantiomeric mixture slightly enriched with the (+)-isomer. Similarly, 5 was analyzed and found to be an enantiomeric mixture enriched with the (−)-isomer at a ratio of 12:1 (Figure 1). An analysis of the isolated enantiomers by LCESIMS with an ODS column extracted at 254 nm showed peaks at the same retention times (Figure S16b). The molecular formula of sulawesin A (1) was established as C25H30O6 based on HRESIMS. The 1H and 13C NMR spectra of 1 (Table 1) were similar to those of ircinin-1 (4).5 Comprehensive analyses of the 2D NMR spectra showed that 1

uranosesterterpene tetronic acids have been isolated from the marine sponges of the order Dictyoceratida, mainly in the genera Ircinia, Sarcotragus, and Psammocinia, and exhibit various biological activities.1 Among congeners, variabilins,2 strobilinins,3 ircinins,4 sarcotins,5 and psammocinins6 are representatives, and their geometric, stereo-, and regio-isomers have been isolated. Regarding the absolute configuration of C18 in variabilins, strobilinins, and ircinins, 18R- and 18Senantiomers were both isolated in the respective cases: 18R-6,7 and 18S-variabilins,8−10 18R-6,7,9,11 and 18S-strobilinins,10 and 18R-5,12 and 18S-ircinins.9,13 Although these findings indicate the presence of both enantiomers in nature, these enantiomers were isolated as a single enantiomer from the sponges. In the course of screening for bioactive secondary metabolites from marine sponges, we isolated three new furanosesterterpene tetronic acids, sulawesins A−C (1−3), along with ircinins-1 (4) and -24 (5). Ircinins 4 and 5 isolated in this experiment were revealed to be enantiomeric mixtures by HPLC with a chiralphase column, and 1 and 2 were also diastereomeric mixtures.

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RESULTS AND DISCUSSION A Psammocinia sp. marine sponge was collected in Indonesia and immediately soaked in EtOH. The extract was partitioned between EtOAc and H2O, and the EtOAc-soluble fraction was further partitioned between n-hexane and 90% MeOH. The © 2017 American Chemical Society and American Society of Pharmacognosy

Received: March 3, 2017 Published: June 16, 2017 2045

DOI: 10.1021/acs.jnatprod.7b00184 J. Nat. Prod. 2017, 80, 2045−2050

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Table 1. 1H and 13C NMR Data (MeOH-d4) for Sulawesins A (1) and B (2) 1 no. 1 2 3 4 5 6 7 8 9 10

144.5, 110.7, 122.1, 141.4, 54.4, 206.1, 129.2, 182.9, 79.0, 30.7,

CH CH C CH CH C CH C CH CH2

11 12 13 14 15

26.7, 124.4, 137.6, 16.0, 40.4,

CH2 CH C CH3 CH2

16 17 18 19 20 21 22 23 24 25

Figure 1. HPLC chromatograms of 4 (1 mg) and 5 (50 μg) with a chiral-phase column.

δC, type

26.4, CH2 37.7, CH2 31.7, 21.2, 114.0, 147.0, 170.6, 95.7, 175.7, 6.0,

CH CH3 CH C C C C CH3

2

δH, mult (J in Hz) 7.46, brs 6.33, brs 7.46, brs 3.37, d (2.4) 5.98, brs 4.67, 2.53, 2.62, 2.35, 5.17,

brs m m m t (6.6)

1.60, 1.97, 2.01, 1.39, 1.29, 1.38, 2.71, 1.03, 5.21,

s m m m m m m d (7.0) d (10.2)

1.68, s

δC, type 144.5, 110.8, 122.1, 141.4, 54.5, 206.1, 128.9, 183.2, 79.5, 30.5,

CH CH C CH CH C CH C CH CH2

26.2, 32.4, 135.9, 23.5. 126.7,

CH2 CH2 C CH3 C

27.0, CH2 38.6, CH2 31.7, 21.2, 115.2, 145.7, 166.3, 98.0, 174.1, 6.1,

CH CH3 CH C C C C CH3

δH, mult (J in Hz) 7.46, brs 6.35, brs 7.47, brs 3.38, d (3.0) 5.98, brs 4.67, 2.44, 2.54, 1.70, 2.10,

d (3.0) m m m t (7.8)

1.70, s 5.17, t (7.2) 1.99, 1.39, 1.47, 2.73, 1.05, 5.27,

m m m m d (6.8) d (10.2)

1.71, s

Figure 2. COSY (bold lines) and key HMBC (red arrows) correlations of 1.

contained a γ-hydroxy α,β-unsaturated γ-lactone ring (δH 3.37 (d, J = 2.4, H-5)/δC 54.4 (C-5); δC 206.1 (C-6); δH 5.98 (1H, brs, H-7)/δC 129.2 (C-7); δC 182.9 (C-8); δH 4.67, (brs, H-9)/ δC 79.0 (C-9)) between C-3 of the furan ring and the methylene C-10 (Figure 2). The residual structure of 1 was indicated to be identical to that of 4 by an NMR analysis. Thus, the planar structure of 1 was elucidated. In order to obtain the relative configuration of H-5/H-9, chemical shift calculations14 were conducted for the simplified isomers, 6 (cis) and 7 (trans) (Figure 3a), and the calculated 13C chemical shifts of C-5 and C-9 were shown to be different among the cis and trans isomers. The observed 13C chemical shifts of C-5 and C-9 of 1 and 2 matched the trans isomer (Figure 3b), and, thus, the configurations of C-5/C-9 in 1 and 2 both were indicated as trans. Because 4 and 5 were isolated as enantiomeric mixtures, 1 was presumed to be a C-18 epimeric mixture. An analysis of 1 by HPLC with a chiral-phase column showed four peaks, 1a− 1d (Figure 4a), which strongly indicated that 1 is a mixture of (5R,9R,18R)-, (5R,9R,18S)-, (5S,9S,18R)-, and (5S,9S,18S)-

Figure 3. (a) Calculated 13C chemical shifts of the simplified isomers 6 and 7. (b) Observed 13C chemical shifts of 1 and 2.

diastereomers. The four isomers 1a−1d were then separated by chiral-phase HPLC and showed peaks with m/z 427 [M + H]+ 2046

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bond position isomer of 1. The 13C chemical shifts of methyl groups on isolated double bonds were previously reported to be characteristic of the E and Z isomers,10 and the resonances of C-14 at δC 16.0 (1) and δC 23.5 (2) strongly indicated the 12E and 13Z configurations, respectively. Although 2 showed a single set of signals in the 1H and 13C NMR spectra (Figures S6 and S7), the analysis of 2 by HPLC with a chiral-phase column showed four peaks, 2a−2d (Figure 5). Separated 2a−2d were

Figure 5. HPLC chromatogram of 2 (0.1 mg) with a chiral column. Three small peak/shoulders with asterisks were also analyzed in the same method and showed peaks with 427 [M + H]+ at the same retention time. These results might be caused by overlapping with peak 2c or 2d, and the identification of these small peaks remains unknown.

analyzed by LC-ESIMS with an ODS column and showed peaks with m/z 427 [M + H]+ at the same retention time (Figure S16d). These results clearly indicated that 2 was composed of (5R,9R,18R)-, (5R,9R,18S)-, (5S,9S,18R)-, and (5S,9S,18S)-diastereomers, similar to 1. HR-ESIMS of sulawesin C (3) showed a negative ion peak at m/z 817.3992 for a deprotonated molecule, and its molecular formula was established as C50H58O10. The 1H and 13C NMR data (Table 2) indicated a dimeric nature derived from ircinin-1 (4). An analysis of the 2D NMR spectra including the HMBC correlations, H-5′ (δ 5.23)/C-8 (δ 121.8) and C-9 (δ 148.1), showed that two monomeric units of 4 were connected at C-9 and C-5′ to form 3. The small value of the specific rotation ([α]D −7.0) and the flat ECD spectrum suggested that 3 was a mixture of diastereomers. Due to decomposition during storage in the freezer, an analysis of 3 using chiral-phase HPLC was not possible. Variabilins,8−10,13 strobilinins,7,9−11 and ircinins5,9,12,13 have been isolated as 18R- and 18S-enantiomers from marine sponges. In the present study, we isolated iricinin-1 (4) and iricinin-2 (5) as enantiomeric mixtures, and this is the first study to isolate furanosesterterpene tetronic acids as enantiomeric mixtures from a marine sponge. Sulawesins A (1) and B (2) are the first examples containing a 4-hydroxycyclopent-2enone moiety in furanosesterterpene tetronic acids, and these were also obtained as mixtures of four diastereomers. Sulawesin C (3) is the first dimer in this family and may also be a diastereomeric mixture. A plausible route of formation for 1 from 4 is suggested in Scheme 1. Iricinin-1 (4) could plausibly be oxidized to afford an intermediate, oxonide 9. After cleavage of the endoperoxide of 9, a new bond (C-5−C-9) could be formed from 10, generating 1 with a cyclopentenone ring. Alternatively, 2 may be produced from 5 in the same mechanism.

Figure 4. (a) HPLC chromatogram of 1 (0.1 mg) with a chiral-phase column. (b) Calculated ECD spectra of 5R,9R-7 and 18R-8. (c) Experimental ECD spectra of 1a−1d.

at the same retention time by LC-ESIMS with an ODS column (Figure S16c). The calculated electronic circular dichroism (ECD) spectra of the simplified models 5R,9R-7 and 18R-8 showed a strong positive band at 225 nm and a weak positive band at 260 nm, respectively (Figure 4b). These results indicated that the absolute configuration of C-5/C-9 could be elucidated by examination of the Cotton effects at 225 nm. The experimental ECD spectra of 1b/1c and 1a/1d showed positive and negative Cotton effects at 225 nm, respectively (Figure 4c), which suggested 5R,9R and 5S,9S configurations for 1b/1c and 1a/1d, respectively. The C-18 configurations of 1a−1d could not be assigned due to their weak absorption around 260 nm. Although 1 was composed of four diastereomers, the 1H and 13 C NMR spectra of 1 showed only one set of signals (Figures S1 and S2). These results suggested that two chromophores, represented by 7 and 8, were located at a distance in 1 and were not affected by each other. Sulawesin B (2) showed the same molecular formula as that of 1 by HRESIMS. The 1H and 13C NMR spectra (Table 1) were very similar to those of 1, except for the resonances of C11−C-16, suggesting that 2 was a geometric and/or double2047

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Table 2. 1H and 13C NMR Data (MeOH-d4) for Sulawesin C (3)

a−k

no.

δC, type

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

144.0, CH 112.2, CH 123.1, C 140.9, CH 24.7, CH2 153.4, C 109.0, CH 121.8, C 148.1, C 25.8, CH2 29.8, CH2 125.1, CH 136.56,a C 16.0, CH3 40.49,b CH2 26.79,c CH2 37.7,d CH2

18 19 20 21 22 23 24 25

31.7,e CH 21.19,f CH3 114.6,g CH 146.4,h C 169.04,i C 96.5,j C 175.1,k C 6.1, CH3

δH, mult (J in Hz) 7.38, brs 6.29, brs 7.27, brs 3.68, s 5.88, brs

2.30, t (7.5) 2.11, q (7.2) 5.05, t (6.9) 1.45, 1.91, 1.33, 1.25, 1.32, 2.69, 1.02, 5.23,

s m m m m m d (6.6) d (10.0)

1.69, s

no.

δC, type

1′ 2′ 3′ 4′ 5′ 6′ 7′ 8′ 9′ 10′ 11′ 12′ 13′ 14′ 15′ 16′ 17′

143.9, CH 112.0, CH 125.7, C 141.3, CH 35.2, CH 155.9, C 109.3, CH 127.0, C 138.9, CH 26.1, CH2 29.5, CH2 125.2, CH 136.60,a C 16.0, CH3 40.52,b CH2 26.81,c CH2 37.8,d CH2

18′ 19′ 20′ 21′ 22′ 23′ 24′ 25′

31.8,e CH 21.21,f CH3 114.7,g CH 146.5,h C 168.98,i C 96.6,j C 175.2,k C 6.1, CH3

δH, mult (J in Hz) 7.39, brs 6.33, brs 7.22, brs 5.23, s 5.86, brs 7.11, 2.35, 2.17, 5.11,

brs t (7.5) q (7.2) t (6.9)

1.50, 1.91, 1.33, 1.25, 1.32, 2.69, 1.02, 5.23,

s m m m m m d (6.6) d (10.0)

1.69, s

May be interchanged.

the degradation of Mdm2 by a USP7 inhibitor leads to the suppression of cancer, and intensive studies on the development of USP7 inhibitors have been executed by screening libraries of synthetic molecules and by chemical modifications of lead compounds.23−25 On the other hand, we have been searching for new USP7 inhibitors from natural sources and have isolated spongiacidin C26 and petroquinones27 from marine sponges. In the present study, we isolated 1−5 from a Psammocinia sp. marine sponge, and 1, 2, 4, and 5 inhibited USP7 with IC50 values of 2.8, 4.6, 2.7, and 3.5 μM, respectively.28 Due to the limited amount available, the inhibitory activity of 3 was not measured. This is a preliminary result, and more extensive studies are needed in the future in order to elucidate the underlying inhibitory mechanisms.

Scheme 1. Plausible Route of Formation of 1 from 4

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a JASCO DIP-1000 polarimeter in MeOH. UV spectra were measured on a JASCO V-550 spectrophotometer in MeOH. ECD spectra were measured on a JASCO J-820 spectropolarimeter in MeOH. IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker Avance 600 NMR spectrometer in MeOH-d4. Chemical shifts were referenced to the residual solvent peaks (δH 3.30 and δC 49.0). HR-ESIMS spectra were measured on a Bruker Bio-TOF mass spectrometer. LC-MS experiments were performed on a Shimadzu LC-20AD solvent delivery system with a Shimadzu SPD-M20A photodiode array detector, which was interfaced to a Bruker amaZon Speed mass spectrometer. The preparative HPLC system comprised a Waters 515 HPLC pump, Waters 2489 UV/visible detector, and Pantos Unicorder U-228. Animal Material. The Psammocinia sp. sponge was collected in North Sulawesi, Indonesia, in September 2007 and immediately soaked in EtOH. The specimen has a low and spreading morphology

The proteasome inhibitor Velcade (bortezomib)15 was approved as a powerful agent for the treatment of multiple myeloma by the FDA in 2003, followed by Kyprolis (carfilzomib)16 and Ninlaro (ixazomib)17 in 2012 and 2015, respectively. After the approval of Velcade, components of the ubiquitin−proteasome system emerged as attractive targets for therapeutic interventions.18−20 Of these, USP7, a deubiquitinating enzyme, has been extensively studied as an anticancer target because it stabilizes Mdm2, a major E3 for the tumor suppressor protein p53.21,22 The stabilization of p53 through 2048

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and a gray coloration. The specimen was identified by one of the authors (N.J.d.V.), and a voucher specimen was deposited in the sponge collection of Naturalis Biodiversity Center (Leiden, The Netherlands) as Psammocinia sp. (RMNH POR. 10909 (#07M027)). The specimen belongs to an unknown species of the genus Psammocinia (family Irciniidae, order Dictyoceratida). This genus was originally proposed as a subgenus of Ircinia, but it was established as a genus in 1980. The differences between the two genera are difficult; however, Psammocinia is characterized by the presence of a distinct sand-armored crust. The present species clearly has a thick crust that is consistently present across the sponge body. All fibers are heavily and fully cored with foreign particles such as sand grains and spicules. The primary fibers show little fasciculation and are very much obscured by the high amount of coarse foreign material scattered interstitially. The filaments are clearly present and often are tangled up. They have a diameter of 5−7.5 mm. This genus is known from New Zealand, Australia, Korea, and the Atlantic coast of the United States, and 25 species are currently valid. The present species looks superficially like P. hirsuta, as it has the similar bristly appearance and the presence of dense filaments. This species occurs at the North Island of New Zealand, and it is unlikely that this species also occurs in the warm waters of Indonesia. Extraction and Isolation. The sponge (600 g, wet weight) was extracted with EtOH. The EtOH extract was concentrated under vacuum, and the residual aqueous fraction was extracted with EtOAc. The EtOAc-soluble fraction was partitioned between n-hexane and 90% MeOH. The 90% MeOH-soluble fraction (1.1 g) was subjected to SiO2 column chromatography with stepwise gradient elution using n-hexane−EtOAc (2:1 and 1:2) and CH2Cl2−MeOH (9:1). A portion (20 mg) of the first fraction (590 mg), which was eluted with nhexane−EtOAc (2:1), was purified by HPLC (COSMOSIL 5C18-MSII (20 × 250 mm), 88% MeOH−H2O) to yield 4 (15 mg) and 5 (3.5 mg). The second fraction (59 mg), which eluted with n-hexane− EtOAc (1:2), was purified by HPLC (COSMOSIL 5C18-MS-II (20 × 250 mm), MeOH−H2O) to yield 4 (25 mg) (95% MeOH−H2O) and 3 (2.7 mg) (90% MeOH−H2O). The third fraction (87 mg), which eluted with CH2Cl2−MeOH (9:1), was subjected to HPLC (Asahipak GS-310P (21.5 × 500 mm), CH2 Cl2−MeOH−H2O (6:4:1); COSMOSIL 5C18-MS-II column (20 × 250 mm), 68% MeOH− H2O) to afford 1 (5.0 mg) and 2 (1.7 mg). Sulawesin A (1): yellow oil; [α]21D −0.26 (c 2.3, MeOH); UV (MeOH) λmax (log ε) 308 (3.69) and 250 (sh, 4.01) nm; IR (film) νmax 3386, 2959, 2926, 2854, 1704, 1619, 1566, 1414, 1303, and 1026 cm−1; 1 H and 13C NMR data, see Table 1; HRESIMS m/z 449.1975 [M + Na]+ (calcd for C25H30O6Na, 449.1940). Sulawesin B (2): yellow oil; [α]21D −19 (c 1.3, MeOH); UV (MeOH) λmax (log ε) 308 (3.78) and 250 (4.10) nm; IR (film) νmax 3396, 2959, 2926, 2865, 1704, 1623, 1566, 1435, 1306, and 1029 cm−1; 1 H and 13C NMR data, see Table 1; HRESIMS m/z 449.1978 [M + Na]+ (calcd for C25H30O6Na, 449.1940). Sulawesin C (3): brownish oil; [α]21D −7.0 (c 1.8, MeOH); UV (MeOH) λmax (log ε) 308 (sh, 4.00), and 250 (4.36) nm; IR (film) νmax 2959, 2927, 2859, 1730, 1638, 1312, and 1067 cm−1; 1H and 13C NMR data, see Table 2; HRESIMS m/z 817.3992 [M − H]− (calcd for C50H57O10, 817.3952). Separation of 4 by HPLC with a Chiral-Phase Column. Ircinin-1 (4) (1 mg) was separated into (+)-18R- (0.21 mg) and (−)-18S-isomers (0.16 mg) by HPLC with a chiral-phase column (CHIRAL CELL OJ-H (4.6 × 250 mm), 95% n-hexane−2-PrOH, 0.32 mL/min, UV 254 nm). (+)-18R-4: [α]25D +36 (c 0.050, MeOH); ECD spectrum (MeOH), see Figure S16a. (−)-18S-4: [α]25D −27 (c 0.055, MeOH); ECD spectrum (MeOH), see Figure S16a. Analysis of 5 by HPLC with a Chiral-Phase Column. Ircinin-2 (5) (50 μg) was analyzed by HPLC with a chiral-phase column (CHIRAL CELL OJ-H (4.6 × 250 mm), 95% n-hexane−2-PrOH, 0.32 mL/min, UV 254 nm). Separation of 1 and 2 by HPLC with a Chiral-Phase Column. Sulawesins A (1) (0.1 mg) and B (2) (0.1 mg) was separated into four

isomers, 1a−1d and 2a−2d, respectively, by HPLC with a chiral-phase column (CHIRAL CELL OJ-H (4.6 × 250 mm), 95% n-hexane−2PrOH, 0.32 mL/min, UV 254 nm). LC-MS Analyses of 1a−1d and 2a−2d. Diastereomers 1a−1d and 2a−2d were analyzed by LC-MS on a Cosmosil 2.5C18-MS-II column (2.5 mm × 100 mm) at 40 °C, eluting with a gradient of two solvents, 0.1% acetic acid in H2O (solvent A) and 0.1% acetic acid in CH3CN (solvent B), at 0.30 mL/min. The gradient program was conducted as follows: 10−100% B from 0 to 10 min and 100% B from 10 to 15 min. Mass spectra were detected in positive and negative ion modes, and data were analyzed using Hystar data analysis software. Chemical Shift Calculations for 6 and 7. These experiments were performed as previously described.27 Conformational Analysis and ECD Calculations for 5R,9R-7 and 18R-8. These experiments were performed as previously described.27 USP7 Inhibition Assay. This experiment was performed as previously described.27

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00184. 1D and 2D NMR spectra of 1−3 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel and Fax: +81 96 371 4380. E-mail: sachiko@kumamoto-u. ac.jp. ORCID

Sachiko Tsukamoto: 0000-0002-7993-381X Author Contributions §

A. H. Afifi and I. Kagiyama contributed equally to this study.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Prof. M. Namikoshi and Dr. K. Ukai of Tohoku Pharmaceutical University, Dr. H. Kobayashi of the University of Tokyo, and Dr. H. Rotinsulu of Universitas Pembangunan for collecting the sponges. This work was supported by Grantsin-Aid for Scientific Research (Nos. 18406002, 25293025, and 26305005 to S.T.) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

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DEDICATION This study is dedicated to the memory of Tatsuo Higa, Emeritus Professor at University of the Ryukyus, who passed away last year.

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REFERENCES

(1) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2016, 33, 382−431 and earlier reviews therein.. (2) Faulkner, D. J. Tetrahedron Lett. 1973, 14, 3821−3822. (3) Rothberg, I.; Shubiak, P. Tetrahedron Lett. 1975, 16, 769−772. (4) Cimino, G.; Stefano, S. D.; Minale, L.; Fattorusso, E. Tetrahedron 1972, 28, 333−341. (5) Liu, Y.; Bae, B. H.; Alam, N.; Hong, J.; Sim, C. J.; Lee, C. O.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2001, 64, 1301−1304. (6) Choi, K.; Hong, J.; Lee, C.-O.; Kim, D.-K.; Sim, C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2004, 67, 1186−1189.

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Journal of Natural Products

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DOI: 10.1021/acs.jnatprod.7b00184 J. Nat. Prod. 2017, 80, 2045−2050